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Childhood Extracranial Germ Cell Tumors Treatment (PDQ®)–Health Professional Version

Childhood Extracranial Germ Cell Tumors Treatment (PDQ®)–Health Professional Version

General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

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GCTs arise from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads (see Figure 1).[1,2] Childhood extracranial GCTs can generally be divided into gonadal and extragonadal. These tumors can also be broadly classified as teratomas, malignant GCTs, or mixed GCTs.

EnlargeDiagram showing extracranial germ cell development from primordial germ cells.
Figure 1. Extracranial germ cell development from primordial germ cells. Credit: Thomas Olson, M.D.

Incidence

Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancers in this age group.[3–6] In the fetal/neonatal age group, most extracranial GCTs are benign teratomas occurring at midline locations, including the head and neck, sacrococcyx, and retroperitoneum.[7,8] Despite the small percentage of malignant teratomas that occur in this age group, perinatal tumors have a high morbidity rate caused by hydrops fetalis and premature delivery.[8–10]

The incidence of malignant extracranial GCTs increases with the onset of puberty. These tumors represent approximately 15% of cancers in male adolescents aged 15 to 19 years and 4% of cancers in female adolescents aged 15 to 19 years.[3]

Figure 2 shows the age-incidence profile by sex for malignant extracranial/extragonadal GCTs (left panel) and malignant gonadal GCTs (right panel) between 2014 and 2018 for 23 U.S. Cancer registries that represent 66% of all U.S. children, adolescents, and young adults (blue triangles, females; green triangles, males).[3] For males, there is a peak in incidence in children younger than 2 years for both extragonadal and gonadal sites, which is followed by low rates between the ages of 2 and 12 years, and then higher rates throughout adolescence. For females, the peak in young children is present only for extragonadal tumors, with rates increasing after the age of puberty for both extragonadal and gonadal sites. However, the incidence of each tumor is lower for females during adolescence than for males during adolescence.

EnlargeDrawing of two graphs showing age-incidence profiles for extracranial, extragonadal germ cell tumors (left graph) and for gonadal germ cell tumors (right graph). The blue triangles represent males, and the green triangles represent females.
Figure 2. Age-incidence profiles for extracranial, extragonadal germ cell tumors (left graph) and for gonadal germ cell tumors (right graph). The blue triangles represent females, and the green triangles represent males. (See text for details.)

The incidence of extracranial GCTs according to age group, sex, and gonadal versus extragonadal primary site is shown in Table 1.[3]

Table 1. Incidence of Extracranial Germ Cell Tumors by Age Group and Sexa,b
Tumor Site Sex Age <1 y Ages 1–4 y Ages 5–9 y Ages 10–14 y Ages 15–19 y
aRates are per 1 million children from 2014 to 2018 for NCCR Registries, 23 U.S. Cancer registries that represent 66% of all U.S. children, adolescents, and young adults.
bData from National Cancer Institute; National Childhood Cancer Registry: NCCR*Explorer.[3]
Extragonadal Female 17.7 2.1 0.1 0.1 0.7
Male 8.8 0.7 0 0.6 2.2
Gonadal Female 0.6 0.7 2.1 7.6 8.3
Male 7 2.5 0.1 1.5 36.1

Risk Factors

Cryptorchidism, the presence of an abdominal undescended testis, has been associated with a 10.8-fold increased risk of developing a GCT.[11] Gonadal dysgenesis, as well as the presence of Y-chromosome material in an abdominal gonad, also increases the risk of developing a gonadal GCT, especially gonadoblastoma. Gonadoblastoma is a rare gonadal tumor consisting of a mixture of germ cells and sex-cord stromal derivatives resembling immature granulosa and Sertoli cells.[12,13]

There are few data about the potential genetic or environmental risk factors associated with childhood extragonadal extracranial GCTs. Patients with the following syndromes are at an increased risk of extragonadal extracranial GCTs:

  • Klinefelter syndrome: Increased risk of mediastinal GCTs.[14–17]

    Most mediastinal GCTs in adolescents and young adults occur in males, and 22% to 50% have cytogenetic changes consistent with Klinefelter syndrome.[15,18] The age of tumor presentation is younger in patients with Klinefelter syndrome, and testing all younger males for Klinefelter syndrome should be considered.[15,18]

    Patients with GCTs were identified from the Children’s Oncology Group (COG) Childhood Cancer Research Network. Twenty-nine patients in the study had mediastinal primary tumors, and nine patients (31%) had Klinefelter syndrome. In the Centers for Disease Control and Prevention’s large 2013 WONDER database, 3% of patients with GCTs had Klinefelter syndrome (70% were mediastinal). In comparison, 0.2% of males in the general population have Klinefelter syndrome.[17]

  • Swyer syndrome: Increased risk of gonadoblastomas and seminomas.[19,20]
  • Turner syndrome: Increased risk of gonadoblastomas and dysgerminomas.[21,22]

Histological Classification of Childhood Extracranial GCTs

Childhood extracranial GCTs comprise a variety of histological diagnoses and can be broadly classified as the following:

The histological properties of extracranial GCTs are heterogeneous and vary by primary tumor site and the sex and age of the patient.[23,24] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.[25]

Mature teratoma

Mature teratomas can occur at gonadal or at extragonadal locations. They are the most common histological subtype of childhood GCT.[10,26–28] Mature teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers. Any tissue type may be found within this tumor.

Mature teratomas are benign, although some mature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, and prolactin.[29,30]

Immature teratoma

Immature teratomas contain tissues from the ectodermal, mesodermal, and endodermal germ cell layers. Immature tissues, primarily neuroepithelial, are also present. Immature teratomas are graded from 0 to 3 on the basis of the amount of immature neural tissue found in the tumor specimen.[31,32] Tumors of higher grade are more likely to have foci of yolk sac tumor.[33] Immature teratomas can exhibit malignant behavior and metastasize.

Immature teratomas occur primarily in young children at extragonadal sites and in the ovaries of girls near the age of puberty. However, there is no correlation between tumor grade and patient age.[33,34] Some immature teratomas may secrete enzymes or hormones such as vasopressin.[35]

Malignant GCTs

Most childhood extragonadal GCTs arise in midline sites (i.e., head and neck, sacrococcygeal, mediastinal, and retroperitoneal). The midline location may represent aberrant embryonic migration of the primordial germ cells.

GCTs contain malignant tissues of germ cell origin and, rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly mature or immature teratoma.[34,36]

Malignant germ cell elements of children, adolescents, and young adults can be grouped broadly by location (see Table 2).

Table 2. Histology of Malignant Germ Cell Tumors in Children, Adolescents, and Young Adultsa
Malignant Germ Cell Elements Location
E = extragonadal; O = ovarian; T = testicular.
aModified from Perlman et al.[37]
Seminomatous
  Seminoma T
  Dysgerminoma O
  Germinoma E
Nonseminomatous
  Yolk sac tumor (endodermal sinus tumor) E, O, T
  Choriocarcinoma E, O, T
  Embryonal carcinoma E, T
  Gonadoblastoma O
Mixed Germ Cell Tumors
  Mixed germ cell tumors E, O, T

GCT Biology

Childhood extracranial GCTs develop at many sites, including testicles, ovaries, mediastinum, retroperitoneum, sacrum, coccyx, and head and neck (see Figure 3).[7] The clinical features at presentation are specific for each site.

EnlargeExtracranial germ cell tumor; drawing shows parts of the body where extracranial germ cell tumors may form, including the head and neck, mediastinum (the area between the lungs, shown in blue), retroperitoneum (the area behind the abdominal organs, shown in red), sacrum, coccyx, testicles (in males), and ovaries (in females). Also shown are the heart and peritoneum.
Figure 3. Extracranial germ cell tumors form in parts of the body other than the brain. This includes the testicles, ovaries, sacrococcyx (usually originating from the coccyx and including the sacrum), mediastinum, and retroperitoneum.

The following biologically distinct subtypes of GCTs are found in children and adolescents:

Biological distinctions between GCTs in children and GCTs in adults may not be absolute, and biological factors have not been shown to predict risk.[38–40]

Testicular GCTs

  • Children (aged <11 years): During early childhood, both testicular teratomas and malignant testicular GCTs are identified. The malignant tumors are commonly composed of pure yolk sac tumor (also known as endodermal sinus tumor) and are generally diploid or tetraploid. Up to approximately 44% of testicular GCTs contain the isochromosome of the short arm of chromosome 12 (i12p) that characterizes testicular cancer in young adults.[38,41–45] Deletions of chromosomes 1p, 4q, and 6q and gains of chromosomes 1q, 3, and 20q are reported as recurring chromosomal abnormalities for this group of tumors.[43–46]
  • Adolescents and young adults (aged ≥11 years): Testicular GCTs in the adolescent and young adult population almost always possess an i12p chromosomal abnormality [47–50] and are aneuploid.[41,50]

Ovarian GCTs

Ovarian GCTs occur primarily in adolescent and young adult females. While most ovarian GCTs are benign mature teratomas (dermoid cysts), a heterogeneous group of malignant GCTs, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCTs, do occur in females. The malignant ovarian GCT commonly shows increased copies of the short arm of chromosome 12.[51]

Extragonadal extracranial GCTs

Extragonadal extracranial GCTs occur outside of the brain and gonads.

  • Children (aged <11 years): These tumors typically present at birth or during early childhood. Most of these tumors are benign teratomas occurring in the sacrococcygeal region, and thus are not included in Surveillance, Epidemiology, and End Results (SEER) Program data.[52,53] Malignant yolk sac tumor histology occurs in a minority of these tumors; however, they may have cytogenetic abnormalities similar to those observed for tumors occurring in the testes of young males.[42–44,46] Mediastinal GCTs in children younger than 8 years share the same genetic gains and losses as do sacrococcygeal and testicular tumors in young children.[18,54,55]
  • Older children, adolescents, and young adults (aged ≥11 years): The mediastinum is the most common primary site for extragonadal GCTs in older children and adolescents.[27]

For information about the treatment of intracranial GCTs, see Childhood Central Nervous System Germ Cell Tumors Treatment.

Diagnostic and Staging Evaluation

Diagnostic evaluation of GCTs includes measurement of serum tumor markers and imaging studies. In suspected cases, tumor markers can suggest the diagnosis before surgery and/or biopsy. This information can be used by the multidisciplinary team to make appropriate treatment choices.

Tumor markers

Tumor markers are measured with each cycle of chemotherapy for all pediatric patients with malignant GCTs. After initial chemotherapy, tumor markers may show a transient elevation.[56]

Common tumor markers include the following:

  • Alpha-fetoprotein (AFP).

    The fetal liver produces AFP, and during the first year of life, infants have elevated serum AFP levels, which are not associated with the presence of a GCT. Normal ranges have been described.[57,58] The serum half-life of AFP is 5 to 7 days.

    Yolk sac tumors produce AFP. Most children with malignant GCTs will have a component of yolk sac tumor and have elevations of AFP levels,[59,60] which are serially monitored during treatment to help assess response to therapy.[34,36,59] Benign teratomas and immature teratomas may produce small elevations of AFP and beta-human chorionic gonadotropin (beta-hCG).

    A COG study measured AFP levels in children who received chemotherapy for GCTs. AFP decline was defined as automatically satisfactory if AFP normalized after two cycles of chemotherapy and was calculated satisfactory if the AFP half-life decline was less than or equal to 7 days after the start of chemotherapy. Other decline in AFP was defined as unsatisfactory.[61][Level of evidence C1]

    • The cumulative incidence of relapse was 11% for patients with a satisfactory decline in AFP (n = 117) and 38% for patients with an unsatisfactory decline in AFP (n = 14).
  • Beta-hCG.

    Beta-hCG is produced by all choriocarcinomas and by some germinomas (seminomas and dysgerminomas) and embryonal carcinomas, resulting in elevated serum levels of these substances. The serum half-life of beta-hCG is 1 to 2 days.

  • MicroRNAs.

    In a prospective multicentric study, the serum level of microRNA-371a-3p was shown to be a sensitive and specific biomarker for adult testicular GCTs.[62] The study included 616 patients with GCTs of varying histologies and 258 controls without malignant GCTs. Elevation of microRNA-371a-3p levels was noted in all malignant histologies, including seminomas. Normal controls and patients with benign teratomas did not have the biomarker elevation. MicroRNA-371a-3p levels were related to tumor volume, and the levels decreased in response to chemotherapy. More studies about microRNA-371a-3p are needed to assess its use in patients with pediatric GCTs.

Imaging tests

Imaging tests may include the following:

  • Computed tomography (CT) scan of the chest.
  • CT or magnetic resonance imaging (MRI) of the primary site.
  • Radionuclide bone scan, if clinically indicated.
  • MRI of the brain, if clinically indicated.

Prognostic Factors

Prognostic factors for extracranial GCTs depend on many patient and tumor characteristics and include the following (obtained from historical national GCT trials):[59,63–65]

  • Age (e.g., young children vs. adolescents).
  • Stage of disease.
  • Primary site of disease.
  • Histology (e.g., seminomatous vs. nonseminomatous).
  • Tumor marker decline (AFP and beta-hCG) in response to therapy.
  • Presence of gonadal dysgenesis.

To better identify prognostic factors, data from five U.S. trials and two U.K. trials for malignant extracranial GCTs in children and adolescents were merged by the Malignant Germ Cell Tumor International Collaborative. The goal was to ascertain the important prognostic factors in 519 young patients who received chemotherapy, incorporating age at diagnosis, stage, and site of primary tumor, along with pretreatment AFP level and histology.[66][Level of evidence C2] In this age-focused investigation of these factors in young children and adolescents, outcomes included the following (see Figure 4):[66]

  • Patients aged 11 years and older with stage III or stage IV extragonadal disease or stage IV ovarian disease had a less than 70% likelihood of long-term disease-free survival, ranging from 40% (extragonadal stage IV) to 67% (ovarian stage IV).
  • Boys (aged 11 years and older) with International Germ Cell Consensus Classification [67] intermediate-risk or poor-risk features also had inferior outcomes.
  • Presence of a yolk sac tumor predicted better outcome, but it did not achieve statistical significance at the .05 level.
  • Preoperative AFP levels were not prognostic. Postoperative AFP levels were prognostic in adult men.[67]

A subsequent study used a database of 11 GCT trials and identified 593 patients with metastatic testicular, mediastinal, or retroperitoneal GCTs. The distribution of patients by age groups included 90 children (aged 0 to <11 years), 109 adolescents (aged 11 to <18 years), and 394 young adults (aged 18 to ≤30 years).[67]; [68][Level of evidence C1]

  • The 5-year event-free survival (EFS) rate was lower for adolescents (72%; 95% confidence interval [CI], 62%–79%) than it was for children (90%; 95% CI, 81%–95%; P = .003) or young adults (88%; 95% CI, 84%–91%; P = .0002).
  • After adjusting for the International Germ Cell Consensus Classification risk group,[67] only the difference in EFS between adolescents and children remained significant (hazard ratio, 0.30; P = .001).

Although few pediatric data exist, adult studies have shown that an unsatisfactory decline of elevated tumor markers after the first cycle of chemotherapy is a poor prognostic finding.[69,70]

The presence of gonadal dysgenesis in patients with ovarian nondysgerminomas is associated with worse outcomes. In a report from the COG AGCT0132 study, seven patients with gonadal dysgenesis and ovarian nondysgerminomas had an estimated 3-year EFS rate of 67%, compared with 89% for 100 patients with nondysgerminoma ovarian tumors who did not have gonadal dysgenesis.[13] These dysgenetic gonads contain Y-chromosome material, and intra-abdominal gonads with Y-chromosome material are at increased risk of tumor development.[12,71] In contrast to nondysgerminomas, gonadal dysgenesis was identified in 7 of 48 patients with ovarian dysgerminomas in a report from the French Society of Pediatric Oncology. With a medium follow-up of 14 years, all patients survived.[72]

EnlargeTable showing the predicted fraction of pediatric germ cell tumors cured by site, age, and stage using parameter estimates from Cure model.
Figure 4. Predicted fraction of pediatric germ cell tumors cured by site, age, and stage using parameter estimates from cure model. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved. Frazier AL, Hale JP, Rodriguez-Galindo C, et al: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol, Vol. 33 (Issue 2), 2015: 195-201.

For more information about prognosis and prognostic factors for childhood extragonadal extracranial GCTs, see the sections on Treatment of Mature and Immature Teratomas in Children, Treatment of Malignant Gonadal GCTs in Children, and Treatment of Malignant Extragonadal Extracranial GCTs in Children.

Follow-up After Treatment

The following tests and procedures may be performed at the physician’s discretion for monitoring children with extracranial GCTs:

  • AFP and beta-hCG. Monitor AFP and beta-hCG levels monthly for 6 months (period of highest risk) and then every 3 months, for a total of 2 years (3 years for sacrococcygeal teratoma).

    A COG trial of patients with low-risk and intermediate-risk GCTs reported the following results:[73][Level of evidence C2]

    • Forty-eight patients with elevated tumor markers at diagnosis relapsed during the surveillance phase.
    • At the time of relapse (after central review), 47 of 48 (98%) relapses were detected by tumor marker elevation.
  • Imaging tests.
    • MRI/CT may be performed at the completion of therapy.
    • Guided imaging of the primary site may be performed every 3 months for the first year and every six months for the second year. Seminomas and dysgerminomas may recur later, so the imaging schedule may need to be extended.
    • Chest x-ray annually.
    • When tumor markers are normal at diagnosis, ultrasonography or CT/MRI may be performed every 3 months for 2 years and then annually for 5 years for germinomas.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[74] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,74,75] During the period from 2002 to 2010, cancer mortality continued to decrease by 2.4% per year for children and adolescents with gonadal tumors, as compared with the period from 1975 to 1998 (plateauing from 1998 to 2001).[74] Childhood and adolescent cancer survivors require close monitoring because late effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects of childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

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  53. Marsden HB, Birch JM, Swindell R: Germ cell tumours of childhood: a review of 137 cases. J Clin Pathol 34 (8): 879-83, 1981. [PUBMED Abstract]
  54. Dal Cin P, Drochmans A, Moerman P, et al.: Isochromosome 12p in mediastinal germ cell tumor. Cancer Genet Cytogenet 42 (2): 243-51, 1989. [PUBMED Abstract]
  55. Aly MS, Dal Cin P, Jiskoot P, et al.: Competitive in situ hybridization in a mediastinal germ cell tumor. Cancer Genet Cytogenet 73 (1): 53-6, 1994. [PUBMED Abstract]
  56. Vogelzang NJ, Lange PH, Goldman A, et al.: Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors. Cancer Res 42 (11): 4855-61, 1982. [PUBMED Abstract]
  57. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 15 (1): 50-2, 1981. [PUBMED Abstract]
  58. Blohm ME, Vesterling-Hörner D, Calaminus G, et al.: Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15 (2): 135-42, 1998 Mar-Apr. [PUBMED Abstract]
  59. Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000. [PUBMED Abstract]
  60. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992. [PUBMED Abstract]
  61. O’Neill AF, Xia C, Krailo MD, et al.: α-Fetoprotein as a predictor of outcome for children with germ cell tumors: A report from the Malignant Germ Cell International Consortium. Cancer 125 (20): 3649-3656, 2019. [PUBMED Abstract]
  62. Dieckmann KP, Radtke A, Geczi L, et al.: Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study. J Clin Oncol 37 (16): 1412-1423, 2019. [PUBMED Abstract]
  63. Rogers PC, Olson TA, Cullen JW, et al.: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study–Pediatric Oncology Group 9048 and Children’s Cancer Group 8891. J Clin Oncol 22 (17): 3563-9, 2004. [PUBMED Abstract]
  64. Cushing B, Giller R, Cullen JW, et al.: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study–Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol 22 (13): 2691-700, 2004. [PUBMED Abstract]
  65. Göbel U, Schneider DT, Calaminus G, et al.: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 19 (7): 1943-50, 2001. [PUBMED Abstract]
  66. Frazier AL, Hale JP, Rodriguez-Galindo C, et al.: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol 33 (2): 195-201, 2015. [PUBMED Abstract]
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  68. Shaikh F, Stark D, Fonseca A, et al.: Outcomes of adolescent males with extracranial metastatic germ cell tumors: A report from the Malignant Germ Cell Tumor International Consortium. Cancer 127 (2): 193-202, 2021. [PUBMED Abstract]
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Stage Information for Childhood Extracranial GCTs

As with other childhood solid tumors, stage of disease at diagnosis directly impacts the outcome of patients with malignant germ cell tumors (GCTs).[1–3] The most commonly used staging systems in the United States are as follows:[4]

Testicular GCT Staging From COG (Patients Aged <11 Years)

Table 3 describes the testicular GCT staging for males younger than 11 years from the COG AGCT1531 (NCT03067181) trial.

Table 3. Testicular GCT Staging From the COG AGCT1531 Triala,b
Stage Extent of Disease
COG = Children’s Oncology Group; CT = computed tomography; GCT = germ cell tumor.
aMales younger than 50 years are eligible for the AGCT1531 trial.
bCOG trials include patients younger than 15 years with testicular GCT. Although data are scarce, patients between the ages of 11 years and 15 years might be more appropriately staged according to adult testicular guidelines. For more information about the staging of adult testicular GCTs, see Testicular Cancer Treatment.
I (1) Tumor limited to testis (testes) with negative microscopic margins, completely resected by high inguinal orchiectomy;
(2) Tumor capsule cannot have been violated by needle biopsy, incisional biopsy, or tumor rupture. Patients who have undergone scrotal orchiectomy without violation of the tumor capsule and with removal of the spermatic cord to the level of the internal ring are stage I. Patients who have undergone excisional biopsy for frozen section analysis with complete orchiectomy and cord excision at the same operation can be designated stage I;
(3) No clinical, radiographic, or histological evidence of disease beyond the testes;
(4) Lymph nodes all <1 cm maximum short-axis diameter on multiplanar imaging. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm.)
II (1) Complete orchiectomy with violation of the tumor capsule in situ (includes preoperative needle biopsy and incisional biopsy or intraoperative tumor capsule rupture);
(2) Microscopic disease in scrotum or high in spermatic cord (<5 cm from proximal end). Failure of tumor markers to normalize or decrease with an appropriate half-life;
(3) Lymph nodes negative.
III (1) Retroperitoneal lymph node involvement, but no visceral or extra-abdominal involvement;
(2) Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks.
IV (1) Distant metastases, including liver, lung, bone, and brain.

Testicular GCT Staging (Patients Aged ≥11 Years)

Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage disease in males younger than 15 years. Data on adolescent males with testicular GCTs are limited. Retroperitoneal lymph node dissection is used for both staging and treatment in adult testicular GCT trials.[5]

In males older than 15 years, there are only stage I tumors and metastatic tumors. Metastatic tumors are assigned risk according to the International Germ Cell Consensus Classification.[6]

For more information about the American Joint Committee on Cancer staging criteria for testicular GCT in males aged 11 years and older, see Testicular Cancer Treatment.

Ovarian GCT Staging From COG

Table 4 describes the ovarian GCT staging for females younger than 11 years from the COG AGCT1531 (NCT03067181) trial.

Table 4. Ovarian GCT Staging From the COG AGCT1531 Triala
Stage Extent of Disease
COG = Children’s Oncology Group; CT = computed tomography; GCT = germ cell tumor.
aBilateral ovarian tumors may be any stage as long as other stage criteria are met. Tumor staged according to ovary with most advanced features.
I (1) Ovarian tumor removed without violation of the tumor capsule;
(2) No evidence of partial or complete capsular penetration;
(3) Peritoneal cytology negative for malignant cells;
(4) Peritoneal surfaces and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance;
(5) Lymph nodes all <1 cm by short-axis diameter on multiplanar imaging or biopsy proven negative. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm.)
II (1) Ovarian tumor completely removed but with preoperative biopsy, violation of tumor capsule in situ, or presence of partial or complete capsule penetration at histology;
(2) Tumor >10 cm removed laparoscopically;
(3) Tumor morcellated for removal so that capsule cannot be assessed for penetration;
(4) Peritoneal cytology must be negative for malignant cells;
(5) Lymph nodes, peritoneal surfaces, and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance.
III (1) Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks;
(2) Ovarian tumor biopsy or removal with gross residual;
(3) Positive peritoneal fluid cytology for malignant cells, including immature teratoma;
(4) Lymph nodes positive for malignant cells, including immature teratoma;
(5) Peritoneal implants positive for malignant cells, including immature teratoma.
III–X Patients otherwise stage I or II by COG criteria but with the following:
  (1) Failure to collect peritoneal cytology;
  (2) Failure to biopsy lymph nodes >1 cm on short axis by multiplanar imaging;
  (3) Failure to sample abnormal peritoneal surfaces or omentum; or
  (4) Delayed completion of surgical staging at a second procedure for patients who had only oophorectomy at first procedure.
IV (1) Metastatic disease to the parenchyma of the liver (surface implants are stage III) or metastases outside the peritoneal cavity to any other viscera (bone, lung, or brain) and pleural fluid with positive cytology.

Ovarian GCT Staging From FIGO

Another ovarian GCT staging system used frequently by gynecologic oncologists is the FIGO staging system, which is based on adequate surgical staging at the time of diagnosis.[7] This system has also been used by some pediatric centers,[2] is most applicable to females older than 11 years, and is described in Table 5. For more information about the FIGO staging system, see Ovarian Germ Cell Tumors Treatment.

Table 5. FIGO Staging for Carcinoma of the Ovarya
Stage Description
FIGO = International Federation of Gynecology and Obstetrics.
aAdapted from Berek et al.[8]
I Tumor confined to the ovary.
IA Tumor limited to one ovary (capsule intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings.
IB Tumor limited to both ovaries (capsules intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings.
IC Tumor limited to one or both ovaries, with any of the following:
  IC1 Surgical spill.
  IC2 Capsule ruptured before surgery or tumor on the surface of the ovary.
  IC3 Malignant cells in the ascites or peritoneal washings.
 
