For information about the treatments listed below, see the Treatment Option Overview section.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed childhood LCH multisystem disease lesions in the spleen, liver, or bone marrow and another organ or site may include:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of progressive, refractory, or recurrent low-risk LCH may include:

Treatment of progressive, refractory, or recurrent high-risk multisystem LCH may include:

Treatments being studied for progressive, refractory, or recurrent childhood LCH include the following:

For more about LCH trials for adults, see the Histiocyte Society website.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more from the National Cancer Institute about Langerhans cell histiocytosis treatment, see the following:

For more childhood cancer information and other general cancer resources, visit:

Histiocytic diseases in children and adults are caused by an abnormal accumulation of cells of the mononuclear phagocytic system. This summary discusses only Langerhans cell histiocytosis (LCH), a myeloid-derived dendritic cell disorder.

Histiocytic diseases have been reclassified into five categories, with LCH in the L group (see Table 1).[1,2] LCH results from the clonal proliferation of immunophenotypically and functionally immature, morphologically rounded LCH cells found in relevant lesions, along with eosinophils, macrophages, lymphocytes, and, occasionally, multinucleated giant cells.[3,4] The pathological histiocytes and normal Langerhans cells of the epidermis (LCs) have identical immunophenotypic characteristics, including the presence of Birbeck granules identified by electron microscopy. There are clear morphological, phenotypic, and gene expression differences between the pathological variant of the LCH lesions (LCH cells) and the normal LCs, hence the term LCH cells.

LCH cells, known for many years to be a clonal proliferation, have now been shown to likely derive from a myeloid precursor whose proliferation