II Tumor involves one or both ovaries with pelvic extension (below pelvic brim) or primary peritoneal cancer.
IIA Extension and/or implants on uterus and/or fallopian tubes.
IIB Extension to other pelvic intraperitoneal tissues.
 
III Tumor involves one or both ovaries or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes.
IIIA1 Positive retroperitoneal lymph nodes only (cytologically or histologically proven):
  IIIA1(i) Lymph nodes ≤10 mm in greatest dimension.
  IIIA1(ii) Lymph nodes >10 mm in greatest dimension.
IIIA2 Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes.
IIIB Macroscopic peritoneal metastasis beyond the pelvis ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes
IIIC Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ).
 
IV Distant metastasis excluding peritoneal metastases.
IVA Pleural effusion with positive cytology.
IVB Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity).

The ovarian staging systems described above require adherence to specific surgical guidelines. However, in a pediatric intergroup trial, guidelines were followed in only 2 of 131 patients with ovarian tumors.[9] In a single-institution retrospective study, guidelines were followed in only 2 of 44 patients with ovarian tumors.[10]

Extragonadal Extracranial GCT Staging From COG

Table 6 describes the extragonadal extracranial GCT staging from the COG AGCT1531 (NCT03067181) trial.

Table 6. Extragonadal Extracranial GCT Staging From the COG AGCT1531 Trial
Stage Extent of Disease
COG = Children’s Oncology Group; CT = computed tomography; GCT = germ cell tumor.
I (1) Complete resection at any site, including coccygectomy for sacrococcygeal site;
(2) Must have negative tumor margins and intact capsule;
(3) For any tumors involving abdominal cavity or retroperitoneum, peritoneal fluid or washings must be done for cytology and be negative for malignant cells;
(4) Lymph nodes ≤1 cm by imaging of abdomen, pelvis, and chest. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm. For any tumors involving abdominal cavity or retroperitoneum, peritoneal fluid or washings must be done for cytology and be negative for malignant cells.)
II (1) Microscopic residual disease;
(2) Gross-total resection with preoperative biopsy, intraoperative biopsy, microscopic residual disease, or pathological evidence of capsular disruption;
(3) Lymph nodes negative by abdomen, pelvic, and chest imaging. Peritoneal fluid negative.
III (1) Gross residual disease or biopsy only;
(2) Lymph nodes positive with tumor resection. Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks.
IV Distant metastases, including liver, lung, bone, and brain.
References
  1. Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991. [PUBMED Abstract]
  2. Mann JR, Pearson D, Barrett A, et al.: Results of the United Kingdom Children’s Cancer Study Group’s malignant germ cell tumor studies. Cancer 63 (9): 1657-67, 1989. [PUBMED Abstract]
  3. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992. [PUBMED Abstract]
  4. Brodeur GM, Howarth CB, Pratt CB, et al.: Malignant germ cell tumors in 57 children and adolescents. Cancer 48 (8): 1890-8, 1981. [PUBMED Abstract]
  5. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006. [PUBMED Abstract]
  6. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997. [PUBMED Abstract]
  7. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993. [PUBMED Abstract]
  8. Berek JS, Renz M, Kehoe S, et al.: Cancer of the ovary, fallopian tube, and peritoneum: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 61-85, 2021. [PUBMED Abstract]
  9. Billmire D, Vinocur C, Rescorla F, et al.: Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg 39 (3): 424-9; discussion 424-9, 2004. [PUBMED Abstract]
  10. Madenci AL, Levine BS, Laufer MR, et al.: Poor adherence to staging guidelines for children with malignant ovarian tumors. J Pediatr Surg 51 (9): 1513-7, 2016. [PUBMED Abstract]

Treatment Option Overview for Childhood Extracranial GCTs

Childhood extracranial germ cell tumors (GCTs) are very heterogenous.

On the basis of clinical factors and tumor histology, appropriate treatment for extracranial GCTs may involve one of the following:

  • Surgical resection followed by careful monitoring for disease recurrence.
  • Initial surgical resection followed by platinum-based chemotherapy.
  • Diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection.[1]

To maximize long-term survival while minimizing treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, and renal dysfunction), children with extracranial malignant GCTs need to be cared for at pediatric cancer centers with experience treating these rare tumors.

Treatment Options for Childhood Extracranial GCTs by Histological Type

Table 7 provides an overview of treatment options for children with extracranial GCTs. Specific details of treatment by primary site and clinical condition are described in subsequent sections.

Table 7. Treatment Options for Childhood Extracranial Germ Cell Tumors (GCTs)
Histology Treatment Options
BEP = bleomycin (weekly), etoposide, and cisplatin; JEb = carboplatin, etoposide, and bleomycin; PEb = cisplatin, etoposide, and bleomycin (bleomycin only on day 1 of each cycle).
aChemotherapy has not been shown to be effective in the treatment of children with stages II–IV immature teratoma. However, the role of chemotherapy in these patients has not been systematically studied. In postpubertal patients, chemotherapy remains the standard treatment, although studies are limited.[2]
bIn prepubertal females with reported stage I disease, but in whom strict surgical staging guidelines were not followed, chemotherapy (PEb) can be considered standard treatment.[3]
cIn postpubertal females with stage I disease, the strategy of observation after surgery has not been established. This treatment strategy is under investigation in a clinical trial (AGCT1531 [NCT03067181]).
Mature teratoma  
  Sacrococcygeal site Surgery and observation
  Nonsacrococcygeal site Surgery and observation
Immature teratoma Surgery and observation (stage I)
Surgery and observation or chemotherapy (stages I–IV) a
Malignant gonadal GCTs in children:  
  Childhood malignant testicular GCTs:  
    Malignant testicular GCTs in prepubertal males Surgery and observation (stage I)
Surgery and chemotherapy (PEb) (stages II–IV)
    Malignant testicular GCTs in postpubertal males For information, see Testicular Cancer Treatment.
  Childhood malignant ovarian GCTs:  
    Dysgerminomas of the ovary Surgery and observation (stage I)
Surgery and chemotherapy (PEb) (stages II–IV)
    Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs) in prepubertal females Surgery and observation for prepubertal females (stage I following strict surgical staging guidelines) b. For information about the treatment of ovarian mature teratoma, see the Childhood Malignant Ovarian GCTs section.
Surgery and chemotherapy (PEb) for prepubertal and postpubertal females (purported stage I and stages II–IV)
    Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs) in postpubertal females Surgery and chemotherapy (BEP) for prepubertal and postpubertal females (purported stage I and stages II–IV) c
    Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs) that are initially unresectable Biopsy followed by chemotherapy and surgery (initially unresectable ovarian GCT)
Malignant extragonadal extracranial GCTs in children:  
  Malignant extragonadal extracranial GCTs in prepubertal children Surgery and chemotherapy (PEb or JEb) (stages I –IV)
Biopsy followed by chemotherapy with or without surgery (stages III and IV)
  Malignant extragonadal extracranial GCTs in postpubertal children Surgery
Chemotherapy (BEP)
Chemotherapy followed by surgery to remove residual tumor
Enrollment in a clinical trial
Recurrent malignant GCTs in children Surgery alone
Surgery with neoadjuvant or adjuvant chemotherapy

GCTs with non-GCT elements (teratoma with malignant transformation)

The treatment of GCTs with other non-GCT somatic elements is complex, and few data exist to direct treatment. In adolescents, central primitive neuroectodermal tumors and sarcomas have been found in teratomas.[4,5] The Italian Pediatric Germ Cell Tumor group identified 14 patients with malignant GCTs with a somatic malignancy, such as neuroblastoma or rhabdomyosarcoma, embedded in teratomas (<2% of extracranial GCTs).[6]

The optimal treatment strategy for GCTs with non-GCT elements has not been determined. Separate treatments for both malignant GCTs and non-GCT elements may be required.

Surgery

Surgery is an essential component of treatment. Specific treatments will be discussed for each tumor type.

Surgery and Observation

For patients with completely resected immature teratomas of all grades and at any location, and for patients with localized, completely resected (stage I) seminomatous and nonseminomatous GCTs (testicular and ovarian), additional therapy may not be necessary. However, close monitoring of patients is important.[7,8] The watch-and-wait approach requires scheduled serial physical examination, tumor marker determination, and primary tumor imaging to ensure that a recurrent tumor is detected without delay.

Chemotherapy

In the United States, the standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]).[9–12] U.S. pediatric trials included patients aged 15 years and younger with testicular GCTs and patients aged 21 years and younger with ovarian and extragonadal GCTs. Patients received bleomycin only on day 1 of each cycle (cisplatin, etoposide, and bleomycin [PEb]).[3,13] The combination of carboplatin, etoposide, and bleomycin (JEb) underwent clinical investigation in the United Kingdom in children younger than 16 years. Treatment with this regimen produced event-free survival (EFS) rates by site and stage similar to those produced using treatment with PEb.[14,15]; [16][Level of evidence C1] For information about adult BEP and pediatric PEb and JEb chemotherapy dosing schedules, see Table 8.[3,9–11,13] In both adult and pediatric trials, the number of adolescent subjects was small. The optimal therapy for adolescents (aged ≥11 years) is not clear.[17]

The use of JEb appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEb.[14] In a retrospective meta-analysis of data from the Children’s Oncology Group (COG) and the Children’s Cancer and Leukaemia Group germ cell studies conducted contemporaneously, the multivariate cure model showed no difference in 4-year EFS rates. The 4-year EFS rate was 86% (95% confidence interval [CI], 83%–89%) for patients who received the cisplatin regimen (n = 620) and 86% (95% CI, 79%–90%) for patients who received the carboplatin regimen (n = 163) (P = .87).[18][Level of evidence C1] However, PEb and JEb have not been compared in a randomized pediatric GCT trial.

Table 8. Comparison of Adult BEP and Pediatric PEb and JEb Chemotherapy Dosing Schedules
Regimen Bleomycin Etoposide Cisplatin Carboplatin
BEP = bleomycin, etoposide, and cisplatin; GFR = glomerular filtration rate; JEb = carboplatin, etoposide, and bleomycin; PEb = cisplatin, etoposide, and bleomycin.
Adult BEP (every 21 days) [11,19] 30 units/m2, days 1, 8, 15 (maximum 30 units) 100 mg/m2, days 1–5 20 mg/m2, days 1–5  
Pediatric PEb (every 21 days) [3,13] 15 units/m2, day 1 (maximum 30 units) 100 mg/m2, days 1–5 20 mg/m2, days 1–5  
Pediatric JEb (every 21–28 days) [14] 15 units/m2, day 3 (maximum 30 units) 120 mg/m2, days 1–3   600 mg/m2 or GFR-based dosing, day 2

Several trials were conducted by the COG (previously the Children’s Cancer Group and the Pediatric Oncology Group).[3,7,13] These trials explored the use of PEb for the treatment of localized gonadal GCT [3] and intensified regimens for patients with poor-risk features. The strategies included high-dose cisplatin (200 mg/m2) and cyclophosphamide or the protective agent amifostine.[13,20] None of these strategies had a significant effect on survival or decreased toxicity.

The COG conducted a trial of compressed and reduced PEb chemotherapy (three cycles in 3 days) for patients with low-risk or intermediate-risk malignant GCTs. This study was designed as a noninferior trial with a P value of .1. The 4-year EFS rate of 89% was significantly lower than the rate for the historical control model (92%; P = .08).[21] However, the number of patients in each stratum was small, and further investigation in patients with lower-stage disease may be warranted.

Radiation Therapy

Testicular and mediastinal seminomas in males and ovarian dysgerminomas in females are sensitive to radiation, but radiation therapy is rarely recommended because of the known late effects.

References
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  2. Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 37 (5): 2359-72, 1976. [PUBMED Abstract]
  3. Rogers PC, Olson TA, Cullen JW, et al.: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study–Pediatric Oncology Group 9048 and Children’s Cancer Group 8891. J Clin Oncol 22 (17): 3563-9, 2004. [PUBMED Abstract]
  4. Ehrlich Y, Beck SD, Ulbright TM, et al.: Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor. Ann Oncol 21 (9): 1846-50, 2010. [PUBMED Abstract]
  5. Rice KR, Magers MJ, Beck SD, et al.: Management of germ cell tumors with somatic type malignancy: pathological features, prognostic factors and survival outcomes. J Urol 192 (5): 1403-9, 2014. [PUBMED Abstract]
  6. Terenziani M, D’Angelo P, Bisogno G, et al.: Teratoma with a malignant somatic component in pediatric patients: the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer 54 (4): 532-7, 2010. [PUBMED Abstract]
  7. Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999. [PUBMED Abstract]
  8. Schlatter M, Rescorla F, Giller R, et al.: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children’s Cancer Group/Pediatric Oncology Group. J Pediatr Surg 38 (3): 319-24; discussion 319-24, 2003. [PUBMED Abstract]
  9. de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001. [PUBMED Abstract]
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  14. Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000. [PUBMED Abstract]
  15. Stern JW, Bunin N: Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol 39 (3): 163-7, 2002. [PUBMED Abstract]
  16. Depani S, Stoneham S, Krailo M, et al.: Results from the UK Children’s Cancer and Leukaemia Group study of extracranial germ cell tumours in children and adolescents (GCIII). Eur J Cancer 118: 49-57, 2019. [PUBMED Abstract]
  17. Frazier AL, Hale JP, Rodriguez-Galindo C, et al.: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol 33 (2): 195-201, 2015. [PUBMED Abstract]
  18. Frazier AL, Stoneham S, Rodriguez-Galindo C, et al.: Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: A report of the Malignant Germ Cell International Consortium. Eur J Cancer 98: 30-37, 2018. [PUBMED Abstract]
  19. Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989. [PUBMED Abstract]
  20. Marina N, Chang KW, Malogolowkin M, et al.: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children’s Oncology Group study. Cancer 104 (4): 841-7, 2005. [PUBMED Abstract]
  21. Shaikh F, Cullen JW, Olson TA, et al.: Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children’s Oncology Group. J Clin Oncol 35 (11): 1203-1210, 2017. [PUBMED Abstract]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons.
  • Transplant surgeons.
  • Pathologists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists and hematologists.
  • Ophthalmologists.
  • Rehabilitation specialists.
  • Pediatric oncology nurses.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
  • Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References
  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
  2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.

Treatment of Mature and Immature Teratomas in Children

Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children and in the ovaries of pubescent girls. Less commonly, these tumors are found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.[1–3] The primary treatment for teratomas is surgery with complete resection. Surgical options for sacrococcygeal teratomas are complex.

Benign head and neck teratomas and immature teratomas can cause morbidity and mortality through obstruction. In preterm infants and neonates, head and neck teratomas and immature teratomas can cause significant airway compromise. In a single-institutional report, airway obstruction was overcome by using the ex utero intrapartum treatment (EXIT) procedure.[4] Complete resection of a teratoma can be achieved.

Treatment of Mature Teratomas

Standard treatment options for mature teratomas (sacrococcygeal sites)

The sacrococcygeal region is the primary tumor site for most benign and malignant germ cell tumors (GCTs) diagnosed in neonates, infants, and children younger than 4 years. These tumors occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported.[5]

Sacrococcygeal tumors present in the following two clinical patterns related to the child’s age, tumor location, and likelihood of tumor malignancy:[1]

  • Neonates: Neonatal tumors present at birth protruding from the sacral site. However, saccrococcygeal tumors may extend into the retroperitoneal space without outward protrusion. They are usually mature or immature teratomas.
  • Infants and young children: In infants and young children, tumors present as a palpable mass in the sacro-pelvic region, compressing the bladder or rectum. These pelvic tumors are more likely to be malignant.

    The older the child at presentation, the more likely a malignant component is present in addition to the teratoma. An early survey found that the rate of tumor malignancy was 48% for girls and 67% for boys older than 2 months at the time of sacrococcygeal tumor diagnosis, compared with a malignant tumor incidence of 7% for girls and 10% for boys younger than 2 months at the time of diagnosis.[6] The pelvic primary tumor site has been reported to be an adverse prognostic factor. This could be due to a delayed diagnosis because it was overlooked at birth or incomplete resection at the time of original surgery.[6–9]

Standard treatment options for mature teratomas in a sacrococcygeal site include the following:

  1. Surgery and observation.

Surgery is an essential component of treatment. Complete resection of the coccyx is vital to minimize the likelihood of tumor recurrence.[2]

Standard treatment options for mature teratomas (nonsacrococcygeal sites)

Standard treatment options for mature teratomas in a nonsacrococcygeal site include the following:

  1. Surgery and observation.

Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation and have an excellent prognosis.[1,10]

In a review of 153 children with nontesticular mature teratomas, the 6-year relapse-free survival rate was 96% for patients with completely resected disease and 55% for patients with incompletely resected disease.[2] Another series included 57 girls with mature teratomas of the ovary. Two patients experienced tumor recurrences (8 and 12 months after ovarian-sparing surgery), and seven patients developed metachronous tumors (as late as 79 months after initial diagnosis).[11][Level of evidence C1]

A multidisciplinary team should treat and monitor neonates with head and neck GCTs. Although most head and neck GCTs are benign, they can be life-threatening and present significant challenges to surgeons, especially in newborns.[4] Some tumors develop malignant elements, which may change the treatment strategy.[12,13]

Mature teratomas in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.[14]

Treatment of Immature Teratomas

Treatment options for immature teratomas

Treatment options for immature teratomas include the following:

  1. Surgery and observation (stage I).
  2. Surgery and observation or chemotherapy (stages I–IV). The use of chemotherapy is controversial. For more information, see evidence on the role of chemotherapy for immature teratomas.
Surgery and observation (stage I)

Immature teratomas in children are primarily managed with surgery and observation.

Evidence (surgery and observation for stage I disease):

  1. A surgery-alone approach was investigated in a study by the Pediatric Oncology Group and Children’s Cancer Group. Surgical resection followed by careful observation was used to treat patients with immature teratomas.[15]
    • Surgery alone was curative for most children and adolescents with resected ovarian immature teratomas of any grade, even when elevated levels of serum alpha-fetoprotein (AFP) or microscopic foci of yolk sac tumor were present.
    • The 3-year event-free survival (EFS) rates were 97.8% for patients with ovarian tumors, 100% for patients with testicular tumors, and 80% for patients with extragonadal tumors.
Surgery and observation or chemotherapy (stages I–IV)

The use of chemotherapy is controversial in the treatment of immature teratomas. There are no clinical trials supporting the use of chemotherapy in children. In adult women with ovarian tumors, surgery followed by chemotherapy has been the standard treatment approach since 1976.[16] As in children, there are no clinical trials supporting the use of chemotherapy in adults.

Evidence (role of chemotherapy for immature teratomas):

  1. A seminal article published in 1976 reported that most women with ovarian immature teratomas were treated with surgery and chemotherapy. This approach has remained standard practice in postpubertal females.[16]
  2. A report on pediatric patients aged 15 years and younger in the United Kingdom found that immature teratomas did not respond to chemotherapy.[17]
  3. A report from the Malignant Germ Cell Tumor International Collaborative (MaGIC) analyzed data from 98 pediatric patients and 81 adult patients with ovarian immature teratomas. Ninety pediatric patients underwent surgery alone. All 81 adult patients received adjuvant chemotherapy.[18][Level of evidence C1]
    • The 5-year EFS rate was 91% for pediatric patients and 98% for adult patients.
    • The overall survival (OS) rate was 83% for pediatric patients and 93% for adult patients.
    • There were no relapses in patients with grade I tumors. One adult patient with a grade II tumor relapsed after chemotherapy.
    • For pediatric patients with grade III, stage I/II tumors, the 5-year EFS rate was 92%. For patients with grade III, stage III tumors, the 5-year EFS rate was 52%.
    • For adult patients with grade III, stage I/II tumors, the 5-year EFS rate was 91%. For patients with grade III, stage III/IV tumors, the 5-year EFS rate was 65%.

Additional studies on the treatment of ovarian immature teratomas with chemotherapy are needed. For more information about the treatment of ovarian immature teratomas in postpubertal females, see Ovarian Germ Cell Tumors Treatment.

Treatment options under clinical evaluation for immature teratomas

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. AGCT1531 (NCT03067181) (Active Surveillance, Bleomycin, Carboplatin, Etoposide, or Cisplatin in Treating Pediatric and Adult Patients with GCTs): Patients with ovarian pure-cell immature teratomas that are Children’s Oncology Group stage I (International Federation of Gynecology and Obstetrics [FIGO] stage IA and IB), grade 2 or 3, and have an AFP level of less than 1,000 ng/mL are eligible for surgery and observation on this trial.

Follow-up After Treatment of Mature and Immature Teratomas

After successful resection, neonates diagnosed with benign mature and immature teratomas are closely observed with follow-up exams and serial serum AFP determinations. These tests are done for several years to ensure that AFP measurements normalize to expected physiological levels and to facilitate early detection of tumor relapse.[19,20] Several oncology groups have reported significant rates of recurrence among these benign tumors, ranging from 10% to 21%. Most relapses occur within 3 years of resection.[5,19,21,22]

While there is no standard follow-up schedule, tumor markers are measured frequently for 3 years in all children. With early detection, recurrent malignant GCTs can be treated successfully with surgery and chemotherapy (OS rate, 92%).[23] Long-term survivors are monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.[24]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999. [PUBMED Abstract]
  2. Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998. [PUBMED Abstract]
  3. Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997. [PUBMED Abstract]
  4. Dharmarajan H, Rouillard-Bazinet N, Chandy BM: Mature and immature pediatric head and neck teratomas: A 15-year review at a large tertiary center. Int J Pediatr Otorhinolaryngol 105: 43-47, 2018. [PUBMED Abstract]
  5. Rescorla FJ, Sawin RS, Coran AG, et al.: Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Childrens Cancer Group. J Pediatr Surg 33 (2): 171-6, 1998. [PUBMED Abstract]
  6. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974. [PUBMED Abstract]
  7. Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991. [PUBMED Abstract]
  8. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992. [PUBMED Abstract]
  9. Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999. [PUBMED Abstract]
  10. Schneider DT, Calaminus G, Reinhard H, et al.: Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96. J Clin Oncol 18 (4): 832-9, 2000. [PUBMED Abstract]
  11. Braungart S, Craigie RJ, Farrelly P, et al.: Ovarian tumors in children: how common are lesion recurrence and metachronous disease? A UK CCLG Surgeons Cancer Group nationwide study. J Pediatr Surg 55 (10): 2026-2029, 2020. [PUBMED Abstract]
  12. Bernbeck B, Schneider DT, Bernbeck B, et al.: Germ cell tumors of the head and neck: report from the MAKEI Study Group. Pediatr Blood Cancer 52 (2): 223-6, 2009. [PUBMED Abstract]
  13. Alexander VR, Manjaly JG, Pepper CM, et al.: Head and neck teratomas in children–A series of 23 cases at Great Ormond Street Hospital. Int J Pediatr Otorhinolaryngol 79 (12): 2008-14, 2015. [PUBMED Abstract]
  14. Metcalfe PD, Farivar-Mohseni H, Farhat W, et al.: Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol 170 (6 Pt 1): 2412-5; discussion 2415-6, 2003. [PUBMED Abstract]
  15. Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999. [PUBMED Abstract]
  16. Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 37 (5): 2359-72, 1976. [PUBMED Abstract]
  17. Mann JR, Gray ES, Thornton C, et al.: Mature and immature extracranial teratomas in children: the UK Children’s Cancer Study Group Experience. J Clin Oncol 26 (21): 3590-7, 2008. [PUBMED Abstract]
  18. Pashankar F, Hale JP, Dang H, et al.: Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative. Cancer 122 (2): 230-7, 2016. [PUBMED Abstract]
  19. Huddart SN, Mann JR, Robinson K, et al.: Sacrococcygeal teratomas: the UK Children’s Cancer Study Group’s experience. I. Neonatal. Pediatr Surg Int 19 (1-2): 47-51, 2003. [PUBMED Abstract]
  20. Egler RA, Gosiengfiao Y, Russell H, et al.: Is surgical resection and observation sufficient for stage I and II sacrococcygeal germ cell tumors? A case series and review. Pediatr Blood Cancer 64 (5): , 2017. [PUBMED Abstract]
  21. Gonzalez-Crussi F, Winkler RF, Mirkin DL: Sacrococcygeal teratomas in infants and children: relationship of histology and prognosis in 40 cases. Arch Pathol Lab Med 102 (8): 420-5, 1978. [PUBMED Abstract]
  22. Gabra HO, Jesudason EC, McDowell HP, et al.: Sacrococcygeal teratoma–a 25-year experience in a UK regional center. J Pediatr Surg 41 (9): 1513-6, 2006. [PUBMED Abstract]
  23. De Corti F, Sarnacki S, Patte C, et al.: Prognosis of malignant sacrococcygeal germ cell tumours according to their natural history and surgical management. Surg Oncol 21 (2): e31-7, 2012. [PUBMED Abstract]
  24. Derikx JP, De Backer A, van de Schoot L, et al.: Long-term functional sequelae of sacrococcygeal teratoma: a national study in The Netherlands. J Pediatr Surg 42 (6): 1122-6, 2007. [PUBMED Abstract]

Treatment of Malignant Gonadal GCTs in Children

Childhood Malignant Testicular GCTs

Malignant testicular GCTs in prepubertal males

The role of surgery at diagnosis for germ cell tumors (GCTs) depends on patient age and tumor site, and treatment must be individualized. All malignant testicular GCTs should be resected. Resection may be followed by subsequent excision of residual masses after chemotherapy.

Testicular GCTs in children occur almost exclusively in boys younger than 5 years.[1,2] The initial surgical approach to evaluate a testicular mass in a young boy is important because a trans-scrotal biopsy can risk inguinal node metastasis.[3,4] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice.[5]

Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging. Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys.[3,4] Therefore, there may be no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) associated with lymph node dissection.[6,7]

A revised risk stratification was developed by the Malignant Germ Cell Tumor International Consortium (see Figure 4).[8]

Standard treatment options for malignant GCTs in prepubertal males

Standard treatment options for malignant GCTs in prepubertal males (aged <11 years) include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II–IV).

The treatment options for malignant GCTs in prepubertal males differ by stage of disease.

Surgery and observation (stage I)

Surgery and close follow-up observation are indicated to document that tumor marker levels normalize after resection.[3,9]

Evidence (surgery and observation for stage I disease in prepubertal males):

  1. A Children’s Cancer Group (CCG)/Pediatric Oncology Group (POG) clinical trial evaluated surgery followed by observation for boys aged 10 years or younger with stage I testicular tumors.[3,4]
    • This treatment strategy resulted in a 6-year event-free survival (EFS) rate of 82%.
    • Boys who developed recurrent disease received salvage therapy with four cycles of standard-dose cisplatin, etoposide, and bleomycin (PEb), with a 6-year survival rate of 100%.
  2. A subsequent Children’s Oncology Group (COG) study of 80 boys younger than 15 years with stage I disease included 15 boys aged 11 to 15 years who were treated with surgery and observation.[10][Level of evidence C1]
    • The 4-year EFS rate was 80% for the 65 boys younger than 11 years at diagnosis and 48% for the 15 boys aged 11 years and older (P < .01). All patients’ disease was eventually salvaged, with a 4-year overall survival (OS) rate of 100%.
    • Favorable prognostic factors were younger age, presence of pure yolk sac tumor, and lack of lymphovascular invasion by the primary tumor.
    • Adult testicular staging systems classify patients with lymphovascular invasion as stage IB. In the entire cohort, those with lymphovascular invasion had a lower 4-year EFS rate (62% vs. 84%).
  3. A pooled analysis (from the studies above) provided more complete outcome data on patients with stage I disease who were treated with surgery and observation.[11][Level of evidence C2]
    • Most patients were prepubertal, but 13.2% of patients were adolescents (aged 13–15 years).
    • At a median follow-up of 56 months, all patients were alive.
    • There were 25 events.
    • On multivariate analysis, independent prognostic factors were age younger than 12 years (hazard ratio [HR], 8.87; P < .0001) and higher pT stage (pT2: HR, 7.31; P = .0017 and pT3: HR, 13.5; P = .0047).
  4. A German study (MAHO 98) of 128 boys younger than 10 years with testicular GCTs, mostly stage I, also evaluated surgery followed by observation.[12][Level of evidence C1]
    • There were 49 patients with yolk sac tumors that were staged as IA after inguinal orchiectomy. Stage IA includes no evidence of lymphovascular invasion. The 5-year EFS rate was 95%, and the 5-year OS rate was 100% for this group. Two patients relapsed and then were cured after chemotherapy.
    • There were 12 patients who initially had trans-scrotal orchiectomy who were pathologically confirmed to have no lymphovascular invasion (would be considered stage IA, if not for surgery). Ten patients were observed who had no adverse events. Two patients relapsed (17%) and remained in continuous remission after chemotherapy. No patients had hemiscrotectomy. A long-standing question has been whether trans-scrotal orchiectomy necessitates chemotherapy or hemiscrotectomy.
Surgery and chemotherapy (stages II–IV)

Surgery and chemotherapy with four cycles of standard PEb is a common treatment regimen for prepubertal males with stages II through IV disease. Patients treated with this regimen have OS rates exceeding 90%, suggesting that a reduction in therapy could be considered.[13,14]

Surgery and treatment with four to six cycles of carboplatin, etoposide, and bleomycin (JEb) is an alternative treatment regimen.[9]

Evidence (surgery and chemotherapy for stages II–IV disease in prepubertal males):

  1. A CCG/POG clinical trial evaluated boys younger than 10 years with stage II tumors who were treated with four cycles of PEb after diagnosis.[13]
    • The 6-year EFS and OS rates were 100%.
  2. In the same CCG/POG clinical trial, boys and adolescents (aged 14 years and younger) with stage III and stage IV testicular tumors were treated with surgical resection followed by four cycles of standard-dose PEb or high-dose PEb (HD-PEb) therapy.[14]
    • The 6-year survival rate for males younger than 15 years with stage III and stage IV tumors was 100%.
    • The 6-year EFS rate for males younger than 15 years was 100% for stage III tumors and 94% for stage IV tumors.
    • The use of HD-PEb therapy did not improve the outcome for these boys but did cause increased incidence of otologic toxic effects.
  3. European investigators have reported excellent outcomes for boys with testicular GCTs using surgery and observation for stage I tumors and JEb and other cisplatin-containing chemotherapy regimens for stage II, stage III, and stage IV tumors.[6,9]
  4. A phase III, single-arm COG trial (AGCT0132 [NCT00053352]) included 210 intermediate-risk patients (stages II–IV testicular, stages II–III ovarian, stages I–II extragonadal, or stage I gonadal tumors with subsequent recurrence). These patients received three, rather than four, cycles of PEb and the schedule was compressed from 5 days to 3 days per cycle. A parametric comparator model specified that the observed EFS rate would not be significantly less than 92%.[15][Level of evidence B4]
    • The 4-year EFS rate was 89% (95% confidence interval, 83%–92%), which was significantly lower than the 92% threshold of the comparison model (P = .08).
    • In a post hoc analysis, the EFS rate was compared with similar patients treated with four cycles of PEb in two previous studies. Among 181 newly diagnosed patients, the 4-year EFS rate was 87%, compared with 92% for 92 comparable children in the historical cohort (P = .15).
    • The 4-year EFS rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001).
    • These data do not support a reduction in the number of cycles of PEb from four to three.

Malignant testicular GCTs in postpubertal males

The treatment options described for prepubertal males may not be strictly applicable to postpubertal males. In particular, retroperitoneal lymph node dissection is a treatment option and may play a crucial role [16] in the initial treatment of patients or in subsequent treatment of patients with residual disease after chemotherapy for metastatic testicular GCT.[17,18] A meta-analysis showed that patients older than 11 years were at higher risk of recurrence.[8] The number of males aged 11 to 15 years with GCT is small; it is possible that these patients should be treated according to adult standards. For more information about the treatment of malignant testicular GCTs in postpubertal males, see Testicular Cancer Treatment.

Standard treatment options for malignant testicular GCTs in postpubertal males

For information about the treatment of malignant testicular GCTs in postpubertal males, see Testicular Cancer Treatment.

Treatment options under clinical evaluation for malignant testicular GCTs

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. AGCT1531 (NCT03067181) (Active Surveillance, Bleomycin, Carboplatin, Etoposide, or Cisplatin in Treating Pediatric and Adult Patients with GCTs): The aim of this trial is to reduce toxicity and maintain efficacy of treatment for patients with standard-risk GCTs. Patients with stage I malignant GCTs (low risk, age 0–50 years) will be treated with surgery and observation. Patients with intermediate-risk GCTs will be randomly assigned to receive cisplatin or carboplatin and bleomycin and etoposide. Children younger than 11 years will receive bleomycin with each cycle, and those aged 11 years and older will receive weekly bleomycin. Patients with pure seminoma or dysgerminoma are excluded from the trial.
Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Childhood Malignant Ovarian GCTs

Most ovarian neoplasms in children and adolescents are of germ cell origin.[19] Ovarian GCTs are very rare in young girls, but the incidence begins to increase in children aged approximately 8 or 9 years and continues to rise throughout adulthood.[1]

Childhood malignant ovarian GCTs can be divided into germinomatous (dysgerminomas) and nongerminomatous malignant GCTs (i.e., yolk sac carcinomas, mixed GCTs, choriocarcinoma, and embryonal carcinomas).

For more information about childhood mature and immature teratomas arising in the ovary, see the Treatment of Mature Teratomas section. For more information about the treatment of ovarian GCT in postpubertal females, see Ovarian Germ Cell Tumors Treatment.

Dysgerminomas of the ovary

Standard treatment options for dysgerminomas of the ovary

Standard treatment options for dysgerminomas of the ovary include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II–IV).

The treatment options for dysgerminomas of the ovary differ by stage of disease.

Surgery and observation (stage I)

For stage I ovarian dysgerminomas, a cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[9,20–23]

Evidence (surgery and observation for stage I dysgerminomas):

  1. In three successive French Society of Pediatric Oncology studies (TGM-85, TGM-90, and TGM-95), the following was reported:[24][Level of evidence C1]
    • Fifteen patients were identified as stage I, and all patients survived.
    • Before 1998, eight patients were treated with adjuvant radiation or chemotherapy. After a practice change in 1998, seven patients underwent surgery and observation.
    • One of the seven patients (14%) had a tumor event and responded to treatment with chemotherapy.
Surgery and chemotherapy (stages II–IV)

While advanced-stage ovarian dysgerminomas, like testicular seminomas, are highly curable with surgery and radiation therapy, the effects on growth, fertility, and risk of treatment-induced second malignancy in these young patients [25,26] make chemotherapy a more attractive adjunct to surgery.[27,28] Complete tumor resection is the goal for advanced dysgerminomas. Platinum-based chemotherapy can be given preoperatively to facilitate resection or postoperatively (after debulking surgery) to avoid mutilating surgical procedures.[23]

Evidence (surgery and chemotherapy for stage II–IV dysgerminomas):

  1. In a report from the French Society of Pediatric Oncology, 48 girls younger than 19 years (median age, 12.8 years) were registered; 20 patients had localized disease, 28 patients had locoregional disease, and no patients had metastases. Seven patients had positive para-aortic lymph nodes. Forty-seven patients underwent primary surgery. Before 1998, all patients with advanced disease received radiation therapy. After a practice change in 1998, patients were treated with platinum-based chemotherapy.[24][Level of evidence C1]
    • The 5-year EFS rate was 91%, and the 5-year OS rate was 100%.
    • Side effects were not severe, and several patients became pregnant in later years.
  2. A meta-analysis of patients with dysgerminoma by the Malignant Germ Cell Tumor International Consortium reported the following:[29]
    • No difference was seen between patients who were treated with cisplatin (n = 70) (5-year EFS rate, 93%; OS rate, 96%) and patients who were treated with carboplatin (n = 56) (5-year EFS rate, 96%; OS rate, 96%).

This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with dysgerminomas.[27,30]

Malignant nongerminomatous ovarian GCTs

A multidisciplinary approach is essential for treatment of ovarian GCTs. Various surgical subspecialists and the pediatric oncologist must be involved in clinical decisions. The surgical approach for pediatric ovarian GCTs is often guided by the expectation that reproductive function can be preserved.

The treatment of ovarian malignant GCTs that are not dysgerminomas or immature teratomas generally involves surgical resection and adjuvant chemotherapy.[31,32]

The role for surgery at diagnosis depends on patient age and tumor site, and treatment must be individualized. The use of laparoscopy in children with ovarian GCTs has not been well studied.

The use of intraoperative frozen biopsy in pediatric and adolescent patients to determine the presence of malignancy to allow an ovarian-sparing procedure has been questioned. In a retrospective analysis from the COG AGCT0132 (NCT00053352) study, 60 of 131 eligible patients with ovarian tumors had both intraoperative frozen section and final paraffin section diagnoses available.[33] Intraoperative frozen section biopsy was incorrect 38% of the time (23 patients), and it confirmed the final diagnosis 76% of the time. In addition, central pathological review detected additional germ cell components in 23.7% of patients.

Pediatric surgical guidelines to determine stage I disease have been published.[34] Adult surgical guidelines to determine stage are more extensive. For more information about staging of ovarian GCTs in postpubertal females, see the Stage Information for Ovarian Germ Cell Tumors section in Ovarian Germ Cell Tumors Treatment.

Strict surgical staging guidelines need to be followed to determine true stage I disease. Historically, in both pediatric and adult studies, comprehensive staging guidelines have not been followed. If strict surgical staging guidelines are not followed, surgery followed by chemotherapy, rather than surgery followed by observation, is the standard treatment.[9,13,35]

A goal of surgical therapy for pediatric GCTs is to preserve reproductive function. If conservative surgery is the choice, a high rate of cure can be obtained with adjuvant chemotherapy, and adherence to strict surgical guidelines is not necessary.[36]

Standard treatment options for malignant nongerminomatous ovarian GCTs

Standard treatment options for malignant nongerminomatous ovarian GCTs in prepubertal females include the following:

  1. Surgery and observation (stage I following strict surgical staging guidelines).
  2. Surgery and chemotherapy (PEb) (purported stage I and stages II–IV).

Standard treatment options for malignant nongerminomatous ovarian GCTs in postpubertal females include the following:

  1. Surgery and chemotherapy (bleomycin, etoposide, and cisplatin [BEP]) (purported stage I and stages II–IV).

Standard treatment options for malignant nongerminomatous ovarian GCTs that cannot be resected initially include the following:

  1. Biopsy followed by chemotherapy and surgery (initially unresectable tumor).
Surgery and observation for prepubertal females (stage I following strict surgical staging guidelines)

When strict surgical staging guidelines are followed, surgery followed by observation may be an appropriate treatment choice for prepubertal females with stage I disease.

Evidence (surgery and observation for prepubertal females with stage I disease):

  1. In a COG trial, 25 girls with stage I ovarian malignant GCTs were treated with surgery and observation.[34]
    • The 4-year EFS rate was 52%.
    • Relapse was detected in 12 patients by tumor marker elevation (mean time, 2 months). All patients later received salvage therapy with three cycles of PEb. The 4-year OS rate was 96%; one patient’s disease was not salvaged.
  2. Similar results have been reported in other international pediatric trials, but the number of patients has been small.[9]
Surgery and chemotherapy for prepubertal and postpubertal females (purported stage I and stages II–IV)

A revised risk stratification was developed by the Malignant Germ Cell Tumor International Consortium (see Figure 4).[8]

Chemotherapy regimens with cisplatin (PEb) or carboplatin (JEb) have been used successfully in children.[9,13,14,20] BEP is a common regimen in young women with ovarian GCTs.[37,38] BEP differs from PEb with the addition of weekly bleomycin. This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with nondysgerminomas.[32,35] For more information about the dosing schedules for BEP, PEb, and JEb, see Table 8.

In prepubertal females with purported stage I ovarian tumors (when strict surgical staging guidelines are not followed) surgery followed by chemotherapy (four cycles of PEb) is an appropriate treatment choice and results in EFS and OS rates of 95%.[13,14]

In postpubertal females with purported stage I ovarian tumors, chemotherapy after resection remains the standard treatment. In postpubertal females, the strategy of observation after surgery has not been established and is under investigation in the AGCT1531 (NCT03067181) trial.

In prepubertal and postpubertal females with stages II, III, or IV ovarian tumors, surgery and chemotherapy are considered standard treatments. Surgery and chemotherapy with four to six cycles of standard PEb is used to treat younger (prepubertal) girls,[13,14] and BEP is used to treat postpubertal girls.[37,38] Patients with normalization of tumor markers undergo imaging after four cycles of PEb, and any residual tumor is resected. Patients with residual viable tumor after surgery are considered refractory.

Alternatively, surgery and chemotherapy with four to six cycles of JEb is a treatment option (as demonstrated in one study in which all patients were younger than 15 years).[9]

Initially unresectable ovarian GCT

Primary resection of ovarian GCT is usually attempted. However, in rare instances, primary resection of the ovary is not possible without undue risk of damage to adjacent structures. In these cases, an appropriate strategy is biopsy for diagnosis, followed by chemotherapy and then subsequent surgery for patients who have residual masses after undergoing chemotherapy.

Treatment options under clinical evaluation for malignant ovarian GCTs

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. AGCT1531 (NCT03067181) (Active Surveillance, Bleomycin, Carboplatin, Etoposide, or Cisplatin in Treating Pediatric and Adult Patients with GCTs): The aim of this trial is to reduce toxicity and maintain efficacy of treatment for patients with standard-risk GCTs. Patients with stage I malignant GCTs (low risk, age 0–50 years) will be treated with surgery and observation. Patients with intermediate-risk GCTs will be randomly assigned to receive cisplatin or carboplatin and bleomycin and etoposide. Children younger than 11 years will receive bleomycin with each cycle, and those aged 11 years and older will receive weekly bleomycin. Patients with pure seminoma or dysgerminoma are excluded from the trial.
Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
  2. Walsh TJ, Grady RW, Porter MP, et al.: Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000. Urology 68 (2): 402-5; discussion 405, 2006. [PUBMED Abstract]
  3. Schlatter M, Rescorla F, Giller R, et al.: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children’s Cancer Group/Pediatric Oncology Group. J Pediatr Surg 38 (3): 319-24; discussion 319-24, 2003. [PUBMED Abstract]
  4. Canning DA: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children’s Cancer Group/Pediatric Oncology Group [Editorial Comment on Schlatter]. J Urol 174 (1): 310, 2005.
  5. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999. [PUBMED Abstract]
  6. Haas RJ, Schmidt P, Göbel U, et al.: Treatment of malignant testicular tumors in childhood: results of the German National Study 1982-1992. Med Pediatr Oncol 23 (5): 400-5, 1994. [PUBMED Abstract]
  7. Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997. [PUBMED Abstract]
  8. Frazier AL, Hale JP, Rodriguez-Galindo C, et al.: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol 33 (2): 195-201, 2015. [PUBMED Abstract]
  9. Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000. [PUBMED Abstract]
  10. Rescorla FJ, Ross JH, Billmire DF, et al.: Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children’s Oncology Group. J Pediatr Surg 50 (6): 1000-3, 2015. [PUBMED Abstract]
  11. Singla N, Wong J, Singla S, et al.: Clinicopathologic predictors of outcomes in children with stage I testicular germ cell tumors: A pooled post hoc analysis of trials from the Children’s Oncology Group. J Pediatr Urol 18 (4): 505-511, 2022. [PUBMED Abstract]
  12. Göbel U, Haas R, Calaminus G, et al.: Testicular germ cell tumors in boys <10 years: results of the protocol MAHO 98 in respect to surgery and watch & wait strategy. Klin Padiatr 225 (6): 296-302, 2013. [PUBMED Abstract]
  13. Rogers PC, Olson TA, Cullen JW, et al.: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study–Pediatric Oncology Group 9048 and Children’s Cancer Group 8891. J Clin Oncol 22 (17): 3563-9, 2004. [PUBMED Abstract]
  14. Cushing B, Giller R, Cullen JW, et al.: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study–Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol 22 (13): 2691-700, 2004. [PUBMED Abstract]
  15. Shaikh F, Cullen JW, Olson TA, et al.: Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children’s Oncology Group. J Clin Oncol 35 (11): 1203-1210, 2017. [PUBMED Abstract]
  16. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006. [PUBMED Abstract]
  17. Carver BS, Shayegan B, Serio A, et al.: Long-term clinical outcome after postchemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol 25 (9): 1033-7, 2007. [PUBMED Abstract]
  18. Carver BS, Shayegan B, Eggener S, et al.: Incidence of metastatic nonseminomatous germ cell tumor outside the boundaries of a modified postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol 25 (28): 4365-9, 2007. [PUBMED Abstract]
  19. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed December 22, 2023.
  20. Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000. [PUBMED Abstract]
  21. Dark GG, Bower M, Newlands ES, et al.: Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 15 (2): 620-4, 1997. [PUBMED Abstract]
  22. Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999. [PUBMED Abstract]
  23. Gershenson DM: Chemotherapy of ovarian germ cell tumors and sex cord stromal tumors. Semin Surg Oncol 10 (4): 290-8, 1994 Jul-Aug. [PUBMED Abstract]
  24. Duhil de Bénazé G, Pacquement H, Faure-Conter C, et al.: Paediatric dysgerminoma: Results of three consecutive French germ cell tumours clinical studies (TGM-85/90/95) with late effects study. Eur J Cancer 91: 30-37, 2018. [PUBMED Abstract]
  25. Teinturier C, Gelez J, Flamant F, et al.: Pure dysgerminoma of the ovary in childhood: treatment results and sequelae. Med Pediatr Oncol 23 (1): 1-7, 1994. [PUBMED Abstract]
  26. Mitchell MF, Gershenson DM, Soeters RP, et al.: The long-term effects of radiation therapy on patients with ovarian dysgerminoma. Cancer 67 (4): 1084-90, 1991. [PUBMED Abstract]
  27. Brewer M, Gershenson DM, Herzog CE, et al.: Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 17 (9): 2670-75, 1999. [PUBMED Abstract]
  28. Williams SD, Blessing JA, Hatch KD, et al.: Chemotherapy of advanced dysgerminoma: trials of the Gynecologic Oncology Group. J Clin Oncol 9 (11): 1950-5, 1991. [PUBMED Abstract]
  29. Shah R, Xia C, Krailo M, et al.: Is carboplatin-based chemotherapy as effective as cisplatin-based chemotherapy in the treatment of advanced-stage dysgerminoma in children, adolescents and young adults? Gynecol Oncol 150 (2): 253-260, 2018. [PUBMED Abstract]
  30. Gershenson DM: Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 6 (2): 270-5, 1988. [PUBMED Abstract]
  31. Gershenson DM, Morris M, Cangir A, et al.: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 8 (4): 715-20, 1990. [PUBMED Abstract]
  32. Mitchell PL, Al-Nasiri N, A’Hern R, et al.: Treatment of nondysgerminomatous ovarian germ cell tumors: an analysis of 69 cases. Cancer 85 (10): 2232-44, 1999. [PUBMED Abstract]
  33. Dicken BJ, Billmire DF, Rich B, et al.: Utility of frozen section in pediatric and adolescent malignant ovarian nonseminomatous germ cell tumors: A report from the children’s oncology group. Gynecol Oncol 166 (3): 476-480, 2022. [PUBMED Abstract]
  34. Billmire DF, Cullen JW, Rescorla FJ, et al.: Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children’s Oncology Group. J Clin Oncol 32 (5): 465-70, 2014. [PUBMED Abstract]
  35. Palenzuela G, Martin E, Meunier A, et al.: Comprehensive staging allows for excellent outcome in patients with localized malignant germ cell tumor of the ovary. Ann Surg 248 (5): 836-41, 2008. [PUBMED Abstract]
  36. Billmire D, Vinocur C, Rescorla F, et al.: Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg 39 (3): 424-9; discussion 424-9, 2004. [PUBMED Abstract]
  37. Williams SD: Ovarian germ cell tumors: an update. Semin Oncol 25 (3): 407-13, 1998. [PUBMED Abstract]
  38. Williams S, Blessing JA, Liao SY, et al.: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 12 (4): 701-6, 1994. [PUBMED Abstract]

Treatment of Malignant Extragonadal Extracranial GCTs in Children

In initial reports, children with extragonadal malignant germ cell tumors (GCTs), particularly those with advanced-stage (stage III or stage IV) disease, had the highest risk of treatment failure for any GCT presentation.[1,2] Subsequently, an analysis of data from 25 years of pediatric GCT studies in the United States and United Kingdom reported that children younger than 11 years with extragonadal stage III and stage IV GCTs had an event-free survival (EFS) rate of 85%, and adolescents with stage III and stage IV extragonadal disease had poorer outcomes (expected EFS rate, <70%).[3]

The role of surgery at diagnosis for extragonadal tumors depends on patient age and tumor site, and treatment must be individualized. Depending on the clinical setting, the appropriate surgical approach may be primary resection, biopsy before chemotherapy, or no surgery (e.g., for a mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers). An appropriate strategy may be biopsy at diagnosis followed by chemotherapy and subsequent surgery in selected patients who have residual masses after chemotherapy.

Standard Treatment Options for Malignant Extragonadal Extracranial GCTs in Prepubertal Children

Standard treatment options for malignant extragonadal extracranial GCTs in prepubertal children include the following:

  1. Surgery and chemotherapy (stages I–IV).
  2. Biopsy followed by chemotherapy with or without surgery (stages III and IV).

The treatment of malignant extragonadal extracranial GCTs also depends on the site of disease. For more information, see the Site-specific considerations for malignant extragonadal extracranial GCTs section.

Surgery and chemotherapy (stages I–IV)

Surgery and chemotherapy with four cycles of standard cisplatin, etoposide, and bleomycin (PEb) is one treatment option. Patients with stage I and stage II disease treated with this regimen had an overall survival (OS) rate of 90%, suggesting that a reduction in therapy may be considered.[1,4] Patients with stage III and stage IV disease had OS rates of higher than 80%.[1]

An alternative treatment option is surgery and chemotherapy with carboplatin, etoposide, and bleomycin (JEb).[5] Stage III and stage IV patients treated with JEb had an OS rate similar to that with the PEb regimen.[5]

Two pediatric intergroup trials for patients with high-risk disease investigated the use of high-dose cisplatin (200 mg/m2) in a randomized study and a subsequent study that added amifostine to high-dose cisplatin.[1] No benefit in OS was observed, and 75% of patients required hearing aids. A Children’s Oncology Group (COG) trial of patients with high-risk disease investigated the addition of cyclophosphamide to standard-dose PEb. The addition of cyclophosphamide was feasible and well tolerated at all dose levels, but there was no evidence that adding cyclophosphamide improved efficacy.[6]

Biopsy followed by chemotherapy with or without surgery (stages III and IV)

While outcomes have improved remarkably since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach, complete resection before chemotherapy may be possible in some patients without major morbidity.[1,5]

However, for patients with locally advanced sacrococcygeal tumors, mediastinal tumors, or large pelvic tumors, tumor biopsy followed by preoperative chemotherapy may facilitate subsequent complete tumor resection and improve ultimate patient outcome. No decrease in OS has been noted for patients with malignant extragonadal GCTs who have had delayed resection after receiving chemotherapy.[5,7–9]

Site-specific considerations for malignant extragonadal extracranial GCTs

The treatment of malignant extragonadal extracranial GCTs depends in part on the site of disease.

Sacrococcygeal site

Sacrococcygeal GCTs are common extragonadal tumors that occur in very young children, predominantly young females.[10] The tumors are usually diagnosed at birth, when large external lesions predominate (usually mature or immature teratomas), or later in the first years of life, when presacral lesions with higher malignancy rates predominate.[10]

Malignant sacrococcygeal tumors are usually very advanced at diagnosis. Two-thirds of patients have locoregional disease, and metastases are present in 50% of patients.[8,11,12] Because of their advanced stage at presentation, the management of sacrococcygeal tumors requires a multimodal approach with platinum-based chemotherapy followed by delayed tumor resection.

Platinum-based therapies, with either cisplatin or carboplatin, are the cornerstone of treatment. The PEb regimen or the JEb regimen produces EFS rates of 85%.[8,9] Surgery may be facilitated by preoperative chemotherapy. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[8,9]

Completeness of surgical resection is an important prognostic factor, as shown in the following circumstances:[8,9,13]

  • Resected tumors with negative microscopic margins: EFS rates higher than 90%.
  • Resected tumors with microscopic margins: EFS rates of 75% to 85%.
  • Resected tumors with macroscopic residual disease: EFS rates lower than 40%.
Mediastinal site

Mediastinal GCTs account for 15% to 20% of malignant extragonadal extracranial GCTs in children.[5] The histology of mediastinal GCT is dependent on age, with teratomas predominating among infants and yolk sac tumors predominating among children aged 1 to 4 years.[7]

Prepubertal children with mediastinal malignant teratomas are treated with tumor resection, which is curative in almost all patients.[7] Children with stage I to stage III nonmetastatic mediastinal GCTs who receive cisplatin-based chemotherapy have 5-year EFS and OS rates of 90%. However, patients with stage IV mediastinal tumors have EFS rates closer to 80%.[3,5,7]; [14][Level of evidence C1]

Retroperitoneal site

Malignant GCTs located in the retroperitoneum or abdomen usually present in children younger than 5 years. Most of these tumors are advanced stage and locally unresectable at diagnosis.[15] A limited biopsy followed by platinum-based chemotherapy to shrink tumor bulk can lead to complete tumor resection in most patients. Despite the advanced-stage disease in most patients, the 6-year EFS rate using PEb was 83% in the Pediatric Oncology Group/Children’s Cancer Group intergroup study.[15]

Head and neck site

Although rare, benign and malignant GCTs can occur in the head and neck region, especially in infants. The airway is often threatened. Surgery for nonmalignant tumors and surgery plus chemotherapy for malignant tumors can be curative.[16][Level of evidence C2]

Standard Treatment Options for Malignant Extragonadal Extracranial GCTs in Postpubertal Children

In a study of prognostic factors in pediatric extragonadal malignant GCTs, age older than 12 years was the most important prognostic factor. In a multivariate analysis, children aged 12 years and older with thoracic tumors had six times the risk of death compared with children younger than 12 years with primary nonthoracic tumors.[17] In a subsequent meta-analysis, adolescents with stage III and stage IV extragonadal disease had poor outcomes (expected EFS rate, <70%).[3] Extragonadal disease of any stage is considered a poor risk factor in adolescents and young adults.[18]

Standard treatment options for malignant extragonadal extracranial GCTs in postpubertal children include the following:

  1. Surgery.
  2. Chemotherapy (four cycles of bleomycin, etoposide, and cisplatin [BEP]).
  3. Chemotherapy followed by surgery to remove residual tumor.
  4. Enrollment in a clinical trial.

As with sacrococcygeal tumors, primary chemotherapy is usually necessary to facilitate surgical resection of mediastinal GCTs, and the completeness of resection is a very important prognostic indicator.[7,19] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally lower than 60%.[3,17,20–22]; [23][Level of evidence C1]

Patients with a malignant mediastinal primary tumor and extracranial metastases are at the highest risk of developing brain metastases and are monitored closely for signs and symptoms of central nervous system involvement.[24][Level of evidence C1] For more information about the treatment of adult patients, see Extragonadal Germ Cell Tumors Treatment.

Treatment Options Under Clinical Evaluation for Malignant Extragonadal Extracranial GCTs

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. AGCT1531 (NCT03067181) (Active Surveillance, Bleomycin, Carboplatin, Etoposide, or Cisplatin in Treating Pediatric and Adult Patients with GCTs): The aim of this trial is to reduce toxicity and maintain efficacy of treatment for patients with standard-risk GCTs. Patients with stage I malignant GCTs (low risk, age 0–50 years) will be treated with surgery and observation. Patients with intermediate-risk GCTs will be randomly assigned to receive cisplatin or carboplatin and bleomycin and etoposide. Children younger than 11 years will receive bleomycin with each cycle, and those aged 11 years and older will receive weekly bleomycin. Patients with pure seminoma or dysgerminoma are excluded from the trial.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Cushing B, Giller R, Cullen JW, et al.: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study–Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol 22 (13): 2691-700, 2004. [PUBMED Abstract]
  2. Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999. [PUBMED Abstract]
  3. Frazier AL, Hale JP, Rodriguez-Galindo C, et al.: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol 33 (2): 195-201, 2015. [PUBMED Abstract]
  4. Rogers PC, Olson TA, Cullen JW, et al.: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study–Pediatric Oncology Group 9048 and Children’s Cancer Group 8891. J Clin Oncol 22 (17): 3563-9, 2004. [PUBMED Abstract]
  5. Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000. [PUBMED Abstract]
  6. Malogolowkin MH, Krailo M, Marina N, et al.: Pilot study of cisplatin, etoposide, bleomycin, and escalating dose cyclophosphamide therapy for children with high risk germ cell tumors: a report of the children’s oncology group (COG). Pediatr Blood Cancer 60 (10): 1602-5, 2013. [PUBMED Abstract]
  7. Schneider DT, Calaminus G, Reinhard H, et al.: Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96. J Clin Oncol 18 (4): 832-9, 2000. [PUBMED Abstract]
  8. Göbel U, Schneider DT, Calaminus G, et al.: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 19 (7): 1943-50, 2001. [PUBMED Abstract]
  9. Rescorla F, Billmire D, Stolar C, et al.: The effect of cisplatin dose and surgical resection in children with malignant germ cell tumors at the sacrococcygeal region: a pediatric intergroup trial (POG 9049/CCG 8882). J Pediatr Surg 36 (1): 12-7, 2001. [PUBMED Abstract]
  10. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974. [PUBMED Abstract]
  11. Rescorla FJ, Sawin RS, Coran AG, et al.: Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Childrens Cancer Group. J Pediatr Surg 33 (2): 171-6, 1998. [PUBMED Abstract]
  12. Calaminus G, Schneider DT, Bökkerink JP, et al.: Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89. J Clin Oncol 21 (5): 781-6, 2003. [PUBMED Abstract]
  13. Egler RA, Gosiengfiao Y, Russell H, et al.: Is surgical resection and observation sufficient for stage I and II sacrococcygeal germ cell tumors? A case series and review. Pediatr Blood Cancer 64 (5): , 2017. [PUBMED Abstract]
  14. De Pasquale MD, Crocoli A, Conte M, et al.: Mediastinal Germ Cell Tumors in Pediatric Patients: A Report From the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer 63 (5): 808-12, 2016. [PUBMED Abstract]
  15. Billmire D, Vinocur C, Rescorla F, et al.: Malignant retroperitoneal and abdominal germ cell tumors: an intergroup study. J Pediatr Surg 38 (3): 315-8; discussion 315-8, 2003. [PUBMED Abstract]
  16. Bernbeck B, Schneider DT, Bernbeck B, et al.: Germ cell tumors of the head and neck: report from the MAKEI Study Group. Pediatr Blood Cancer 52 (2): 223-6, 2009. [PUBMED Abstract]
  17. Marina N, London WB, Frazier AL, et al.: Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. J Clin Oncol 24 (16): 2544-8, 2006. [PUBMED Abstract]
  18. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997. [PUBMED Abstract]
  19. Billmire D, Vinocur C, Rescorla F, et al.: Malignant mediastinal germ cell tumors: an intergroup study. J Pediatr Surg 36 (1): 18-24, 2001. [PUBMED Abstract]
  20. Vuky J, Bains M, Bacik J, et al.: Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 19 (3): 682-8, 2001. [PUBMED Abstract]
  21. Ganjoo KN, Rieger KM, Kesler KA, et al.: Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors. Cancer 88 (5): 1051-6, 2000. [PUBMED Abstract]
  22. Bokemeyer C, Nichols CR, Droz JP, et al.: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 20 (7): 1864-73, 2002. [PUBMED Abstract]
  23. Kang CH, Kim YT, Jheon SH, et al.: Surgical treatment of malignant mediastinal nonseminomatous germ cell tumor. Ann Thorac Surg 85 (2): 379-84, 2008. [PUBMED Abstract]
  24. Göbel U, von Kries R, Teske C, et al.: Brain metastases during follow-up of children and adolescents with extracranial malignant germ cell tumors: risk adapted management decision tree analysis based on data of the MAHO/MAKEI-registry. Pediatr Blood Cancer 60 (2): 217-23, 2013. [PUBMED Abstract]

Treatment of Recurrent Malignant GCTs in Children

Only a small number of children and adolescents with extracranial germ cell tumors (GCTs) have a recurrence.[1,2] Reports regarding the treatment and outcome of these children are based on small studies.[3]

Treatment options for recurrent pediatric GCTs are modeled after treatment options in adult clinical trials. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.

Standard Treatment Options for Recurrent Malignant GCTs in Children

Standard treatment options for recurrent childhood malignant GCTs include the following:

  1. Surgery alone.
  2. Surgery with neoadjuvant or adjuvant chemotherapy.

For information about salvage therapy after observation for patients with stage I disease, see the following sections:

Surgery with neoadjuvant or adjuvant chemotherapy

Reports of salvage treatment strategies used in adult recurrent GCTs include larger numbers of patients, but the differences between children and adults regarding the location of the primary GCT site, pattern of relapse, and the biology of childhood GCTs may limit the applicability of adult salvage approaches to children. In adults with recurrent GCTs, several chemotherapy combinations (most include the addition of paclitaxel and ifosfamide to a platinum compound) have achieved relatively good disease-free status.[4–9] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular GCTs who relapsed after high-dose chemotherapy and hematopoietic stem cell transplant (HSCT).[10]

Among children with benign sacrococcygeal tumors who recur, a malignant component may be present at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and coccyx (if not done originally) is the basis of salvage treatment. Preoperative chemotherapy with cisplatin, etoposide, and bleomycin (PEb) may assist the surgical resection. In patients who had a malignant sacrococcygeal tumor that recurred after PEb treatment, surgery and additional chemotherapy may be warranted.[3]

In a phase II Children’s Oncology Group (COG) trial (AGCT0521 [NCT00467051]), 20 patients younger than 21 years who relapsed after PEb therapy received two cycles of paclitaxel, ifosfamide, and carboplatin (TIC). Responses were then assessed by a combination of Response Evaluation Criteria In Solid Tumors (RECIST) criteria and marker decline. Eight patients had partial responses, ten patients had stable disease, and two patients had progressive disease. This chemotherapy regimen produced a combined response rate of 44%.[11]

Nonstandard Treatment Options for Recurrent Malignant GCTs in Children

High-dose (HD) chemotherapy and hematopoietic stem cell rescue

The role of HD chemotherapy and hematopoietic stem cell rescue for recurrent pediatric GCTs is not established, despite anecdotal reports. In one European series, 10 of 23 children with relapsed extragonadal GCTs achieved long-term disease-free survival (median follow-up, 66 months) after receiving HD chemotherapy with stem cell support.[12] Additional study in children and adolescents is needed. For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.

HD chemotherapy with autologous stem cell rescue has been explored as a treatment for adults with recurrent testicular GCTs. HD chemotherapy plus hematopoietic stem cell rescue has been reported to cure adult patients with relapsed testicular GCTs, even as third-line therapy and in cisplatin-refractory patients.[10,13–15] A small study also demonstrated efficacy in adolescents and women with ovarian GCTs.[16][Level of evidence C1] While some studies support this approach,[10,14,15,17,18] others do not.[19,20] Salvage attempts using HD chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of HSCT.[13,21]

Radiation therapy followed by surgery (for brain metastases)

In a very small pediatric study, patients with nongerminomatous brain metastases responded to radiation therapy. In the German Maligne Keimzelltümoren (MAKEI) studies, radiation therapy and surgery for patients with brain metastases provided palliation and occasional long-term survival.[22,23][Level of evidence C1] A meta-analysis showed that radiation therapy did not improve outcome compared with surgery and radiation. However, the number of patients treated with radiation therapy was too small to accurately assess outcome.[24]

Treatment Options Under Clinical Evaluation for Recurrent Malignant GCTs in Children and Adolescents

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000. [PUBMED Abstract]
  2. Cushing B, Giller R, Cullen JW, et al.: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study–Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol 22 (13): 2691-700, 2004. [PUBMED Abstract]
  3. Schneider DT, Wessalowski R, Calaminus G, et al.: Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol 19 (7): 1951-60, 2001. [PUBMED Abstract]
  4. Loehrer PJ, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998. [PUBMED Abstract]
  5. Motzer RJ, Sheinfeld J, Mazumdar M, et al.: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18 (12): 2413-8, 2000. [PUBMED Abstract]
  6. Hartmann JT, Einhorn L, Nichols CR, et al.: Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol 19 (6): 1641-8, 2001. [PUBMED Abstract]
  7. Kondagunta GV, Bacik J, Sheinfeld J, et al.: Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 25 (1): 85-90, 2007. [PUBMED Abstract]
  8. Schmoll HJ, Kollmannsberger C, Metzner B, et al.: Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21 (22): 4083-91, 2003. [PUBMED Abstract]
  9. Kondagunta GV, Bacik J, Bajorin D, et al.: Etoposide and cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 23 (36): 9290-4, 2005. [PUBMED Abstract]
  10. Einhorn LH, Brames MJ, Juliar B, et al.: Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 25 (5): 513-6, 2007. [PUBMED Abstract]
  11. Pashankar F, Frazier AL, Krailo M, et al.: Treatment of refractory germ cell tumors in children with paclitaxel, ifosfamide, and carboplatin: A report from the Children’s Oncology Group AGCT0521 study. Pediatr Blood Cancer 65 (8): e27111, 2018. [PUBMED Abstract]
  12. De Giorgi U, Rosti G, Slavin S, et al.: Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 93 (4): 412-7, 2005. [PUBMED Abstract]
  13. Einhorn LH, Williams SD, Chamness A, et al.: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357 (4): 340-8, 2007. [PUBMED Abstract]
  14. Motzer RJ, Mazumdar M, Sheinfeld J, et al.: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18 (6): 1173-80, 2000. [PUBMED Abstract]
  15. Rick O, Bokemeyer C, Beyer J, et al.: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19 (1): 81-8, 2001. [PUBMED Abstract]
  16. Meisel JL, Woo KM, Sudarsan N, et al.: Development of a risk stratification system to guide treatment for female germ cell tumors. Gynecol Oncol 138 (3): 566-72, 2015. [PUBMED Abstract]
  17. Bhatia S, Abonour R, Porcu P, et al.: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18 (19): 3346-51, 2000. [PUBMED Abstract]
  18. Feldman DR, Sheinfeld J, Bajorin DF, et al.: TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol 28 (10): 1706-13, 2010. [PUBMED Abstract]
  19. Beyer J, Rick O, Siegert W, et al.: Salvage chemotherapy in relapsed germ cell tumors. World J Urol 19 (2): 90-3, 2001. [PUBMED Abstract]
  20. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996. [PUBMED Abstract]
  21. Rick O, Bokemeyer C, Weinknecht S, et al.: Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer. J Clin Oncol 22 (18): 3713-9, 2004. [PUBMED Abstract]
  22. Göbel U, von Kries R, Teske C, et al.: Brain metastases during follow-up of children and adolescents with extracranial malignant germ cell tumors: risk adapted management decision tree analysis based on data of the MAHO/MAKEI-registry. Pediatr Blood Cancer 60 (2): 217-23, 2013. [PUBMED Abstract]
  23. Göbel U, Schneider DT, Teske C, et al.: Brain metastases in children and adolescents with extracranial germ cell tumor – data of the MAHO/MAKEI-registry. Klin Padiatr 222 (3): 140-4, 2010. [PUBMED Abstract]
  24. Feldman DR, Lorch A, Kramar A, et al.: Brain Metastases in Patients With Germ Cell Tumors: Prognostic Factors and Treatment Options–An Analysis From the Global Germ Cell Cancer Group. J Clin Oncol 34 (4): 345-51, 2016. [PUBMED Abstract]

Latest Updates to This Summary (11/05/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood extracranial germ cell tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Extracranial Germ Cell Tumors Treatment are:

  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta – Egleston Campus)
  • D. Williams Parsons, MD, PhD (Texas Children’s Hospital)
  • Stephen J. Shochat, MD (St. Jude Children’s Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/extracranial-germ-cell/hp/germ-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389316]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Extragonadal Germ Cell Tumors—Patient Version

Extragonadal Germ Cell Tumors—Patient Version

Overview

Extragonadal germ cell tumors develop from germ cells (fetal cells that give rise to sperm and eggs). Extragonadal germ cell tumors form outside the gonads (testicles and ovaries). Explore the links on this page to learn more about extragonadal germ cell tumors, how they are treated, and clinical trials that are available.

Treatment

PDQ Treatment Information for Patients

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of extragonadal germ cell tumors.

More information

Screening

NCI does not have PDQ evidence-based information about screening for extragonadal germ cell tumors.

More information

Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

Emotions and Cancer Adjusting to Cancer Support for Caregivers Survivorship Advanced Cancer Managing Cancer Care

Extracranial Germ Cell Tumors—Patient Version

Extracranial Germ Cell Tumors—Patient Version

Overview

Extracranial germ cell tumors are tumors that develop from germ cells (fetal cells that give rise to sperm and eggs) and can form in many parts of the body. They are most common in teenagers and can often be cured. Explore the links on this page to learn more about extracranial germ cell tumors, how they are treated, and clinical trials that are available.

Treatment

PDQ Treatment Information for Patients

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of extracranial germ cell tumors.

More information

Screening

NCI does not have PDQ evidence-based information about screening for extracranial germ cell tumors.

More information

Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

Emotions and Cancer Adjusting to Cancer Support for Caregivers Survivorship Advanced Cancer Managing Cancer Care

Extracranial Germ Cell Tumors—Health Professional Version

Extracranial Germ Cell Tumors—Health Professional Version

Treatment

PDQ Treatment Information for Health Professionals

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of extracranial germ cell tumors.

More information

Screening

NCI does not have PDQ evidence-based information about screening for extracranial germ cell tumors.

More information

Supportive & Palliative Care

We offer evidence-based supportive and palliative care information for health professionals on the assessment and management of cancer-related symptoms and conditions.

Cancer Pain Nausea and Vomiting Nutrition in Cancer Care Transition to End-of-Life Care Last Days of Life View all Supportive and Palliative Care Summaries

Esophageal Cancer Research

Esophageal Cancer Research

Preoperative Chemotherapy, Radiation Improve Survival in Esophageal Cancer (Updated)

Preoperative Chemotherapy, Radiation Improve Survival in Esophageal Cancer (Updated)

Patients with esophageal cancer who received chemotherapy and radiation before surgery survived, on average, nearly twice as long as patients treated with surgery alone. The findings, from a large randomized trial of neoadjuvant chemoradiotherapy for the disease, were published May 31, 2012, in the New England Journal of Medicine.

Patients treated with carboplatin and paclitaxel chemotherapy plus radiation prior to surgery had a median overall survival of nearly 50 months, compared with 24 months for patients treated with surgery alone.

Pieter van Hagen, M.D., of Erasmus University Medical Center and his colleagues enrolled 368 patients who had cancer of the esophagus or of the junction between the stomach and the esophagus that had not spread to other organs. Participants in the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) were mostly men, and the median age was 60. Patients benefited from preoperative therapy regardless of whether they had adenocarcinoma, the most prevalent form of esophageal cancer in the United States, or squamous cell carcinoma, the most prevalent form of the disease worldwide.

Previous trials to test the superiority of preoperative chemotherapy and radiation in esophageal cancer failed to enroll enough patients to reach definitive conclusions. “The successful completion of this trial is an impressive effort, and the results should be considered high-level evidence in favor of this preoperative regimen,” commented Jack Welch, M.D., Ph.D., head of gastrointestinal therapeutics for NCI’s Cancer Therapy Evaluation Program, who was not involved in the study.

Patients randomly assigned to the chemoradiotherapy arm of the study received five courses of chemotherapy with carboplatin and paclitaxel plus concurrent external-beam radiation therapy, followed by surgery, usually within 4 to 6 weeks of completing preoperative treatment. This preoperative regimen has been widely adopted in the United States within the past year and has also been adopted as a standard therapy in some trials being conducted by NCI-supported cooperative groups, Dr. Welch said. For example, a phase III trial is testing a combination of neoadjuvant chemoradiotherapy with the targeted agent trastuzumab in patients whose tumors express the HER2 biomarker, explained Dr. Welch.

In another study, patients initially treated with chemotherapy based either on the Dutch study regimen or an alternative regimen are being assessed with PET scans; those who do not respond are switched to the other therapy, which is then combined with radiation. In both studies, researchers are trying to tailor the chemoradiation regimen used in Dr. van Hagen’s study to obtain the best possible result for individual patients, Dr. Welch said.

Update:

Long-term results from the CROSS trial, published August 5, 2015, in Lancet Oncology, confirmed the overall survival benefit of adding neoadjuvant chemoradiotherapy to surgery that was reported in 2012. With a median follow-up of 84.1 months, the median overall survival was 48.6 months for patients who received neoadjuvant chemoradiotherapy plus surgery and 24.0 months for patients who received surgery alone. At the longer follow-up, patients continued to benefit from preoperative therapy, regardless of whether they had adenocarcinoma or squamous cell carcinoma.

Gastrointestinal Stromal Tumors Treatment (PDQ®)–Health Professional Version

Gastrointestinal Stromal Tumors Treatment (PDQ®)–Health Professional Version

General Information About Gastrointestinal Stromal Tumors (GISTs)

Go to Patient Version

Incidence

GISTs comprise less than 1% of all gastrointestinal (GI) tumors but are the most common mesenchymal tumors of the GI tract.[1–3] There are estimated to be over 6,000 new GIST cases per year in the United States, with an age-adjusted yearly incidence of 6.78 per million from 2001 to 2011. GISTs can affect patients of all ages but are most predominant in older adults (median age, 65–69 years).[4,5] Globally, GISTs affect men and women with equal frequency. Geographically, GISTs are most prevalent in China (Shanghai), Taiwan, Korea, and Norway.[5] In the United States, GISTs are more commonly diagnosed in Black Americans (13.7 per million) and Asian or Pacific Islander Americans (11 per million) than in White Americans (6.5 per million).[4]

The true incidence is not known, in part, because small indolent GISTs (i.e., <1 cm) are either not clinically apparent or are not included in cancer registries.[5–7]

Most GISTs are sporadic, but there are rare familial forms associated with neurofibromatosis type 1 (NF1) or heritable variants in KIT and SDH.[2,3] GISTs rarely affect children and young adults (<1% of cases), with a median age of 15 years. Those cases are nearly always associated with an underlying genetic predisposition.[8,9] For more information, see Childhood Gastrointestinal Stromal Tumors Treatment.

Clinical Presentation

GISTs can occur anywhere along the GI tract, but most often are found in the stomach or small intestine. The American Joint Committee on Cancer (AJCC) Cancer Staging Manual lists the following approximate distributions:[10]

  • Stomach (60%).
  • Small intestine, jejunum, and ileum (30%).
  • Duodenum (5%).
  • Rectum (3%).
  • Colon (1%).
  • Esophagus (<1%).
  • Disseminated tumors without a known primary (rare).
  • Omentum/mesentery (rare).
EnlargeDrawing of the gastrointestinal tract showing the esophagus, stomach, colon, small intestine, and rectum. An inset shows the greater omentum (part of the tissue that surrounds the stomach and other organs in the abdomen).
Gastrointestinal stromal tumors (GISTs) may be found anywhere in or near the gastrointestinal tract.

GISTs range in size from less than 1 cm to more than 40 cm, with an average size of approximately 5 cm when diagnosed clinically. They typically arise within the muscle wall of the GI tract.[11] Small GISTs may form solid subserosal, intramural, or, less frequently, polypoid intraluminal masses. Large tumors tend to form external masses attached to the outer aspect of the bowel wall involving the muscular layers.[11]

The clinical presentation of patients with GISTs varies depending on the following:[12,13]

  • Anatomical location.
  • Tumor size.
  • Rate of tumor growth.

The signs and symptoms of GISTs include:

  • GI bleeding (most common presentation), which may be acute (melena or hematemesis) or chronic, resulting in anemia.
  • Acute tumor rupture.
  • GI obstruction.
  • Pain.
  • Dysphagia.
  • Early satiety.

Smaller lesions may be found incidentally during surgery, radiological studies, or endoscopy. The natural history of these incidental tumors and the frequency of progression to symptomatic disease are unknown. There may be a substantial reservoir of small GISTs that do not progress to symptomatic stages.

Common sites of metastasis include the liver and peritoneal dissemination within the abdominal cavity. In adults, lymph node involvement and spread to the lungs or other extra-abdominal sites is unusual.[14]

Rare paraneoplastic consumptive hypothyroidism (from overexpression of a thyroid-inactivating enzyme) has been reported in a few patients.[15]

Pediatric GISTs are typically associated with germline SDH loss. The clinical behavior is distinct with typically a gastric location, more indolent course, multifocal presentation, and lymph node metastases. Germline SDH loss is also associated with hereditary kidney cancer, paragangliomas, and other tumors.[16,17]

Diagnostic Evaluation

GISTs should be included in the differential diagnosis of any intra-abdominal nonepithelial malignancy. Standard diagnostic interventions may include:[12]

  • Computed tomography (CT).
  • Magnetic resonance imaging (MRI).
  • Positron emission tomography (PET).
  • Endoscopy.

Endoscopic ultrasound with fine-needle aspiration (FNA) biopsy is useful in the diagnosis of GISTs in the upper GI tract, as most tumors arise below the mucosal layer and grow in an endophytic fashion. Endoscopic ultrasound–guided FNA biopsy is preferred to percutaneous biopsy, given the risk of tumor hemorrhage and peritoneal dissemination.[12,18,19] For localized resectable GISTs with classic imaging findings, some surgeons proceed directly to surgery without biopsy.

Prognosis

Prognostic factors for nonmetastatic GISTs include:

  • Mitotic index.
  • Tumor size.
  • Tumor location (gastric, nongastric, rectal).
  • Tumor rupture.
  • Imaging characteristics.

Approximately 20% to 25% of gastric GISTs and 40% to 50% of small intestinal GISTs are clinically aggressive.[13,20] It is estimated that approximately 10% to 25% of patients present with metastatic disease.[14,20] For nonmetastatic GISTs, the key parameters that impact the risk of recurrence or metastasis include mitotic index (mitoses per 50 high-power fields), tumor size, and tumor location (see Table 1).[11,21–25]

It is also recognized that tumor rupture markedly worsens recurrence-free survival.[26–28] In addition, tumor appearance on CT imaging may predict recurrence risk. Tumors with higher metastatic risk include lobulated or heterogeneously enhancing tumors, as well as those with mesenteric fat infiltration, ulceration, regional lymphadenopathy, or exophytic growth.[29–32]

Table 1. Risk Assessment of Gastric GISTs by Tumor Size and Mitotic Indexa
Mitotic Index (mitoses/HPF) Size (cm) Metastasis Rate (%) Risk of Progressive Disease
GISTs = gastrointestinal stromal tumors; HPF = high-power field.
aAdapted from Miettinen et al.[25] and Laurini et al.[33]
≤5 per 50 ≤2 0 None
>2 to ≤5 1.9 Very low
>5 to ≤10 3.6 Low
>10 12 Moderate
>5 per 50 ≤2 0 None
>2 to ≤5 16 Moderate
>5 to ≤10 55 High
>10 86 High
Table 2. Risk Assessment of Nongastric GISTs by Tumor Size and Mitotic Indexa
Mitotic Index (mitoses/HPF) Size (cm) Metastasis Rate (%) Risk of Progressive Disease
GISTs = gastrointestinal stromal tumors; HPF = high-power field.
aAdapted from Miettinen et al.[25] and Laurini et al.[33]
≤5 per 50 ≤2 0 None
>2 to ≤5 1.9–8.5 Low
>5 to ≤10 24 Insufficient data–Moderate
>10 34–52 High
>5 per 50 ≤2 50–54 Insufficient data–High
>2 to ≤5 50–73 High
>5 to ≤10 85 High
>10 71–90 High

Follow-Up

Response to therapy

CT, fluorine F 18-fludeoxyglucose (18F-FDG) PET, and MRI are used to monitor the effects of systemic therapy in patients with unresectable, metastatic, or recurrent disease.[34]

A baseline PET should be performed before tyrosine kinase inhibitor (TKI) therapy in patients who will be monitored for response with 18F-FDG PET. PET imaging may detect the activity of imatinib in GISTs much earlier than CT imaging, with decreased tumor avidity detected as soon as 24 hours after the first dose. Thus, PET may be a useful diagnostic modality for the very early assessment of response to imatinib therapy and for detecting resistance to TKIs.[12]

Surveillance for metastatic or recurrent disease

The optimal modality and frequency for surveillance of metastatic or recurrent disease in patients who have undergone GIST resection has not been studied. Based on the likelihood of recurrence, follow-up recommendations are derived from expert opinion and clinical judgment.

For patients with surgically treated localized disease, routine follow-up schedules may differ across institutions and depend on the risk status of the tumor.[35] Abdominal/pelvic imaging may be performed every 3 to 6 months, but very low-risk lesions may not need to be imaged this frequently.[35]

References
  1. Judson I, Demetri G: Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol 18 (Suppl 10): x20-4, 2007. [PUBMED Abstract]
  2. Miettinen M, Lasota J: Gastrointestinal stromal tumors–definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 438 (1): 1-12, 2001. [PUBMED Abstract]
  3. Miettinen M, Sarlomo-Rikala M, Lasota J: Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 30 (10): 1213-20, 1999. [PUBMED Abstract]
  4. Ma GL, Murphy JD, Martinez ME, et al.: Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev 24 (1): 298-302, 2015. [PUBMED Abstract]
  5. Søreide K, Sandvik OM, Søreide JA, et al.: Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. Cancer Epidemiol 40: 39-46, 2016. [PUBMED Abstract]
  6. Kawanowa K, Sakuma Y, Sakurai S, et al.: High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 37 (12): 1527-35, 2006. [PUBMED Abstract]
  7. Agaimy A, Wünsch PH, Hofstaedter F, et al.: Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol 31 (1): 113-20, 2007. [PUBMED Abstract]
  8. Benesch M, Wardelmann E, Ferrari A, et al.: Gastrointestinal stromal tumors (GIST) in children and adolescents: A comprehensive review of the current literature. Pediatr Blood Cancer 53 (7): 1171-9, 2009. [PUBMED Abstract]
  9. Joensuu H, Hohenberger P, Corless CL: Gastrointestinal stromal tumour. Lancet 382 (9896): 973-83, 2013. [PUBMED Abstract]
  10. Gastrointestinal stromal tumor. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 523–9.
  11. Corless CL, Heinrich MC: Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol 3: 557-86, 2008. [PUBMED Abstract]
  12. Casali PG, Dei Tos AP, Gronchi A: Gastrointestinal stromal tumor. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 895-906.
  13. Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130 (10): 1466-78, 2006. [PUBMED Abstract]
  14. DeMatteo RP, Lewis JJ, Leung D, et al.: Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231 (1): 51-8, 2000. [PUBMED Abstract]
  15. Maynard MA, Marino-Enriquez A, Fletcher JA, et al.: Thyroid hormone inactivation in gastrointestinal stromal tumors. N Engl J Med 370 (14): 1327-34, 2014. [PUBMED Abstract]
  16. Janeway KA, Pappo A: Treatment guidelines for gastrointestinal stromal tumors in children and young adults. J Pediatr Hematol Oncol 34 (Suppl 2): S69-72, 2012. [PUBMED Abstract]
  17. Miettinen M, Lasota J, Sobin LH: Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. Am J Surg Pathol 29 (10): 1373-81, 2005. [PUBMED Abstract]
  18. Nickl NJ: Gastrointestinal stromal tumors: new progress, new questions. Curr Opin Gastroenterol 20 (5): 482-7, 2004. [PUBMED Abstract]
  19. Vander Noot MR, Eloubeidi MA, Chen VK, et al.: Diagnosis of gastrointestinal tract lesions by endoscopic ultrasound-guided fine-needle aspiration biopsy. Cancer 102 (3): 157-63, 2004. [PUBMED Abstract]
  20. Joensuu H: Gastrointestinal stromal tumor (GIST). Ann Oncol 17 (Suppl 10): x280-6, 2006. [PUBMED Abstract]
  21. Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29 (1): 52-68, 2005. [PUBMED Abstract]
  22. Miettinen M, Makhlouf H, Sobin LH, et al.: Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol 30 (4): 477-89, 2006. [PUBMED Abstract]
  23. Miettinen M, Kopczynski J, Makhlouf HR, et al.: Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol 27 (5): 625-41, 2003. [PUBMED Abstract]
  24. Miettinen M, Furlong M, Sarlomo-Rikala M, et al.: Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 25 (9): 1121-33, 2001. [PUBMED Abstract]
  25. Miettinen M, Lasota J: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23 (2): 70-83, 2006. [PUBMED Abstract]
  26. Hohenberger P, Ronellenfitsch U, Oladeji O, et al.: Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br J Surg 97 (12): 1854-9, 2010. [PUBMED Abstract]
  27. Hølmebakk T, Bjerkehagen B, Boye K, et al.: Definition and clinical significance of tumour rupture in gastrointestinal stromal tumours of the small intestine. Br J Surg 103 (6): 684-691, 2016. [PUBMED Abstract]
  28. Joensuu H: Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39 (10): 1411-9, 2008. [PUBMED Abstract]
  29. Chun HJ, Byun JY, Chun KA, et al.: Gastrointestinal leiomyoma and leiomyosarcoma: CT differentiation. J Comput Assist Tomogr 22 (1): 69-74, 1998 Jan-Feb. [PUBMED Abstract]
  30. Levy AD, Remotti HE, Thompson WM, et al.: Gastrointestinal stromal tumors: radiologic features with pathologic correlation. Radiographics 23 (2): 283-304, 456; quiz 532, 2003 Mar-Apr. [PUBMED Abstract]
  31. Ghanem N, Altehoefer C, Furtwängler A, et al.: Computed tomography in gastrointestinal stromal tumors. Eur Radiol 13 (7): 1669-78, 2003. [PUBMED Abstract]
  32. Burkill GJ, Badran M, Al-Muderis O, et al.: Malignant gastrointestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread. Radiology 226 (2): 527-32, 2003. [PUBMED Abstract]
  33. Laurini JA, et al.: Protocol For the Examination of Resection Specimens From Patients With Gastrointestinal Stromal Tumor (GIST) Version 4.2.0.0. College of American Pathologists, 2021. Available online. Last accessed December 13, 2024.
  34. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
  35. Casali PG, Jost L, Reichardt P, et al.: Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 19 (Suppl 2): ii35-8, 2008. [PUBMED Abstract]

Cellular and Molecular Classification of GISTs

Gastrointestinal stromal tumors (GISTs) appear to originate from interstitial cells of Cajal (ICC) or their stem cell-like precursors.[1–4] ICC are pacemaker-like intermediates between the gastrointestinal (GI) autonomic nervous system and smooth muscle cells regulating GI motility and autonomic nerve function.[5,6] ICC are located around the myenteric plexus and the muscularis propria throughout the GI tract. ICC or their stem cell-like precursors can differentiate into smooth muscle cells if KIT signaling is disrupted.[7]

GISTs are composed of spindle cells (70%), epithelioid cells (20%), or mixed spindle and epithelioid cells (10%).[8] The histological patterns range from bland-appearing tumors with very low mitotic activity to very aggressive-appearing patterns.[9]

Approximately 85% of GISTs contain oncogenic variants in one of two receptor tyrosine kinases (RTKs):[10,11]

  • KIT.
  • PDGFRA.

Constitutive activation of either of these RTKs plays a central role in the pathogenesis of GISTs.[1,12] Tumors without detectable KIT or PDGFRA variants account for 12% to 15% of all GISTs. Less than 5% of GISTs occur in patients with syndromic diseases, such as neurofibromatosis type 1 (NF1), Carney triad syndrome (SDH deletion), and other familial diseases.[10,13–15]

Approximately 95% of GISTs are positive for the CD117 antigen, an epitope of KIT RTK expressed by ICC.[10] However, CD117 immunohistochemistry (IHC) is not specific for GISTs and can be seen in other mesenchymal, neural, and neuroendocrine neoplasms.[10] IHC staining for DOG1 helps distinguish GISTs from other mesenchymal tumors, particularly those that are KIT negative.[10,16–18]

Subtypes of GISTs include:

  • KIT-variant GISTs. Approximately 80% of all GISTs contain a variant in the KIT gene that results in constitutive activation.[10] The KIT gene maps to 4q12-13, in the vicinity of genes encoding the RTKs PDGFRA and VEGFR2.[19] Variants in five different KIT exons have been observed in GISTs: exon 11 (67%), exon 9 (10%), and exons 8, 13, and 17 (3%).[10,20] Typically, GISTs are heterozygous for a particular variant, but loss of the remaining wild-type KIT allele occurs in approximately 8% to 15% of tumors and may be associated with malignant progression.[20–22] KIT variants exhibit distinct anatomical distributions: exon 8 (small bowel), exon 9 (small bowel, colon), and exons 11, 13, and 17 (all sites).[10] KIT-variant tumors express PKC theta and DOG1, a distinguishing feature of mesenchymal tumors.[17,18,23]
  • PDGFRA-variant GISTs. Approximately 5% to 8% of GISTs harbor a variant in PDGFRA, a close homolog of KIT with similar extracellular and cytoplasmic domains.[12] PDGFRA-variant GISTs may differ from KIT-variant GISTs in a number of ways, including a marked predilection for the stomach, epithelioid morphology, myxoid stroma, nuclear pleomorphism, and variable expression of CD117.[23–28] As with KIT-variant GISTs, PDGFRA-variant tumors express PKC theta and DOG1.[17,18,24] A PDGFRA variant most commonly occurs in exon 18 (80%–90%), and it can be either a D842V (62%) or non-D842V (27%) variant. PDGFRA D842V variants confer resistance to imatinib therapy.[29]
  • KIT-negative GISTs. In approximately 5% of GISTs, IHC for CD117 is completely negative or uncertain. In these instances, IHC may lack sufficient sensitivity to detect small amounts of variant kinase.[10] Approximately 30% of these tumors harbor PDGFRA pathogenic variants while more than one-half have KIT variants.[10,24,25,28]
  • KIT/PDGFRA wild-type GISTs. The so-called wild-type GISTs comprise approximately 12% to 15% of all GISTs. In these tumors, no detectable variants have been identified in either KIT or PDGFRA. Many of these tumors are SDH-deficient or associated with NF1.
    • SDH-deficient GISTs are characterized by loss-of-function of one of more enzymes within the SDH family (SDHA–D, collectively termed SDHx) either by variant, such as in Carney-Stratakis syndrome, or epigenetic silencing, such as in Carney triad (gastric epithelioid GISTs, extra-adrenal paraganglioma, and pulmonary chondroma). SDH-deficient GISTs can be identified with IHC by an absence of SDHB. SDH-deficient GISTs are generally found in younger patients, are typically multifocal, and are located in the stomach. They also tend to have an indolent course and are poorly responsive to tyrosine kinase inhibitor therapy.[13–15,30]
    • NF1-related GISTs have a propensity for multicentricity within the GI tract and spindle cell morphology. They are typically positive for the CD117 antigen but do not harbor KIT or PDGFRA variants.[13] The clinical course is typically indolent.
    • Other variants seen in KIT/PDGFRA wild-type GISTs include BRAF V600E [31,32] and NTRK.[33]
  • Familial GISTs. Approximately two dozen kindreds with heritable variants in KIT or PDGFRA have been identified. Penetrance in these kindreds is high, with most affected members developing one or more GISTs by middle age. However, in many patients, the tumors follow a benign course.[10]
References
  1. Hirota S, Isozaki K, Moriyama Y, et al.: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279 (5350): 577-80, 1998. [PUBMED Abstract]
  2. Kindblom LG, Remotti HE, Aldenborg F, et al.: Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152 (5): 1259-69, 1998. [PUBMED Abstract]
  3. Wang L, Vargas H, French SW: Cellular origin of gastrointestinal stromal tumors: a study of 27 cases. Arch Pathol Lab Med 124 (10): 1471-5, 2000. [PUBMED Abstract]
  4. Sircar K, Hewlett BR, Huizinga JD, et al.: Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol 23 (4): 377-89, 1999. [PUBMED Abstract]
  5. Maeda H, Yamagata A, Nishikawa S, et al.: Requirement of c-kit for development of intestinal pacemaker system. Development 116 (2): 369-75, 1992. [PUBMED Abstract]
  6. Huizinga JD, Thuneberg L, Klüppel M, et al.: W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373 (6512): 347-9, 1995. [PUBMED Abstract]
  7. Torihashi S, Nishi K, Tokutomi Y, et al.: Blockade of kit signaling induces transdifferentiation of interstitial cells of cajal to a smooth muscle phenotype. Gastroenterology 117 (1): 140-8, 1999. [PUBMED Abstract]
  8. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 22 (18): 3813-25, 2004. [PUBMED Abstract]
  9. Gastrointestinal stromal tumor. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 523–9.
  10. Corless CL, Heinrich MC: Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol 3: 557-86, 2008. [PUBMED Abstract]
  11. Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130 (10): 1466-78, 2006. [PUBMED Abstract]
  12. Heinrich MC, Corless CL, Duensing A, et al.: PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299 (5607): 708-10, 2003. [PUBMED Abstract]
  13. Andersson J, Sihto H, Meis-Kindblom JM, et al.: NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol 29 (9): 1170-6, 2005. [PUBMED Abstract]
  14. Agaimy A, Pelz AF, Corless CL, et al.: Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization. Oncol Rep 18 (1): 9-15, 2007. [PUBMED Abstract]
  15. Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74 (6): 543-52, 1999. [PUBMED Abstract]
  16. Blay P, Astudillo A, Buesa JM, et al.: Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clin Cancer Res 10 (12 Pt 1): 4089-95, 2004. [PUBMED Abstract]
  17. Duensing A, Joseph NE, Medeiros F, et al.: Protein Kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Res 64 (15): 5127-31, 2004. [PUBMED Abstract]
  18. West RB, Corless CL, Chen X, et al.: The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 165 (1): 107-13, 2004. [PUBMED Abstract]
  19. Stenman G, Eriksson A, Claesson-Welsh L: Human PDGFA receptor gene maps to the same region on chromosome 4 as the KIT oncogene. Genes Chromosomes Cancer 1 (2): 155-8, 1989. [PUBMED Abstract]
  20. Heinrich MC, Corless CL, Demetri GD, et al.: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21 (23): 4342-9, 2003. [PUBMED Abstract]
  21. O’Riain C, Corless CL, Heinrich MC, et al.: Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features. Am J Surg Pathol 29 (12): 1680-3, 2005. [PUBMED Abstract]
  22. Antonescu CR, Besmer P, Guo T, et al.: Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11 (11): 4182-90, 2005. [PUBMED Abstract]
  23. Wasag B, Debiec-Rychter M, Pauwels P, et al.: Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site. Mod Pathol 17 (8): 889-94, 2004. [PUBMED Abstract]
  24. Debiec-Rychter M, Wasag B, Stul M, et al.: Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. J Pathol 202 (4): 430-8, 2004. [PUBMED Abstract]
  25. Medeiros F, Corless CL, Duensing A, et al.: KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 28 (7): 889-94, 2004. [PUBMED Abstract]
  26. Sakurai S, Hasegawa T, Sakuma Y, et al.: Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations: a subtype of GIST with mutations of platelet-derived growth factor receptor alpha gene. Hum Pathol 35 (10): 1223-30, 2004. [PUBMED Abstract]
  27. Wardelmann E, Hrychyk A, Merkelbach-Bruse S, et al.: Association of platelet-derived growth factor receptor alpha mutations with gastric primary site and epithelioid or mixed cell morphology in gastrointestinal stromal tumors. J Mol Diagn 6 (3): 197-204, 2004. [PUBMED Abstract]
  28. Pauls K, Merkelbach-Bruse S, Thal D, et al.: PDGFRalpha- and c-kit-mutated gastrointestinal stromal tumours (GISTs) are characterized by distinctive histological and immunohistochemical features. Histopathology 46 (2): 166-75, 2005. [PUBMED Abstract]
  29. Corless CL, Schroeder A, Griffith D, et al.: PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23 (23): 5357-64, 2005. [PUBMED Abstract]
  30. Boikos SA, Pappo AS, Killian JK, et al.: Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2 (7): 922-8, 2016. [PUBMED Abstract]
  31. Agaram NP, Wong GC, Guo T, et al.: Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47 (10): 853-9, 2008. [PUBMED Abstract]
  32. Hostein I, Faur N, Primois C, et al.: BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol 133 (1): 141-8, 2010. [PUBMED Abstract]
  33. Atiq MA, Davis JL, Hornick JL, et al.: Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST). Mod Pathol 34 (1): 95-103, 2021. [PUBMED Abstract]

Stage Information for GISTs

A formal staging system for gastrointestinal stromal tumors (GISTs) is available from the American Joint Committee on Cancer (AJCC) Staging Manual. In practice, however, AJCC staging is not routinely implemented when risk assessment is determined by the clinical features noted in the Prognosis section.[1]

References
  1. Gastrointestinal stromal tumor. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 523–9.

Treatment Option Overview for GISTs

The management of patients with gastrointestinal stromal tumors (GISTs) is a multidisciplinary effort involving close collaboration between pathologists, medical oncologists, surgeons, and imaging experts.[1]

Surgery

Surgical resection is the primary treatment modality for the following types of patients:[2][Level of evidence C2]

  • Those with primary GISTs who do not have evidence of metastasis.
  • Those with tumors that are technically resectable (e.g., GISTs that do not require a formal gastrectomy, pancreatectomy, or other major organ resection) if the risks of morbidity are acceptable.

Endoscopic surveillance is an option for patients with tumors measuring 2 cm or smaller with a mitotic index of 5 or less per 50 high-power fields. The low rates of progression and metastasis in these tumors make endoscopic surveillance viable in place of surgical resection.[3]

The goal of surgery is complete gross resection with an intact pseudocapsule and negative microscopic margins.[4] Because GISTs are generally encapsulated and relatively less infiltrative than other malignancies, wide excision is not necessary. Lymphadenectomy is typically unnecessary, given that lymph node metastasis is rare with GISTs. However, lymphadenectomy should be considered in patients with SDH-deficient GISTs and pathologically enlarged lymph nodes.

If anatomically feasible, laparoscopic surgery is increasingly performed instead of laparotomy. Reports demonstrate lower rates of recurrence, shorter hospital stays, and lower morbidity.[5–8]

Neoadjuvant imatinib therapy can be given to patients with large tumors or difficult-to-access GISTs that are considered marginally resectable. Significant tumor shrinkage is often seen with targeted therapy, so this approach can potentially avoid major organ resection, or enable organ-sparing surgery. Genetic sequencing may be considered to identify sensitive or resistant variants prior to neoadjuvant imatinib therapy.

For patients with oligometastatic recurrences (e.g., isolated intra-abdominal implants or solitary liver lesions), surgical resection may be used in conjunction with tyrosine kinase inhibitors (TKIs).[9,10][Level of evidence C1] This should only be considered after multidisciplinary consultation.

Chemotherapy

There is universal agreement that standard chemotherapy has no role in the primary therapy of GISTs.[4,11,12]

Before the advent of molecularly targeted therapy with TKIs, efforts to treat GISTs with conventional cytotoxic chemotherapy were essentially futile.[1] The extreme resistance of GISTs to chemotherapy may be partly caused by the increased expression of P-glycoprotein, the product of the MDR-1 gene, and MRP1, which are cellular efflux pumps that may prevent chemotherapeutic agents from reaching therapeutic intracellular concentrations in GIST cells.[1,13]

Tyrosine Kinase Inhibitor (TKI) Therapy

TKIs work by inhibiting aberrantly functioning KIT or PDGFRA receptor tyrosine kinases and inducing rapid reduction in tumor growth. TKI therapy is indicated for patients with unresectable, borderline resectable, metastatic, or recurrent GISTs. It is also indicated as adjuvant therapy for patients with GISTs at high risk of recurrence.

The TKI imatinib mesylate is used as first-line therapy for most patients with KIT– and PDGFRA-variant GISTs.[14] For patients with GISTs characterized by a PDGFRA D842V variant, avapritinib is used as first-line therapy, given the high clinical benefit and imatinib-resistance in this subtype.[15] Other TKI agents approved for subsequent lines of therapy in patients with KIT/PDGFRA-variant GISTs include sunitinib, regorafenib, and ripretinib. Additional TKI agents that are occasionally given include nilotinib, sorafenib, and pazopanib.

Imatinib is not typically given to patients with KIT/PDGFRA wild-type GISTs (i.e., SDH-deficient or neurofibromatosis type 1 [NF1]-related GISTs) because of high rates of resistance. Other TKIs (i.e., sunitinib or regorafenib) may have some activity, but most patients are recommended to consider enrolling in clinical trials, if eligible.

For more information on the efficacy, safety, and management of toxicity of imatinib, or additional agents in the setting of imatinib resistance or intolerance, see the sections on Treatment of Resectable Primary GISTs, Treatment of Unresectable Primary GISTs, and Treatment of Metastatic or Recurrent GISTs.

Radiation Therapy

Radiation therapy rarely has a role in the management of patients with GISTs. It may occasionally be used for palliation of painful metastases or for patients with unresectable bleeding tumors.[1]

References
  1. Casali PG, Dei Tos AP, Gronchi A: Gastrointestinal stromal tumor. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 895-906.
  2. Judson I, Demetri G: Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol 18 (Suppl 10): x20-4, 2007. [PUBMED Abstract]
  3. Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29 (1): 52-68, 2005. [PUBMED Abstract]
  4. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
  5. Huguet KL, Rush RM, Tessier DJ, et al.: Laparoscopic gastric gastrointestinal stromal tumor resection: the mayo clinic experience. Arch Surg 143 (6): 587-90; discussion 591, 2008. [PUBMED Abstract]
  6. Otani Y, Furukawa T, Yoshida M, et al.: Operative indications for relatively small (2-5 cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 139 (4): 484-92, 2006. [PUBMED Abstract]
  7. Novitsky YW, Kercher KW, Sing RF, et al.: Long-term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 243 (6): 738-45; discussion 745-7, 2006. [PUBMED Abstract]
  8. Chen K, Zhou YC, Mou YP, et al.: Systematic review and meta-analysis of safety and efficacy of laparoscopic resection for gastrointestinal stromal tumors of the stomach. Surg Endosc 29 (2): 355-67, 2015. [PUBMED Abstract]
  9. Kanda T, Masuzawa T, Hirai T, et al.: Surgery and imatinib therapy for liver oligometastasis of GIST: a study of Japanese Study Group on GIST. Jpn J Clin Oncol 47 (4): 369-372, 2017. [PUBMED Abstract]
  10. Pawlik TM, Vauthey JN, Abdalla EK, et al.: Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver. Arch Surg 141 (6): 537-43; discussion 543-4, 2006. [PUBMED Abstract]
  11. Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347 (7): 472-80, 2002. [PUBMED Abstract]
  12. Edmonson JH, Marks RS, Buckner JC, et al.: Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Cancer Invest 20 (5-6): 605-12, 2002. [PUBMED Abstract]
  13. Plaat BE, Hollema H, Molenaar WM, et al.: Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 18 (18): 3211-20, 2000. [PUBMED Abstract]
  14. Blanke CD, Demetri GD, von Mehren M, et al.: Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26 (4): 620-5, 2008. [PUBMED Abstract]
  15. Heinrich MC, Jones RL, von Mehren M, et al.: Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 21 (7): 935-946, 2020. [PUBMED Abstract]

Treatment of Resectable Primary GISTs

Treatment Options for Resectable Primary GISTs

Treatment options for resectable primary gastrointestinal stromal tumors (GISTs) include:

  1. Surgery.
  2. Postoperative adjuvant tyrosine kinase inhibitor (TKI) therapy. 

Surgery

All GISTs measuring 2 cm or larger are typically surgically resected. The management of incidentally encountered GISTs measuring smaller than 2 cm remains controversial. There is no evidence for re-excision in patients with a complete resection of all macroscopic disease but microscopically positive margins. Watchful waiting and adjuvant imatinib therapy may be appropriate for these patients.[1,2]

In general, gastric GISTs may be removed by laparoscopic wedge resection, when technically feasible. GISTs rarely involve the locoregional lymph nodes. Thus, extensive lymph node dissection is not indicated unless there is clinically apparent nodal involvement. These tumors may have fragile pseudocapsules, so care must be taken to avoid rupturing the pseudocapsule during surgery, which could result in peritoneal dissemination.

Postoperative adjuvant TKI therapy

Imatinib

Results from three phase III studies support the use of postoperative adjuvant imatinib for patients with completely resected localized GISTs who have a high risk of recurrence based on tumor size, tumor location, mitotic index, and presence of tumor rupture.[3–10]

Evidence (phase III studies of postoperative imatinib):

  1. ACOSOG Z9001 (NCT00041197) was a phase III, double-blind, placebo-controlled trial of 713 patients with fully resected KIT-variant GISTs measuring at least 3 cm. Patients were randomly assigned to receive either imatinib 400 mg daily (n = 359) or placebo (n = 354) for 1 year after surgical resection.[4]
    • After a median follow-up of 19.7 months, disease recurrence or death occurred in 30 patients (8.4%) in the imatinib arm and 70 patients (19.8%) in the placebo arm.
    • The 1-year recurrence-free survival (RFS) rate was 98% in patients who received imatinib (95% confidence interval [CI], 96%–100%) and 83% (95% CI, 78%–88%) in patients who received placebo (hazard ratio [HR], 0.35; 95% CI, 0.22–0.53; P < .0001).[4][Level of evidence B1] No difference was noted in overall survival (OS) (HR, 0.66; 95% CI, 0.22–2.03; P = .4714).
    • Dose-reduction or interruption because of adverse events occurred in 14.5% of patients in the imatinib arm and 2.8% of patients in the placebo arm. Grade 3 or 4 events occurred in 30.9% of patients in the imatinib arm and 18.3% of patients in the placebo arm.
  2. EORTC-62024 (NCT00103168) was a phase III open-label trial of 908 patients with fully resected (R0 or R1 margin) KIT-variant GISTs at intermediate or high risk of recurrence. Patients were randomly assigned to receive either imatinib 400 mg daily (n = 454) or observation (n = 454) for 2 years.[10]
    • At a median follow-up of 4.7 years, RFS rates were improved for patients who received imatinib compared with patients who underwent observation at 3 years (84% vs. 66%) and 5 years (69% vs. 63%) (log-rank P < .001).[10][Level of evidence B1] The 5-year OS rate did not differ between the imatinib and observation arms (91.8% vs. 92.7%).
    • The 5-year imatinib failure-free survival rate (day of randomization to the start of a new systemic treatment or death) was 87% in the imatinib arm and 84% in the observation arm (HR, 0.79; 98.5% CI, 0.50–1.25; P = .21).[10][Level of evidence B1]
    • A final analysis at a median follow-up of 9.1 years showed RFS rates of 70% and 63% at 5 and 10 years, respectively, for patients in the imatinib arm, and rates of 63% and 61% at 5 and 10 years, respectively, for patients in the observation arm (HR, 0.71; 95% CI, 0.57–0.89; P = .002). There was no difference in OS between patients who received imatinib and patients who underwent observation (93% vs. 92% at 5 years, 80% vs. 78% at 10 years; HR, 0.88; 95% CI, 0.65–1.21; P = .43).[9][Levels of evidence B1 and A1]
  3. SSG XVIII (NCT00116935) was a phase III open-label trial of 400 patients with fully resected, high-risk GISTs. Patients were randomly assigned to receive imatinib 400 mg daily for either 1 year (n = 200) or 3 years (n = 200) after resection.[5]
    • After a median follow-up of 54 months, the RFS rate was 65.6% in the 3-year arm and 47.9% in the 1-year arm (HR, 0.46; 95% CI, 0.32–0.65; P < .001).[5][Level of evidence B1]
    • The 5-year OS rate was 92% in the 3-year arm and 81.7% in the 1-year arm (HR, 0.45; 95% CI, 0.22–0.89; P = .02).[5]
    • Although generally well-tolerated in both groups, grade 3 or 4 events occurred in 32.8% of patients in 3-year arm and 20.1% of patients in the 1-year arm. Treatment discontinuation occurred in 25.8% of patients in 3-year arm and 12.6% of patients in the 1-year arm.
    • A post-hoc exploratory analysis suggested that patients with KIT exon 11–variant GISTs derived the most benefit from a longer duration of imatinib (5-year RFS, 71.0% vs. 41.3%; P < .001).[6]

The recommended length of adjuvant treatment remains unknown. However, based on the SSG XVIII study results, at least 3 years of therapy is generally used in practice. It is important to note that evidence suggests that, instead of being cytotoxic, imatinib may suppress GIST growth. Therefore, recurrence may be delayed by the suppression of undetectable metastatic disease.[5,11–13] For example, the rate of recurrence increased within 6 to 12 months of discontinuing adjuvant imatinib in both the 1-year and 3-year arms in the SSG XVIII trial.[5] This concept has led to higher-risk patients being given imatinib indefinitely, although there is no direct trial evidence to support that.

Most patients initiate imatinib therapy at a dosage of 400 mg per day. Molecular genotyping of patients with GISTs is recommended as it can impact the use of adjuvant imatinib, as well as the optimal dose. Patients whose tumor harbors a KIT exon 9 variant may benefit from higher-dose imatinib (800 mg per day) based on data in the metastatic setting.[14] Patients with KIT/PDGFRA wild-type GISTs (i.e., SDH-deficient and neurofibromatosis type 1 [NF1]-related GISTs) or PDGFRA D842V-variant GISTs are unlikely to benefit from adjuvant imatinib therapy.[5]

Although not fully conclusive, there is some phase II evidence to support continuing adjuvant imatinib therapy for 5 years or more.

Evidence (phase II studies of postoperative imatinib):

  1. PERSIST-5 (NCT00867113) was a single-arm phase II trial of 91 patients with fully resected, high-risk GISTs. Patients received imatinib (400 mg daily) for up to 5 years.[15][Level of evidence C1]
    • The median treatment duration was 55.1 months, but with a large range (0.5–60.6 months). Only 46 patients (51%) completed all 5 years of therapy. Thus, 49% of patients stopped treatment early because of patient choice (21%), adverse events (16%), or other reasons (12%).
    • At a median follow-up of 19.6 months, the estimated 5-year RFS rate was 90% (95% CI, 80%–95%). The OS rate was 95% (95% CI, 86%–99%). Seven patients (7.6%) had a recurrence, 6 of which occurred after treatment discontinuation.
  2. A small, single-institution, retrospective analysis included 234 patients with R0-resected GISTs at moderate to high risk of recurrence. The study evaluated the effect of differing durations of postoperative imatinib on 5-year RFS and OS rates.[13][Level of evidence C1]
    • At a median follow-up of 54 months, the 5-year RFS rate across all groups was 76.2%. The OS rate across all groups was 83.4%.
    • In high-risk patients, longer durations of imatinib therapy were associated with higher RFS rates (36.5% in the 1-year group, 68.7% in the 1–3-years group, 71.2% in the 3–5-years group, and 90.8% in the >5-years group; P < .001). Longer imatinib therapy duration was also associated with higher OS rates (36.7% in the 1-year group, 76.6% in the 1–3-years group, 84.0% in the 3–5-years group, and 97.4% in the >5-years group; P < .001).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
  2. Otani Y, Furukawa T, Yoshida M, et al.: Operative indications for relatively small (2-5 cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 139 (4): 484-92, 2006. [PUBMED Abstract]
  3. DeMatteo RP, Owzar K, Antonescu CR, et al.: Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: the U.S. Intergroup phase II trial ACOSOG Z9000. [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-8, 2008.
  4. Dematteo RP, Ballman KV, Antonescu CR, et al.: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9669): 1097-104, 2009. [PUBMED Abstract]
  5. Joensuu H, Eriksson M, Sundby Hall K, et al.: One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 307 (12): 1265-72, 2012. [PUBMED Abstract]
  6. Joensuu H, Wardelmann E, Sihto H, et al.: Effect of KIT and PDGFRA Mutations on Survival in Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib: An Exploratory Analysis of a Randomized Clinical Trial. JAMA Oncol 3 (5): 602-609, 2017. [PUBMED Abstract]
  7. Raut CP, Espat NJ, Maki RG, et al.: Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study. [Abstract] J Clin Oncol 35 (Suppl 15): A-11009, 2017. Also available online. Last accessed December 13, 2024.
  8. DeMatteo RP, Ballman KV, Antonescu CR, et al.: Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial. Ann Surg 258 (3): 422-9, 2013. [PUBMED Abstract]
  9. Casali PG, Le Cesne A, Velasco AP, et al.: Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆. Ann Oncol 32 (4): 533-541, 2021. [PUBMED Abstract]
  10. Casali PG, Le Cesne A, Poveda Velasco A, et al.: Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol 33 (36): 4276-83, 2015. [PUBMED Abstract]
  11. Joensuu H, Eriksson M, Sundby Hall K, et al.: Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial. J Clin Oncol 34 (3): 244-50, 2016. [PUBMED Abstract]
  12. Blanke CD, DeMatteo RP: Duration of Adjuvant Therapy for Patients With Gastrointestinal Stromal Tumors: Where Is Goldilocks When We Need Her? JAMA Oncol 2 (6): 721-2, 2016. [PUBMED Abstract]
  13. Lin JX, Chen QF, Zheng CH, et al.: Is 3-years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long-term follow-up. J Cancer Res Clin Oncol 143 (4): 727-734, 2017. [PUBMED Abstract]
  14. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST): Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 28 (7): 1247-53, 2010. [PUBMED Abstract]
  15. Raut CP, Espat NJ, Maki RG, et al.: Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PERSIST-5 Clinical Trial. JAMA Oncol 4 (12): e184060, 2018. [PUBMED Abstract]

Treatment of Unresectable Primary GISTs

Treatment Options for Unresectable Primary GISTs

Treatment options for unresectable primary gastrointestinal stromal tumors (GISTs) include:

  1. Neoadjuvant tyrosine kinase inhibitor (TKI) therapy. 

Neoadjuvant TKI therapy

Imatinib

Neoadjuvant imatinib may be used for patients with very large primary GISTs or poorly positioned small GISTs (considered unresectable without the risk of significant morbidity or functional deficit, such as needing a formal gastrectomy, pancreatectomy, or other major organ resection) until surgical therapy is feasible, which can take as long as 6 to 12 months.[1,2] Neoadjuvant imatinib therapy in patients with GISTs is supported by the early results of two phase II studies in the United States [3] and Asia [4], as well as several case series and small retrospective reports.[2,5–10] Neoadjuvant imatinib may be particularly beneficial in rectal GISTs, given the large bulky nature of the disease and the extensive surgery required for complete resection.[11,12]

Evidence (phase II studies of neoadjuvant imatinib):

  1. RTOG-0132/ACRIN-6665 (NCT00028002) was a phase II single-arm study of 52 patients with primary GISTs (n = 30) or operable metastatic GISTs (n = 22). Patients received preoperative imatinib (600 mg daily) for 8 to 12 weeks followed by postoperative imatinib for at least 2 years.[3][Level of evidence C3]
    • Among patients with primary GISTs, 83% had stable disease and 7% had a partial response (7%). Among patients with metastatic GISTs, 91% had stable disease, 4.5% had a partial response, and 4.5% had disease progression.
    • At a median follow-up of 36 months, the 2-year PFS rate was 83% in patients with primary GISTs and 77% in patients with metastatic GISTs. The OS rate was 93% in patients with primary GISTs and 91% in patients with metastatic GISTs.
    • Seventy-seven percent of patients with primary GISTs and 58% of patients with metastatic GISTs went on to have R0 resections. Five patients (10%) had unresectable disease.
    • Imatinib was generally well tolerated, although 35% of patients had grade 3 to 5 adverse events. The median preoperative duration of imatinib was 65 days, and the median time of imatinib discontinuation before surgery was 2 days.
  2. A phase II single-arm study conducted in Asia included 53 evaluable patients with gastric GISTs larger than 10 cm. Patients received preoperative imatinib (400 mg daily) for 6 to 9 months, followed by at least 1 year of postoperative imatinib.[4][Level of evidence C3]
    • Forty-six patients (87%) received at least 6 months of preoperative imatinib and 50 patients ultimately underwent gastrectomy. The median duration of preoperative imatinib was 26 weeks. The most common grade 3 to 4 adverse events were neutropenia and rash.
    • The objective response rate was 62%, and the maximal reduction occurred most commonly at 24 weeks (63% of patients). The R0 resection rate was 91% overall, and at least one-half of the stomach was preserved in 79% of patients.
    • At a median follow-up of 32 months, the 2-year PFS rate was 89%, and the OS rate was 98%.

If a preoperative TKI is planned, a biopsy to confirm the diagnosis and, potentially, molecular profiling should be considered. Mutational analysis may help to exclude nonsensitive variants before starting imatinib cytoreduction therapy. Biopsy and molecular profiling may also determine whether a tumor harbors a KIT exon 9 variant, which may require an increase in initial imatinib dosing.[1,13] Neoadjuvant imatinib is not used for patients with GISTs harboring a PDGFRA D842V variant. Some guidelines, such as those from the European Society of Medical Oncology, recommend considering neoadjuvant avapritinib.[14] However, avapritinib has not been tested or validated in the neoadjuvant setting. In addition, patients with KIT/PDGFRA wild-type GISTs (i.e., SDH-deficient or neurofibromatosis type 1 [NF1]-related GISTs) would not benefit from neoadjuvant therapy and should proceed directly to surgery, if feasible.

If indicated, neoadjuvant imatinib is initiated at 400 mg per day in most patients. Patients with KIT exon 9–variant GISTs may be offered a higher dose (800 mg per day) based on data from the advanced setting.[15] Follow-up imaging, with either computed tomography (CT) or positron emission tomography (PET)-CT, is performed at close intervals. PET-CT can be particularly helpful in assessing initial early response if baseline molecular profiling was not done before neoadjuvant therapy.[16] The optimal duration of neoadjuvant treatment is unknown and should be individualized based on multidisciplinary discussion. Neoadjuvant TKI therapy precludes the ability to risk stratify after surgical resection. Therefore, patients should continue imatinib after surgery for at least 3 total years.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
  2. Bonvalot S, Eldweny H, Péchoux CL, et al.: Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol 13 (12): 1596-603, 2006. [PUBMED Abstract]
  3. Eisenberg BL, Harris J, Blanke CD, et al.: Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 99 (1): 42-7, 2009. [PUBMED Abstract]
  4. Kurokawa Y, Yang HK, Cho H, et al.: Phase II study of neoadjuvant imatinib in large gastrointestinal stromal tumours of the stomach. Br J Cancer 117 (1): 25-32, 2017. [PUBMED Abstract]
  5. Andtbacka RH, Ng CS, Scaife CL, et al.: Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 14 (1): 14-24, 2007. [PUBMED Abstract]
  6. Katz D, Segal A, Alberton Y, et al.: Neoadjuvant imatinib for unresectable gastrointestinal stromal tumor. Anticancer Drugs 15 (6): 599-602, 2004. [PUBMED Abstract]
  7. Raut CP, Posner M, Desai J, et al.: Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24 (15): 2325-31, 2006. [PUBMED Abstract]
  8. Scaife CL, Hunt KK, Patel SR, et al.: Is there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate? Am J Surg 186 (6): 665-9, 2003. [PUBMED Abstract]
  9. Machlenkin S, Pinsk I, Tulchinsky H, et al.: The effect of neoadjuvant Imatinib therapy on outcome and survival after rectal gastrointestinal stromal tumour. Colorectal Dis 13 (10): 1110-5, 2011. [PUBMED Abstract]
  10. Rutkowski P, Gronchi A, Hohenberger P, et al.: Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG experience. Ann Surg Oncol 20 (9): 2937-43, 2013. [PUBMED Abstract]
  11. Cavnar MJ, Wang L, Balachandran VP, et al.: Rectal Gastrointestinal Stromal Tumor (GIST) in the Era of Imatinib: Organ Preservation and Improved Oncologic Outcome. Ann Surg Oncol 24 (13): 3972-3980, 2017. [PUBMED Abstract]
  12. Tielen R, Verhoef C, van Coevorden F, et al.: Surgical management of rectal gastrointestinal stromal tumors. J Surg Oncol 107 (4): 320-3, 2013. [PUBMED Abstract]
  13. Debiec-Rychter M, Sciot R, Le Cesne A, et al.: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42 (8): 1093-103, 2006. [PUBMED Abstract]
  14. Casali PG, Blay JY, Abecassis N, et al.: Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 33 (1): 20-33, 2022. [PUBMED Abstract]
  15. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST): Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 28 (7): 1247-53, 2010. [PUBMED Abstract]
  16. Van den Abbeele AD, Gatsonis C, de Vries DJ, et al.: ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression. J Nucl Med 53 (4): 567-74, 2012. [PUBMED Abstract]

Treatment of Metastatic or Recurrent GISTs

Treatment Options for Metastatic or Recurrent GISTs

Treatment options for metastatic or recurrent gastrointestinal stromal tumors (GISTs) include:

  1. Initial tyrosine kinase inhibitor (TKI) therapy.
  2. Initial TKI therapy for PDGFRA D842-variant GISTs.
  3. TKI therapy for imatinib-resistant GISTs.
  4. Additional TKI therapy options.
  5. TKI therapy for KIT/PDGFRA wild-type GISTs.
  6. Surgery.
  7. Clinical trials.

The primary treatment of patients with metastatic or recurrent GISTs involves medical therapy with a TKI. In select cases, surgical therapy may be added. Patients with metastatic or recurrent tumors that do not respond to these measures may be candidates for clinical trials.

Initial TKI therapy

Imatinib

Therapy with imatinib is the standard first-line treatment for most patients with metastatic or recurrent disease. The initial dose is 400 mg daily, except for patients with tumors containing KIT exon 9 variants, who may receive 800 mg daily.[1] The only exception is for patients with GISTs characterized by the PDGFRA D842V variant. In this subtype, avapritinib is used as first-line therapy given high clinical benefit and imatinib resistance.[2] Most patients can initiate imatinib empirically while awaiting confirmation of their tumor’s molecular profile. That profile may necessitate an imatinib dosing change (i.e., KIT exon 9), a change to avapritinib (i.e., PDGFRA D842V variant), or indicate likelihood for TKI resistance (i.e., SDH-deficient or neurofibromatosis type 1 [NF1]-related GISTs).

All patients receiving TKI therapy are closely monitored for tumor response and side effects, which may require dose reductions, interruptions, or cessation of TKI therapy in cases of persistent, excessive toxicity. In addition, dose modification of the TKI or substitution with medications that do not affect cytochrome P450 isoenzyme 3A4 (CYP450 3A4) levels may be necessary for patients taking drugs that affect CYP450 3A4 levels.[3]

Response is evaluated with computed tomography (CT), magnetic resonance imaging (MRI), or fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET).[3–7] Treatment is usually continued indefinitely in the absence of disease progression or unacceptable toxicity, with a median time to progression of 24 to 40 months and median survival approaching 45 to 60 months.[3,8–14] A cohort of patients from early imatinib trials have continued on therapy with long-term survival. In a multivariable analysis, age younger than 60 years, performance status 0, smaller size of the largest lesion, and exon 11 KIT variant were significant prognostic factors for the probability of surviving beyond 10 years.[10] A similar finding for exon 11 was seen in a phase II study.[9]

Evidence (imatinib therapy):

  1. A phase III trial included 746 patients with advanced unresectable or metastatic GISTs. Patients were randomly assigned to receive either higher-dose treatment with 800 mg imatinib daily or 400 mg imatinib daily as primary systemic therapy.
    • No statistically significant differences in objective response rates, progression-free survival (PFS), or overall survival (OS) were observed between patients who received the 800 mg dose and patients who received the 400 mg dose.[15][Levels of evidence A1; B1; and B3]
    • Among patients who progressed at 400 mg daily and crossed over to 800 mg daily, approximately one-third were able to achieve an objective response or disease stabilization.
  2. Similar findings were seen in a European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG) study of 946 patients with GISTs who were randomly assigned to receive 400 mg or 800 mg of imatinib, with crossover permitted at progression.[16]
  3. It is now recognized that specific kinase variants in KIT and PDGFRA impact sensitivity/response to imatinib (e.g., exon 11 is imatinib sensitive and exon 9 is imatinib resistant).[17–21] In addition, meta-analyses of both trials mentioned above have demonstrated that patients with KIT exon 9 variants have significant benefit with higher-dose imatinib.[22]

In the event of tumor progression in patients without KIT exon 9 variants on lower dose imatinib (i.e., 400 mg daily), the imatinib dosage may be increased to 800 mg daily (in split doses). Alternatively, in the management of imatinib resistance, the patient may be switched directly to sunitinib.[23]

The most common toxicities associated with imatinib therapy, all of which may improve with prolonged treatment, include:[6,11,24–26]

  • Fluid retention (especially periorbital edema or peripheral edema; occasionally pleural effusion or ascites).
  • Diarrhea.
  • Nausea (may be diminished if taken with food).
  • Fatigue.
  • Muscle cramps.
  • Abdominal pain.
  • Rash.
  • Mild (macrocytic) anemia.
  • Hypophosphatemia.

There are rare reports of heart failure related to imatinib use,[27] primarily in patients with preexisting heart disease. No excess cardiac toxicity was noted in either of the phase III trials of imatinib mentioned above for patients with advanced GISTs.[15,16] However, it is best to inform patients of this risk before starting imatinib and monitor clinically for signs of heart failure or left ventricular dysfunction.

Initial TKI therapy for PDGFRA D842V-variant GISTs

Avapritinib

Patients with GISTs that harbor a PDGFRA exon 18 D842V variant should initially be given avapritinib. However, for patients whose GISTs are asymptomatic or indolent, a period of observation is reasonable to avoid treatment toxicities.

Evidence (avapritinib in patients with a PDGFRA D842V variant):

  1. NAVIGATOR (NCT02508532) was a phase I, single-arm, open-label trial of 56 patients with a PDGFRA D842V variant. Patients received avapritinib at a daily dose of either 300 mg or 400 mg.[2][Level of evidence C3]
    • An overall response was seen in 49 of 56 patients (88%) (95% confidence interval [CI], 76%–95%), with five patients (9%) achieving a complete response.
    • The 1-year PFS rate was 81% (95% CI, 67%–94%) and the 1-year duration of response was 70% (95% CI, 54%–87%).
    • At median follow-up of 15.9 months, the estimated 1-year OS rate was 91%, and the estimated 2-year OS rate was 81%.
    • The high overall response rate results of the NAVIGATOR trial led the U.S. Food and Drug Administration (FDA) to approve avapritinib for patients with GISTs with a PDGFRA exon 18 variant, including D842V variants.

Evidence (avapritinib in patients who did not respond to imatinib and at least one additional TKI):

  1. VOYAGER (NCT03465722) was a phase III open-label trial of 476 patients with advanced GISTs that did not respond to imatinib and at least one additional TKI. Patients were randomly assigned to receive either avapritinib 300 mg daily (n = 240) or regorafenib 160 mg daily (3-weeks-on/1-week-off regimen) (n = 236), with crossover allowed from regorafenib to avapritinib.[28]
    • The median PFS was 4.2 months in the avapritinib arm and 5.6 months in the regorafenib arm (hazard ratio [HR], 1.25; 95% CI, 0.99–1.57; P = .055). Among patients without a PDGFRA D842V variant, the median PFS was 3.9 months in the avapritinib arm and 5.6 months in the regorafenib arm (HR, 1.34; 95% CI, 1.06–1.69; P = .012).[28][Level of evidence B1]
    • OS data were immature at the time of the report with no interval differences noted between the study arms.
    • Overall and grade 3 or higher treatment-related adverse events did not differ between groups. However, cognitive effects occurred more often in patients who received avapritinib (25.9%) than in patients who received regorafenib (3.8%).
    • Because avapritinib did not improve PFS or OS compared with regorafenib in the treated population, it is not indicated until patients have failed multiple previous TKI therapies (outside of its specific variant indication above).

If indicated, avapritinib is given at 300 mg daily. Avapritinib is teratogenic, and thus, warrants effective contraception during and up to 6 weeks after the final dose.[29] The 300 mg dose was generally well-tolerated in the phase I NAVIGATOR study, with grade 3 to 4 toxicities including anemia, hyperbilirubinemia, fatigue, abdominal pain, diarrhea, peripheral edema, pleural effusion, and cognitive impairment.[2]

Cognitive effects must be closely monitored, with treatment changes (reductions, modifications, discontinuation) made promptly. Based on a post-hoc analysis of patients receiving 300 mg daily, grade 1 to 2 cognitive effects were seen in 37% of patients and 52% of patients older than 65 years. These effects included cognitive impairment, mood changes, sleep disorder, dizziness, hallucinations, and intracranial hemorrhage. These cognitive effects generally improved once treatment changes were made.[29]

Of note, for patients with GISTs who do not harbor a PDGFRA D842V variant, avapritinib should not be used until imatinib and at least two additional agents (sunitinib and regorafenib) are tried. The open-label phase III VOYAGER trial demonstrated that regorafenib improved PFS more than avapritinib in patients without a PDGFRA D842V variant.[28]

TKI therapy for imatinib-resistant GISTs

Sunitinib

In the case of tumor progression (or intolerance to imatinib), data support second-line therapy with either imatinib dose escalation to 800 mg per day (as described above) or sunitinib.[16,21] Sunitinib is given at a dose of 50 mg daily in a 4-weeks-on/2-weeks-off regimen or a daily dose of 37.5 mg.[30] As with imatinib, the response to sunitinib is evaluated with CT, MRI, or 18F-FDG PET, and treatment is usually continued indefinitely in the absence of disease progression or unacceptable toxicity.[3,4,30–36]

Evidence (sunitinib):

  1. An international phase III trial of 312 patients with imatinib-resistant GISTs randomly assigned patients to receive sunitinib or placebo.[30]
    • On the basis of radiological assessment, the median time to tumor progression was more than four times as long with sunitinib (27.3 weeks; 95% CI, 16.0–32.1) than with placebo treatment (6.4 weeks; 95% CI, 4.4–10.0) (HR, 0.33; 95% CI, 0.23–0.47; P < .0001).[30][Level of evidence A1]
    • OS was similarly better for sunitinib-treated patients (HRdeath, 0.49; 95% CI, 0.29–0.83).[30][Level of evidence A1]

The response to sunitinib is also influenced by the molecular profile of the GIST. Based on a phase I/II study of 97 patients, the highest clinical benefit rate, PFS benefit, and OS benefit were seen in patients with KIT exon 9 variants, compared with patients with KIT/PDGFRA wild-type or KIT exon 11 variants.[33]

Common side effects associated with sunitinib include:[30,37]

  • Fatigue.
  • Nausea and vomiting.
  • Anemia.
  • Neutropenia.
  • Diarrhea.
  • Abdominal pain.
  • Mucositis.
  • Anorexia.
  • Skin or hair discoloration.
  • Proteinuria.
  • Hypothyroidism (thyroid function monitoring is generally recommended).
  • Hypertension.
  • Potential for delayed wound healing (may require holding 3–4 days prior to surgery).

Less frequent toxicities include bleeding, fever, and hand-foot syndrome.[30] Therapy with sunitinib may be cardiotoxic. In a retrospective phase I/II study evaluating the efficacy of sunitinib in patients with imatinib-resistant metastatic GISTs, 8% of patients who received repeated cycles of sunitinib experienced congestive heart failure, while 47% of patients developed hypertension (>150 per 100 mm Hg). Reductions in left ventricular ejection fraction were seen in at least 10% to 28% of patients.[38]

Regorafenib

The FDA has approved regorafenib for the treatment of GISTs that are refractory to first-line therapy. Regorafenib is a multikinase inhibitor with activity against KIT, PDGFRA, and VEGFR, among others. Regorafenib has demonstrated anti-GIST activity in phase II and phase III studies.[39,40]

Evidence (regorafenib):

  1. The phase III double-blind GRID trial (NCT01271712) included 199 patients with advanced GISTs who did not respond to previous imatinib and sunitinib therapy. Patients were randomly assigned in a 2:1 ratio to receive either 160 mg daily of regorafenib (3-weeks-on/1-week-off regimen) (n = 133) or placebo (n = 66). Crossover to open-label regorafenib was allowed for patients who had disease progression on the placebo arm.[40]
    • After a median treatment duration of 23 weeks for regorafenib and 7 weeks for placebo, the median PFS was longer in patients who received regorafenib (4.8 months) compared with patients who received placebo (0.9 months) (HR, 0.27; 95% CI, 0.19–0.39; P < .0001).[40][Level of evidence B1] The OS did not differ between arms (HR, 0.77; 0.4–1.41; P = .199). However, 56 patients in the placebo arm (85%) did cross over to receive regorafenib at the time of disease progression.
    • Adverse events were more common in the regorafenib arm (98.5%) compared with the placebo arm (68.2%). The most common grade 3 or greater events were hypertension (23.5%), hand-foot syndrome (19.7%), and diarrhea (5.3%).

Additional TKI therapy options

Ripretinib

Ripretinib is indicated for patients with advanced GISTs who have disease progression on (or are intolerant to) three or more TKIs, including imatinib. It works as a switch control inhibitor with multiple targets, including KIT exons 9, 11, 13, 14, 18, and it stabilizes the KIT molecule in its active form.

Based on the toxicity profile of ripretinib, a baseline echocardiogram or multigated acquisition (MUGA) scan should be obtained, and blood pressure and clinical signs of heart failure should be serially monitored. Dermatologic exams are warranted, given the association with the development of cutaneous cancers and hand-foot syndrome. Ripretinib is teratogenic and warrants concomitant effective contraception. It should also not be given perioperatively (1 week before or 2 weeks after surgery) because of the risk of delayed wound healing.[41,42]

Evidence (ripretinib):

  1. INVICTUS (NCT03353753) was a phase III, double-blind, placebo-controlled trial of 129 patients with advanced GISTs who had not responded to previous imatinib, sunitinib, and regorafenib therapy. Patients were randomly assigned in a 2:1 ratio to receive either ripretinib 150 mg daily (n = 85) or placebo (n = 44), with an opportunity to cross over at the time of disease progression.[41]
    • After a median follow-up of 6.3 months for the ripretinib arm and 1.6 months for the placebo arm, the median OS was longer for patients who received ripretinib (15.1 months), compared with patients who received placebo (6.6 months) (HR, 0.36; 95% CI, 0.21–0.62).[41][Level of evidence A1]
    • The median PFS was longer for patients who received ripretinib (6.3 months) than patients for who received placebo (1.0 month) (HR, 0.15; 95% CI, 0.09–0.25; P < .0001). The PFS rate at 6 months was 51% in the ripretinib arm (95% CI, 39.4%–61.4%) and 3.2% in the placebo arm (95% CI, 0.2%–13.8%).[41]
    • Twenty-nine patients (66%) in the placebo arm crossed over to the ripretinib arm.
    • Ripretinib was well tolerated. The most common grade 3 or 4 adverse events were lipase increase (5%), hypertension (4%), fatigue (2%), and hypophosphatemia (2%).
  2. INTRIGUE (NCT03673501) was an open-label phase III trial of 453 patients with advanced GISTs who did not respond to imatinib therapy. Patients were randomly assigned to receive either ripretinib 150 mg daily (n = 226) or sunitinib 50 mg (4-weeks-on/2-weeks-off regimen; n = 227).[43]
    • The median PFS did not differ between the ripretinib and sunitinib arms (8.0 months vs. 8.3 months; HR, 1.05; 95% CI, 0.82–1.33; P = .72). In addition, there was no difference in the median PFS in the KIT exon 11 cohort (8.3 months vs. 7.0 months; HR, 0.88; 95% CI, 0.66–1.16; P = .36).[43][Level of evidence B1]
    • OS data were immature at the time of report.
    • Patients who received ripretinib had fewer treatment-emergent adverse events (41.3% vs. 65.6%; P < .0001) and were more likely to develop drug-related grade 3 or 4 hypertension (5.8% vs. 22.6%). Dose modifications, interruptions, or discontinuations were all less common with ripretinib.
    • Ripretinib did not lead to a PFS or OS benefit when compared with sunitinib. Therefore, it is not indicated unless the patient’s tumor does not respond to prior lines of TKI therapy.
Nilotinib

Nilotinib is a second-generation TKI with similar targets to imatinib. A phase III study of nilotinib versus best supportive care in imatinib- and sunitinib-resistant GISTs showed some PFS benefit based on local assessment but no PFS benefit based on central assessment. Post-hoc analysis did reveal a modest but significant median OS difference of 4 months.[44]

Sorafenib

Sorafenib is a multitarget kinase that is similar in structure and mechanism to regorafenib. A phase II trial of patients with imatinib- and sunitinib-resistant GISTs showed that sorafenib offered potential benefit, with a disease control rate of 68% and a median PFS of 5 months.[45]

Pazopanib

Pazopanib inhibits VEGF signaling and showed modest PFS benefit when compared to best supportive care in a small phase II trial of patients with imatinib- and sunitinib-resistant GISTs. However, pazopanib had a high rate of toxicity.[46]

TKI therapy for KIT/PDGFRA wild-type GISTs

Patients without KIT or PDGFRA variants, such as SDH-deficient and NF1-related GISTs, do not benefit from initial TKI treatment with imatinib. However, these patients may have modest response to sunitinib and regorafenib.[47] These tumors tend to have a relatively indolent course, and optimal management of these patients remains unknown. Thus, patients should be encouraged to enroll in a clinical trial, if available.

Surgery

Surgery may be added to medical therapy for selected patients with GISTs in an effort to delay or prevent recurrence, although the benefit of this therapeutic approach in patients with metastatic GISTs has yet to be proven in a randomized clinical trial.

Evidence (surgery):

  1. A retrospective study involving 69 consecutive patients who underwent surgery for unresectable primary or metastatic GISTs while receiving kinase inhibitors reported the following:[48][Levels of evidence C2 and C1]
    • Patients with stable disease or limited progression were found to have prolonged survival after debulking procedures. In this group of patients with GISTs, no evidence of disease was found after surgery in 78% of patients with stable disease, 25% of patients with limited progression, and 7% of patients with generalized progression.
    • The 12-month PFS rate was 80% for patients with stable disease, 33% for patients with limited progression, and 0% for patients with generalized progression.
    • The 12-month OS rate was 95% for patients with stable disease, 86% for patients with limited progression, and 0% for patients with generalized progression.
    • The authors of this study concluded that surgery for patients with generalized progression should be limited to a palliative role.

Overall, the indications for surgery in the management of metastatic or recurrent GISTs include:[3]

  1. Stable disease (i.e., disease that is stable or shrinking on TKI therapy when gross resection is possible).
  2. Limited disease progression (i.e., isolated tumor deposits that are progressing on TKI therapy after initial response [indicating delayed drug resistance], while other sites of disease remain stable).
  3. Oncological emergencies including hemorrhage, perforation, obstruction, or abscess.

Stable disease and limited disease progression identify subsets of patients with advanced disease that are selected for relative disease stability. Therefore, the favorable outcomes that have been noted in case series may be principally the result of selection bias rather than true benefit from surgery.

The median time to the development of secondary resistance to imatinib has been about 2 years.[12] Therefore, it is suggested that surgery for metastatic or recurrent disease in patients receiving imatinib/sunitinib be performed before 2 years. Most experts would recommend considering surgery after 6 to 12 months of disease stability with TKI therapy.[3] Drug therapy may be continued after surgery.

Clinical trials

Patients who have generalized disease progression while receiving standard therapies, or with certain molecular subtypes (i.e., SDH-deficient or NF1-related GISTs) may benefit from enrolling in clinical trials. These patients should be referred to specialized multidisciplinary research centers.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Debiec-Rychter M, Sciot R, Le Cesne A, et al.: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42 (8): 1093-103, 2006. [PUBMED Abstract]
  2. Heinrich MC, Jones RL, von Mehren M, et al.: Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 21 (7): 935-946, 2020. [PUBMED Abstract]
  3. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)–update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
  4. Casali PG, Dei Tos AP, Gronchi A: Gastrointestinal stromal tumor. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 895-906.
  5. Blanke CD, von Mehren M, Joensuu H, et al.: Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI157, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing c-kit (CD117). [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1, 1a, 2001.
  6. van Oosterom AT, Judson I, Verweij J, et al.: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358 (9291): 1421-3, 2001. [PUBMED Abstract]
  7. Choi H, Charnsangavej C, Faria SC, et al.: Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25 (13): 1753-9, 2007. [PUBMED Abstract]
  8. Blay JY, Le Cesne A, Ray-Coquard I, et al.: Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 25 (9): 1107-13, 2007. [PUBMED Abstract]
  9. Blanke CD, Demetri GD, von Mehren M, et al.: Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26 (4): 620-5, 2008. [PUBMED Abstract]
  10. Casali PG, Zalcberg J, Le Cesne A, et al.: Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels. J Clin Oncol 35 (15): 1713-1720, 2017. [PUBMED Abstract]
  11. Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347 (7): 472-80, 2002. [PUBMED Abstract]
  12. Verweij J, Casali PG, Zalcberg J, et al.: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364 (9440): 1127-34, 2004. [PUBMED Abstract]
  13. Van Glabbeke M, Verweij J, Casali PG, et al.: Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 23 (24): 5795-804, 2005. [PUBMED Abstract]
  14. Rutkowski P, Nowecki ZI, Debiec-Rychter M, et al.: Predictive factors for long-term effects of imatinib therapy in patients with inoperable/metastatic CD117(+) gastrointestinal stromal tumors (GISTs). J Cancer Res Clin Oncol 133 (9): 589-97, 2007. [PUBMED Abstract]
  15. Blanke CD, Rankin C, Demetri GD, et al.: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26 (4): 626-32, 2008. [PUBMED Abstract]
  16. Zalcberg JR, Verweij J, Casali PG, et al.: Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41 (12): 1751-7, 2005. [PUBMED Abstract]
  17. Heinrich MC, Corless CL, Demetri GD, et al.: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21 (23): 4342-9, 2003. [PUBMED Abstract]
  18. Debiec-Rychter M, Dumez H, Judson I, et al.: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40 (5): 689-95, 2004. [PUBMED Abstract]
  19. Corless CL, Schroeder A, Griffith D, et al.: PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23 (23): 5357-64, 2005. [PUBMED Abstract]
  20. Heinrich MC, Owzar K, Corless CL, et al.: Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 26 (33): 5360-7, 2008. [PUBMED Abstract]
  21. Patrikidou A, Domont J, Chabaud S, et al.: Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group. Eur J Cancer 52: 173-80, 2016. [PUBMED Abstract]
  22. van Glabbeke MM, Owzar K, Rankin C, et al.: Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): a meta-analyis based on 1,640 patients (pts). [Abstract] J Clin Oncol 25 (Suppl 18): A-10004, 546s, 2007.
  23. Rutkowski P, Nowecki Z, Nyckowski P, et al.: Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 93 (4): 304-11, 2006. [PUBMED Abstract]
  24. Dagher R, Cohen M, Williams G, et al.: Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8 (10): 3034-8, 2002. [PUBMED Abstract]
  25. Benjamin RS, Rankin C, Fletcher C, et al.: Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: Intergroup S0033 early results. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-3271, 2003.
  26. Verweij J, van Oosterom A, Blay JY, et al.: Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 39 (14): 2006-11, 2003. [PUBMED Abstract]
  27. Kerkelä R, Grazette L, Yacobi R, et al.: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12 (8): 908-16, 2006. [PUBMED Abstract]
  28. Kang YK, George S, Jones RL, et al.: Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol 39 (28): 3128-3139, 2021. [PUBMED Abstract]
  29. Joseph CP, Abaricia SN, Angelis MA, et al.: Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors. Oncologist 26 (4): e622-e631, 2021. [PUBMED Abstract]
  30. Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368 (9544): 1329-38, 2006. [PUBMED Abstract]
  31. Prior JO, Montemurro M, Orcurto MV, et al.: Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. J Clin Oncol 27 (3): 439-45, 2009. [PUBMED Abstract]
  32. Demetri GD, Heinrich MC, Fletcher JA, et al.: Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. Clin Cancer Res 15 (18): 5902-9, 2009. [PUBMED Abstract]
  33. Heinrich MC, Maki RG, Corless CL, et al.: Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 26 (33): 5352-9, 2008. [PUBMED Abstract]
  34. Rutkowski P, Bylina E, Klimczak A, et al.: The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure – one institution study. BMC Cancer 12: 107, 2012. [PUBMED Abstract]
  35. Demetri GD, Garrett CR, Schöffski P, et al.: Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res 18 (11): 3170-9, 2012. [PUBMED Abstract]
  36. Reichardt P, Kang YK, Rutkowski P, et al.: Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Cancer 121 (9): 1405-13, 2015. [PUBMED Abstract]
  37. Wolter P, Stefan C, Decallonne B, et al.: The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 99 (3): 448-54, 2008. [PUBMED Abstract]
  38. Chu TF, Rupnick MA, Kerkela R, et al.: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370 (9604): 2011-9, 2007. [PUBMED Abstract]
  39. George S, Wang Q, Heinrich MC, et al.: Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 30 (19): 2401-7, 2012. [PUBMED Abstract]
  40. Demetri GD, Reichardt P, Kang YK, et al.: Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381 (9863): 295-302, 2013. [PUBMED Abstract]
  41. Blay JY, Serrano C, Heinrich MC, et al.: Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 21 (7): 923-934, 2020. [PUBMED Abstract]
  42. Janku F, Abdul Razak AR, Chi P, et al.: Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib. J Clin Oncol 38 (28): 3294-3303, 2020. [PUBMED Abstract]
  43. Bauer S, Jones RL, Blay JY, et al.: Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial. J Clin Oncol 40 (34): 3918-3928, 2022. [PUBMED Abstract]
  44. Reichardt P, Blay JY, Gelderblom H, et al.: Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 23 (7): 1680-7, 2012. [PUBMED Abstract]
  45. Campbell NP, Wroblewski K, Maki RG, et al.: Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM)- and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST). [Abstract] J Clin Oncol 29 (4): A-4, 2011.
  46. Mir O, Cropet C, Toulmonde M, et al.: Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol 17 (5): 632-41, 2016. [PUBMED Abstract]
  47. Boikos SA, Pappo AS, Killian JK, et al.: Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2 (7): 922-8, 2016. [PUBMED Abstract]
  48. Raut CP, Posner M, Desai J, et al.: Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24 (15): 2325-31, 2006. [PUBMED Abstract]

Treatment of Resistant or Refractory GISTs

Eventual development of resistance to imatinib, sunitinib, and regorafenib is nearly universal. There is no standard therapy when this occurs, and patients should consider investigational therapy, such as new oral tyrosine kinase inhibitors. If eligible, patients are encouraged to participate in clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Key References for Treatment of GISTs

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of gastrointestinal stromal tumor (GIST) treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for GISTs. Listed after each reference are the sections within this summary where the reference is cited.

Preoperative Imatinib

8 to 12 weeks

  • Eisenberg BL, Harris J, Blanke CD, et al.: Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 99 (1): 42-7, 2009. [PUBMED Abstract]

    Cited in:

6 to 9 months

Postoperative Imatinib

1 year of imatinib

  • Dematteo RP, Ballman KV, Antonescu CR, et al.: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9669): 1097-104, 2009. [PUBMED Abstract]

    Cited in:

2 years of imatinib

1 year versus 3 years of imatinib

  • Casali PG, Le Cesne A, Poveda Velasco A, et al.: Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol 33 (36): 4276-83, 2015. [PUBMED Abstract]

    Cited in:

5 years of imatinib

  • Raut CP, Espat NJ, Maki RG, et al.: Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PERSIST-5 Clinical Trial. JAMA Oncol 4 (12): e184060, 2018. [PUBMED Abstract]

    Cited in:

Varying duration of imatinib

  • Lin JX, Chen QF, Zheng CH, et al.: Is 3-years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long-term follow-up. J Cancer Res Clin Oncol 143 (4): 727-734, 2017. [PUBMED Abstract]

    Cited in:

Advanced GIST Tyrosine Kinase Inhibitors

Imatinib

Avapritinib

Avapritinib versus regorafenib

  • Kang YK, George S, Jones RL, et al.: Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol 39 (28): 3128-3139, 2021. [PUBMED Abstract]

    Cited in:

Sunitinib

  • Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368 (9544): 1329-38, 2006. [PUBMED Abstract]

    Cited in:

Regorafenib

  • Demetri GD, Reichardt P, Kang YK, et al.: Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381 (9863): 295-302, 2013. [PUBMED Abstract]

    Cited in:

Ripretinib

  • Blay JY, Serrano C, Heinrich MC, et al.: Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 21 (7): 923-934, 2020. [PUBMED Abstract]

    Cited in:

Ripretinib versus sunitinib

  • Bauer S, Jones RL, Blay JY, et al.: Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial. J Clin Oncol 40 (34): 3918-3928, 2022. [PUBMED Abstract]

    Cited in:

Latest Updates to This Summary (12/13/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of gastrointestinal stromal tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Gastrointestinal Stromal Tumors Treatment is:

  • Vinayak Venkataraman, MD (Dana Farber Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Gastrointestinal Stromal Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/soft-tissue-sarcoma/hp/gist-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389157]

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Lasers to Treat Cancer

Lasers to Treat Cancer

apparatus that delivers laser beams pointed at the skin

Laser therapy uses an intense, narrow beam of light to remove or destroy cancer and abnormal cells that can turn into cancer. 

Credit: iStock

What is laser therapy?

Laser therapy uses an intense, narrow beam of light to remove or destroy cancer and abnormal cells that can turn into cancer. Tumor cells absorb light of different wavelengths (or colors) than normal cells do. So, tumor cells can be targeted by selecting the proper wavelength of the laser.  Laser therapy is a type of local treatment, which means it treats a specific part of your body.   

Lasers can also be used in other types of local treatment, including photodynamic therapy and a treatment that is like hyperthermia, called laser interstitial thermal therapy, or LITT.

Laser therapy can also be used with surgery. Doctors can use lasers to seal:

  • nerve endings after surgery, which reduces pain
  • lymph vessels after surgery, which helps reduce swelling and limit the spread of cancer cells
  • blood vessels during surgery, which reduces bleeding

Cancers and precancers treated with laser therapy

Laser therapy is most often used to treat cancers and precancers on the surface of the body or the lining of internal organs. It is used for:

Lasers may also be used to ease certain symptoms of advanced cancer, such as bleeding or blockages. For example, lasers can be used to destroy parts of a tumor that is blocking the windpipe, throat, colon, or stomach.

How laser therapy is given

Laser therapy is often given through an endoscope, a narrow, lighted tube used to look at tissues inside the body. Flexible endoscopes use optical fibers, which are thin fibers, used singly or in bundles to transmit light to the therapy site. It is inserted through an opening in the body, such as the mouth, nose, anus, or vagina. Laser light is then precisely aimed to cut or destroy a tumor.

Types of lasers used in cancer treatment

Three types of lasers are used to treat cancer:

  • carbon dioxide (CO2) lasers
  • argon lasers
  • neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers

CO2 and argon lasers can cut the skin’s surface without going into deeper layers. So, they can be used to remove cancers on the surface of the body, such as skin cancer.

The Nd:YAG laser is more often used through an endoscope to treat internal organs, such as the uterus, esophagus, and colon.

Nd:YAG laser light can also travel through optical fibers into specific areas of the body during LITT.

Argon lasers are often used in photodynamic therapy.

Benefits of laser therapy

When cutting tissue, lasers seal the cut from bleeding, so they may cause less damage to normal tissues when used in surgery. As a result, you usually have less pain, bleeding, swelling, and scarring. With laser therapy, the time in surgery is usually shorter. In fact, laser therapy can often be done on an outpatient basis. It takes less time to heal after laser surgery, and you are less likely to get an infection.

Drawbacks of laser therapy

Surgeons must have special training before they can do laser therapy and strict safety measures must be followed. Laser therapy is expensive and requires specialized equipment. Also, the effects of laser therapy may not last long, so doctors may have to repeat the treatment for you to get the full benefit.

Not every hospital or cancer center in the country has skilled doctors and the machines needed to use lasers in cancer treatment. Talk with your doctor or contact hospitals and cancer centers in your area to find out if they are using lasers.

Laser therapy research

Doctors are testing lasers to treat cancers and precancers. If you are interested in finding a clinical trial that uses lasers, use the advanced clinical trials search form or call NCI’s Cancer Information Service at 1–800–4–CANCER (1–800–422–6237).

Esophageal Cancer Screening (PDQ®)–Patient Version

Esophageal Cancer Screening (PDQ®)–Patient Version

What Is Screening?

Go to Health Professional Version

Screening is looking for cancer before a person has any symptoms. This can help find cancer at an early stage. When abnormal tissue or cancer is found early, it may be easier to treat. By the time symptoms appear, cancer may have begun to spread.

Scientists are trying to better understand which people are more likely to get certain types of cancer. They also study the things we do and the things around us to see if they cause cancer. This information helps doctors recommend who should be screened for cancer, which screening tests should be used, and how often the tests should be done.

It is important to remember that your doctor does not necessarily think you have cancer if he or she suggests a screening test. Screening tests are given when you have no cancer symptoms.

If a screening test result is abnormal, you may need to have more tests done to find out if you have cancer. These are called diagnostic tests.

General Information About Esophageal Cancer

Key Points

  • Esophageal cancer is a disease in which malignant (cancer) cells form in the tissues of the esophagus.
  • Esophageal cancer is found more often in men.
  • Smoking, heavy alcohol use, and Barrett esophagus can affect the risk of developing esophageal cancer.

Esophageal cancer is a disease in which malignant (cancer) cells form in the tissues of the esophagus.

The esophagus is the hollow, muscular tube that moves food and liquid from the throat to the stomach. The wall of the esophagus is made up of several tissue layers, including mucous membrane, muscle, and connective tissue. Esophageal cancer starts in the inside lining of the esophagus and spreads outward through the other layers as it grows.

EnlargeGastrointestinal (digestive) system anatomy; drawing shows the esophagus, liver, stomach, small intestine, and large intestine.
The esophagus and stomach are part of the upper gastrointestinal (digestive) system.

The two most common types of esophageal cancer are named for the type of cells that become cancerous:

  • Squamous cell carcinoma: Cancer forms in the thin, flat cells lining the inside of the esophagus. This cancer is most often found in the upper and middle part of the esophagus but can occur anywhere along the esophagus. This is also called epidermoid carcinoma.
  • Adenocarcinoma: Cancer begins in glandular cells. Glandular cells in the lining of the esophagus produce and release fluids such as mucus. Adenocarcinoma usually forms in the lower part of the esophagus, near the stomach.

Other PDQ summaries containing information related to esophageal cancer include:

Esophageal cancer is found more often in men.

Men are about four times more likely than women to develop esophageal cancer. There are more new cases of esophageal adenocarcinoma each year and fewer new cases of squamous cell carcinoma. Although the rates of squamous cell carcinoma are declining overall, they remain much higher in Black men than in White men. The chance of developing esophageal cancer increases with age in all racial and ethnic groups. White men are more likely to develop esophageal cancer at higher rates than Black men in all age groups. In women, the rates of developing this disease are higher in Black women until age 74 years, after which White women have higher rates.

Smoking, heavy alcohol use, and Barrett esophagus can affect the risk of developing esophageal cancer.

Anything that increases the chance of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. People who think they may be at risk should discuss this with their doctor.

Risk factors for squamous cell esophageal cancer include:

  • using tobacco
  • drinking a lot of alcohol
  • being malnourished (lacking nutrients and/or calories)
  • having a human papillomavirus (HPV) infection
  • having tylosis (a rare inherited disorder that causes thickening of the skin on the hands and feet and is associated with an increased risk of squamous cell esophageal cancer)
  • having achalasia (a rare condition that affects the ability of food and liquids to pass from the esophagus into the stomach)
  • having swallowed lye (a chemical found in some cleaning fluids)
  • drinking very hot liquids on a regular basis

Risk factors for esophageal adenocarcinoma include:

Esophageal Cancer Screening

Key Points

  • Tests are used to screen for different types of cancer when a person does not have symptoms.
  • There is no standard or routine screening test for esophageal cancer.
    • Esophagoscopy
    • Biopsy
    • Brush cytology
    • Balloon cytology
    • Chromoendoscopy
    • Fluorescence spectroscopy
  • Screening tests for esophageal cancer are being studied in clinical trials.

Tests are used to screen for different types of cancer when a person does not have symptoms.

Scientists study screening tests to find those with the fewest harms and most benefits. Cancer screening trials also are meant to show whether early detection (finding cancer before it causes symptoms) helps a person live longer or decreases a person’s chance of dying from the disease. For some types of cancer, the chance of recovery is better if the disease is found and treated at an early stage.

There is no standard or routine screening test for esophageal cancer.

Although there are no standard or routine screening tests for esophageal cancer, the following tests are being used or studied to screen for it:

Esophagoscopy

A procedure to look inside the esophagus to check for abnormal areas. An esophagoscope is inserted through the mouth or nose and down the throat into the esophagus. An esophagoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.

EnlargeEsophagoscopy; shows endoscope inserted through the mouth and into the esophagus. Inset shows patient on table having an esophagoscopy.
Esophagoscopy. A thin, lighted tube is inserted through the mouth and into the esophagus to look for abnormal areas.

Biopsy

The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. Taking biopsy samples from several different areas in the lining of the lower part of the esophagus may detect early Barrett esophagus. This procedure may be used for patients who have risk factors for Barrett esophagus.

Brush cytology

A procedure in which cells are brushed from the lining of the esophagus and viewed under a microscope to see if they are abnormal. This may be done during an esophagoscopy.

Balloon cytology

A procedure in which cells are collected from the lining of the esophagus using a deflated balloon that is swallowed by the patient. The balloon is then inflated and pulled out of the esophagus. Esophageal cells on the balloon are viewed under a microscope to see if they are abnormal.

Chromoendoscopy

A procedure in which a dye is sprayed onto the lining of the esophagus during esophagoscopy. Increased staining of certain areas of the lining may be a sign of early Barrett esophagus.

Fluorescence spectroscopy

A procedure that uses a special light to view tissue in the lining of the esophagus. The light probe is passed through an endoscope and shines on the lining of the esophagus. The light given off by the cells lining the esophagus is then measured. Malignant tissue gives off less light than normal tissue.

Screening tests for esophageal cancer are being studied in clinical trials.

Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Risks of Esophageal Cancer Screening

Key Points

  • Screening tests have risks.
  • The risks of esophageal cancer screening tests include:
    • Finding esophageal cancer may not improve health or help a person live longer.
    • False-negative test results can occur.
    • False-positive test results can occur.
    • Side effects may be caused by the test itself.

Screening tests have risks.

Decisions about screening tests can be difficult. Not all screening tests are helpful, and most have risks. Before having any screening test, you may want to discuss the test with your doctor. It is important to know the risks of the test and whether it has been proven to reduce the risk of dying from cancer.

The risks of esophageal cancer screening tests include:

Finding esophageal cancer may not improve health or help a person live longer.

Screening may not improve your health or help you live longer if you have advanced esophageal cancer or if it has already spread to other places in your body.

Some cancers never cause symptoms or become life-threatening, but if found by a screening test, the cancer may be treated. It is not known if treatment of these cancers will help you live longer than if no treatment were given, and treatments for cancer may have serious side effects.

False-negative test results can occur.

Screening test results may appear to be normal even though esophageal cancer is present. A person who receives a false-negative test result (one that shows there is no cancer when there really is) may delay seeking medical care even if there are symptoms.

False-positive test results can occur.

Screening test results may appear to be abnormal even though no cancer is present. A false-positive test result (one that shows there is cancer when there really isn’t) can cause anxiety and is usually followed by more tests (such as biopsy), which also have risks.

Side effects may be caused by the test itself.

There are rare but serious side effects that may occur with esophagoscopy and biopsy. These include:

  • a small hole (puncture) in the esophagus
  • problems with breathing
  • heart attack
  • passage of food, water, stomach acid, or vomit into the airway
  • severe bleeding that may need to be treated in a hospital

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about esophageal cancer screening. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Screening and Prevention Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Esophageal Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/esophageal/patient/esophageal-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389194]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.

Disclaimer

The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Esophageal Cancer Screening (PDQ®)–Health Professional Version

Esophageal Cancer Screening (PDQ®)–Health Professional Version

Overview

Go to Patient Version

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Esophageal Cancer Prevention; Esophageal Cancer Treatment; and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Benefits

Based on fair evidence, screening would result in no (or minimal) decrease in mortality from esophageal cancer in the U.S. population.

Description of the Evidence

  • Study Design: Evidence from cohort or case-control studies.
  • Internal Validity: Fair.
  • Consistency: Multiple studies.
  • Magnitude of Effects on Health Outcomes: Small positive.
  • External Validity: Poor.

Harms

Based on solid evidence, screening would result in uncommon but serious side effects associated with endoscopy, which may include perforation, cardiopulmonary events and aspiration, and bleeding requiring hospitalization. Potential psychological harms may occur in those identified as having Barrett esophagus who may consider themselves to be ill even though their risk of developing cancer is low.

Description of the Evidence

  • Study Design: Evidence obtained from cohort or case-control studies.
  • Internal Validity: Fair.
  • Consistency: Multiple studies, large number of participants.
  • Magnitude of Effects on Health Outcomes: Fair evidence for no reduction in mortality; good evidence for uncommon but serious harms.
  • External Validity: Poor.

Significance

Natural History, Incidence, and Mortality

In 2025, an estimated 22,070 Americans will be diagnosed with esophageal cancer, and 16,250 will die of this disease. Of the new cases, an estimated 17,430 will occur in men, and 4,640 will occur in women.[1]

Two histological types account for most malignant esophageal neoplasms: adenocarcinoma and squamous carcinoma. The epidemiology of these types varies markedly. In the 1960s, squamous cell cancers comprised more than 90% of all esophageal tumors. The incidence of esophageal adenocarcinomas has risen considerably for the past two decades, such that it is now more prevalent than squamous cell cancer in the United States and Western Europe, with most tumors located in the distal esophagus.[2] Although the overall incidence of squamous cell carcinoma of the esophagus is declining, this histological type remains six times more likely to occur in Black men than in White men.[3] Incidence rates generally increase with age in all racial and ethnic groups, but squamous cell cancer is consistently more common in Black individuals than in White individuals. Incidence rates are higher in White men compared with Black men in all age groups. In women, the incidence rates are higher in Black women through age 74 years, at which point the rates become higher in White women.[4]

Risk Factors

While risk factors for squamous cell carcinoma of the esophagus have been identified (such as tobacco, alcoholism, malnutrition, and infection with human papillomavirus),[5] the risk factors associated with esophageal adenocarcinoma are less defined. The most important epidemiological difference between squamous cell cancer and adenocarcinoma, however, is the strong association between gastroesophageal reflux disease (GERD) and adenocarcinoma. The results of a population-based case-control study suggest that symptomatic gastroesophageal reflux is a risk factor for esophageal adenocarcinoma. The frequency, severity, and duration of reflux symptoms were positively associated with increased risk of esophageal adenocarcinoma.[6–8]

Long-standing GERD predisposes to Barrett esophagus, the condition in which an abnormal intestinal epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus.[9] The intestinal-type epithelium of Barrett esophagus has a characteristic endoscopic appearance that differs from squamous epithelium.[10] Dysplasia in Barrett epithelium represents an alteration of the columnar epithelium that may progress to invasive adenocarcinoma.[11]

An interesting hypothesis relates the rise in incidence of esophageal adenocarcinoma to a declining prevalence of Helicobacter pylori infection in Western countries. Reports have suggested that gastric infection with H. pylori may protect the esophagus from GERD and its complications.[12] According to this theory, H. pylori infections that cause pangastritis also cause a decrease in gastric acid production that protects against GERD.[13] Patients whose duodenal ulcers were treated successfully with antibiotics developed reflux esophagitis twice as often as those in whom infection persisted.[14]

Past use of lower esophageal sphincter (LES)-relaxing drugs was positively associated with risk of esophageal adenocarcinoma. Among daily, long-term users (>5 years) of LES-relaxing drugs, the estimated incidence rate ratio was 3.8 (95% confidence interval [CI], 2.2–6.4) compared with individuals who had never used these drugs. Gastric cardia adenocarcinoma and esophageal squamous cell carcinoma were not associated with use of LES-relaxing drugs.[15]

There exists a strong relationship between body mass index (BMI) and esophageal adenocarcinoma. The adjusted odds ratio (OR) was 7.6 (95% CI, 3.8–15.2) among individuals in the highest BMI quartile compared with individuals in the lowest. Individuals with obesity (those with BMI >30 kg/m2) had an OR of 16.2 (95% CI, 6.3–41.4), compared with those with the leanest BMI (BMI <22 kg/m2). Esophageal squamous cell carcinoma was not associated with BMI.[16]

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Blot WJ, McLaughlin JK: The changing epidemiology of esophageal cancer. Semin Oncol 26 (5 Suppl 15): 2-8, 1999. [PUBMED Abstract]
  3. Devesa SS, Blot WJ, Fraumeni JF: Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83 (10): 2049-53, 1998. [PUBMED Abstract]
  4. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
  5. Oesophagus. In: World Cancer Research Fund, American Institute for Cancer Research: Food, Nutrition and the Prevention of Cancer: A Global Perspective. The Institute, 1997, pp 118-129.
  6. Lagergren J, Bergström R, Lindgren A, et al.: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340 (11): 825-31, 1999. [PUBMED Abstract]
  7. Wijnhoven BP, Tilanus HW, Dinjens WN: Molecular biology of Barrett’s adenocarcinoma. Ann Surg 233 (3): 322-37, 2001. [PUBMED Abstract]
  8. Skacel M, Petras RE, Gramlich TL, et al.: The diagnosis of low-grade dysplasia in Barrett’s esophagus and its implications for disease progression. Am J Gastroenterol 95 (12): 3383-7, 2000. [PUBMED Abstract]
  9. Spechler SJ, Goyal RK: The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 110 (2): 614-21, 1996. [PUBMED Abstract]
  10. Van Dam J, Brugge WR: Endoscopy of the upper gastrointestinal tract. N Engl J Med 341 (23): 1738-48, 1999. [PUBMED Abstract]
  11. Reid BJ, Blount PL, Rubin CE, et al.: Flow-cytometric and histological progression to malignancy in Barrett’s esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 102 (4 Pt 1): 1212-9, 1992. [PUBMED Abstract]
  12. O’Connor HJ: Review article: Helicobacter pylori and gastro-oesophageal reflux disease-clinical implications and management. Aliment Pharmacol Ther 13 (2): 117-27, 1999. [PUBMED Abstract]
  13. Graham DY, Yamaoka Y: H. pylori and cagA: relationships with gastric cancer, duodenal ulcer, and reflux esophagitis and its complications. Helicobacter 3 (3): 145-51, 1998. [PUBMED Abstract]
  14. Labenz J, Blum AL, Bayerdörffer E, et al.: Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 112 (5): 1442-7, 1997. [PUBMED Abstract]
  15. Lagergren J, Bergström R, Adami HO, et al.: Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Ann Intern Med 133 (3): 165-75, 2000. [PUBMED Abstract]
  16. Lagergren J, Bergström R, Nyrén O: Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 130 (11): 883-90, 1999. [PUBMED Abstract]

Evidence of Benefit

Squamous Cell Cancer

Squamous cell carcinoma of the esophagus does not have a highly prevalent predisposing condition, although the incidence increases in individuals who have had long-standing exposure to tobacco and alcohol,[1] achalasia,[2] head and neck squamous cell cancer attributable most likely to long-standing alcohol and/or tobacco exposure,[3] tylosis,[4,5] history of lye ingestion,[6] celiac sprue,[7] and, in South America and China, hot liquid ingestion.[8] The etiological role of human papillomavirus infection in squamous cell cancer is under study.[9,10]

Efforts at early detection of squamous cell cancer of the esophagus have concentrated on cytological or endoscopic screening of populations in countries where there is a high incidence. While these programs have demonstrated that it is possible to detect squamous cell cancers at an early asymptomatic stage, a study from China assessed one-time endoscopic screening on the outcome of patients with esophageal cancer. In this study, communities were chosen nonrandomly in Cixian County, Hibei Province; 14 villages in the north were intervention communities and ten villages in the south were control communities. The intervention was one-time endoscopy, completed by experts, using Lugol’s iodine staining to identify dysplasia or occult cancer. After biopsy was obtained and read, dysplasia and occult cancers were treated by endoscopic mucosal resection or argon plasma coagulation. Among the 6,827 participants aged 40 to 69 years in the intervention group, 3,319 volunteers were screened. Among the 6,200 participants aged 40 to 69 years in the control group, 797 individuals were interviewed. Outcome in each group was monitored to assess incidence and mortality of esophageal squamous cancer. In a 10-year follow-up, there were 542 cases of fatal esophageal squamous cell carcinoma (ESCC), a reduction in cumulative mortality from 5.05% in the control group to 3.35% in the intervention group (P < .001), and lower incidence of ESCC in the intervention group (5.92% vs. 4.17%; P < .001). Potential weaknesses of the study include the following:[11]

  • Participants were not randomly assigned but rather came from different villages, in which underlying rates may have differed geographically (northern vs. southern villages), and it was not clear what the baseline cancer rates were.
  • It was not clear whether cause of death (e.g., ESCC) or cancer incidence was assessed in a blinded manner, which might have been important for assignment of what is a subjective assessment.

Esophageal cytological screening studies have been reported from China,[12,13] Iran,[14] South Africa,[15,16] Italy,[17] and Japan.[18] In the United States, such efforts have been focused on individuals perceived to be at higher risk.[19,20] Studies of primary endoscopic screening have been reported from France [21] and Japan.[22]

Comparisons of both Chinese and U.S. cytological diagnoses with concurrent histological findings showed low (14% to 36%) sensitivities for the cytological detection of biopsy-proven cancers. Specificity ranged from 90% to 99% with a positive predictive value of 23% to 94%.[23] The development of uniform and accurate cytological criteria will require formal cytological-histological correlation studies of esophageal lesions. Such studies should become more feasible with the increasing availability of endoscopy in high-risk populations.

The efficacy of surveillance cytology or endoscopy for high-risk patients with tylosis or long-standing achalasia is not known.

Adenocarcinoma of the Esophagus

Considerable debate has ensued concerning the risk of cancer in patients with Barrett esophagus. Prospective studies have reported annual esophageal cancer incidence rates ranging from 0.2% to 1.9%.[24] Concern over publication bias has led some authors to suggest that the risk may be lower than the literature suggests.[25] A risk of 0.5% per year for development of adenocarcinoma is now thought to be a reasonable estimate for Barrett esophagus.[26]

Barrett esophagus is strongly associated with gastroesophageal reflux disease (GERD), and the changes of Barrett esophagus can be found in approximately 10% of patients who have GERD. However, GERD is very common. Surveys have found that approximately 20% of adult Americans experience symptoms of GERD, such as heartburn, at least once each week.[27] The likelihood of finding Barrett esophagus on endoscopy is related to the duration of symptoms of gastroesophageal reflux. In a series of 701 individuals, 4% of those with symptoms for less than 1 year had Barrett esophagus on endoscopy, whereas Barrett esophagus was found in 21% of those with more than 10 years of symptoms of GERD. It has been estimated that physicians identify only approximately 5% of the population who have Barrett esophagus.[28] There is insufficient evidence that population screening for Barrett esophagus reduces cancer mortality.[29,30]

Surveillance of Barrett esophagus involves the use of tests to identify preneoplastic changes or curable neoplasms in patients who are known to have Barrett esophagus. Certain factors are essential in the implementation of an effective surveillance protocol, including low risk of the surveillance method, correct histological diagnosis of dysplasia, proof that surgical resection for high-grade dysplasia will decrease the risk of cancer, and successful resection of cancer. The interval between endoscopic evaluations is typically determined by histological findings, in accordance with published guidelines by gastroenterological committees.[31] GERD should be treated before surveillance endoscopy to minimize confusion caused by inflammation in the interpretation of biopsy specimens. The technique of random, four-quadrant biopsies taken every 2 cm in the columnar-lined esophagus for standard histological evaluation has been recommended by some clinicians. For patients with no dysplasia, surveillance endoscopy at an interval of every 2 to 3 years has been recommended.[31] For patients with low-grade dysplasia, surveillance every 6 months for the first year has been recommended, followed by annual endoscopy if the dysplasia has not progressed in severity. For patients with high-grade dysplasia, two options have been recommended: surgical resection or repeated endoscopic evaluation until the diagnosis of intramucosal carcinoma is made. Although widely adopted in clinical practice, these practices are based on uncontrolled series and the opinion of expert gastrointestinal endoscopists and pathologists.

Other techniques to potentially identify dysplastic epithelium that could then be sampled extensively include chromoendoscopy [32] and laser-induced fluorescence spectroscopy.[30,33]

References
  1. Bollschweiler E, Schröder W, Hölscher AH, et al.: Preoperative risk analysis in patients with adenocarcinoma or squamous cell carcinoma of the oesophagus. Br J Surg 87 (8): 1106-10, 2000. [PUBMED Abstract]
  2. Aggestrup S, Holm JC, Sørensen HR: Does achalasia predispose to cancer of the esophagus? Chest 102 (4): 1013-6, 1992. [PUBMED Abstract]
  3. Abemayor E, Moore DM, Hanson DG: Identification of synchronous esophageal tumors in patients with head and neck cancer. J Surg Oncol 38 (2): 94-6, 1988. [PUBMED Abstract]
  4. Ellis A, Field JK, Field EA, et al.: Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family–a review of six generations. Eur J Cancer B Oral Oncol 30B (2): 102-12, 1994. [PUBMED Abstract]
  5. Risk JM, Mills HS, Garde J, et al.: The tylosis esophageal cancer (TOC) locus: more than just a familial cancer gene. Dis Esophagus 12 (3): 173-6, 1999. [PUBMED Abstract]
  6. Isolauri J, Markkula H: Lye ingestion and carcinoma of the esophagus. Acta Chir Scand 155 (4-5): 269-71, 1989 Apr-May. [PUBMED Abstract]
  7. Ferguson A, Kingstone K: Coeliac disease and malignancies. Acta Paediatr Suppl 412: 78-81, 1996. [PUBMED Abstract]
  8. Rolón PA, Castellsagué X, Benz M, et al.: Hot and cold mate drinking and esophageal cancer in Paraguay. Cancer Epidemiol Biomarkers Prev 4 (6): 595-605, 1995. [PUBMED Abstract]
  9. Lagergren J, Wang Z, Bergström R, et al.: Human papillomavirus infection and esophageal cancer: a nationwide seroepidemiologic case-control study in Sweden. J Natl Cancer Inst 91 (2): 156-62, 1999. [PUBMED Abstract]
  10. Sur M, Cooper K: The role of the human papilloma virus in esophageal cancer. Pathology 30 (4): 348-54, 1998. [PUBMED Abstract]
  11. Wei WQ, Chen ZF, He YT, et al.: Long-Term Follow-Up of a Community Assignment, One-Time Endoscopic Screening Study of Esophageal Cancer in China. J Clin Oncol 33 (17): 1951-7, 2015. [PUBMED Abstract]
  12. Shen O, Liu SF, Dawsey SM, et al.: Cytologic screening for esophageal cancer: results from 12,877 subjects from a high-risk population in China. Int J Cancer 54 (2): 185-8, 1993. [PUBMED Abstract]
  13. Dawsey SM, Lewin KJ, Wang GQ, et al.: Squamous esophageal histology and subsequent risk of squamous cell carcinoma of the esophagus. A prospective follow-up study from Linxian, China. Cancer 74 (6): 1686-92, 1994. [PUBMED Abstract]
  14. Dowlatshahi K, Daneshbod A, Mobarhan S: Early detection of cancer of oesophagus along Caspian Littoral. Report of a pilot project. Lancet 1 (8056): 125-6, 1978. [PUBMED Abstract]
  15. Jaskiewicz K, Venter FS, Marasas WF: Cytopathology of the esophagus in Transkei. J Natl Cancer Inst 79 (5): 961-7, 1987. [PUBMED Abstract]
  16. Tim LO, Leiman G, Segal I, et al.: A suction-abrasive cytology tube for the diagnosis of esophageal carcinoma. Cancer 50 (4): 782-4, 1982. [PUBMED Abstract]
  17. Aste H, Saccomanno S, Munizzi F: Blind pan-esophageal brush cytology. Diagnostic accuracy. Endoscopy 16 (5): 165-7, 1984. [PUBMED Abstract]
  18. Nabeya K: Markers of cancer risk in the esophagus and surveillance of high-risk groups. In: Sherlock P, Morson BC, Barbara L, et al., eds.: Precancerous Lesions of the Gastrointestinal Tract. Raven Press, 1983, pp 71-86.
  19. Dowlatshahi K, Skinner DB, DeMeester TR, et al.: Evaluation of brush cytology as an independent technique for detection of esophageal carcinoma. J Thorac Cardiovasc Surg 89 (6): 848-51, 1985. [PUBMED Abstract]
  20. Jacob P, Kahrilas PJ, Desai T, et al.: Natural history and significance of esophageal squamous cell dysplasia. Cancer 65 (12): 2731-9, 1990. [PUBMED Abstract]
  21. Meyer V, Burtin P, Bour B, et al.: Endoscopic detection of early esophageal cancer in a high-risk population: does Lugol staining improve videoendoscopy? Gastrointest Endosc 45 (6): 480-4, 1997. [PUBMED Abstract]
  22. Yokoyama A, Ohmori T, Makuuchi H, et al.: Successful screening for early esophageal cancer in alcoholics using endoscopy and mucosa iodine staining. Cancer 76 (6): 928-34, 1995. [PUBMED Abstract]
  23. Dawsey SM, Shen Q, Nieberg RK, et al.: Studies of esophageal balloon cytology in Linxian, China. Cancer Epidemiol Biomarkers Prev 6 (2): 121-30, 1997. [PUBMED Abstract]
  24. Drewitz DJ, Sampliner RE, Garewal HS: The incidence of adenocarcinoma in Barrett’s esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol 92 (2): 212-5, 1997. [PUBMED Abstract]
  25. Shaheen NJ, Crosby MA, Bozymski EM, et al.: Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 119 (2): 333-8, 2000. [PUBMED Abstract]
  26. Spechler SJ: Barrett’s esophagus: an overrated cancer risk factor. Gastroenterology 119 (2): 587-9, 2000. [PUBMED Abstract]
  27. Locke GR, Talley NJ, Fett SL, et al.: Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 112 (5): 1448-56, 1997. [PUBMED Abstract]
  28. Spechler SJ: Barrett’s esophagus: should we brush off this ballooning problem? Gastroenterology 112 (6): 2138-42, 1997. [PUBMED Abstract]
  29. Gerson LB, Triadafilopoulos G: Screening for esophageal adenocarcinoma: an evidence-based approach. Am J Med 113 (6): 499-505, 2002. [PUBMED Abstract]
  30. Wang KK, Wongkeesong M, Buttar NS: American Gastroenterological Association technical review on the role of the gastroenterologist in the management of esophageal carcinoma. Gastroenterology 128 (5): 1471-505, 2005. [PUBMED Abstract]
  31. DeVault KR, Castell DO: Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 94 (6): 1434-42, 1999. [PUBMED Abstract]
  32. Canto MI, Setrakian S, Petras RE, et al.: Methylene blue selectively stains intestinal metaplasia in Barrett’s esophagus. Gastrointest Endosc 44 (1): 1-7, 1996. [PUBMED Abstract]
  33. Panjehpour M, Overholt BF, Vo-Dinh T, et al.: Endoscopic fluorescence detection of high-grade dysplasia in Barrett’s esophagus. Gastroenterology 111 (1): 93-101, 1996. [PUBMED Abstract]

Evidence of Harm

Screening for esophageal cancer by the use of blind nonendoscopically directed balloon cytological sampling for squamous cell carcinoma is minimally inconvenient and uncomfortable. Endoscopic screening for esophageal adenocarcinoma is expensive, inconvenient, and usually requires sedation.

Complications such as perforation and bleeding can occur. The incidence of complications, including perforation, respiratory arrest, and myocardial infarction, has been estimated to be 0 to 13 cases per 10,000 procedures with an associated mortality of 0 to 0.8 cases per 10,000 procedures.[1,2]

Individuals who are informed they have Barrett esophagus may consider themselves to be ill even though their risk of developing cancer is very low.

References
  1. Clarke GA, Jacobson BC, Hammett RJ, et al.: The indications, utilization and safety of gastrointestinal endoscopy in an extremely elderly patient cohort. Endoscopy 33 (7): 580-4, 2001. [PUBMED Abstract]
  2. Sieg A, Hachmoeller-Eisenbach U, Eisenbach T: Prospective evaluation of complications in outpatient GI endoscopy: a survey among German gastroenterologists. Gastrointest Endosc 53 (6): 620-7, 2001. [PUBMED Abstract]

Latest Updates to This Summary (04/10/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about esophageal cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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PDQ® Screening and Prevention Editorial Board. PDQ Esophageal Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/esophageal/hp/esophageal-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389241]

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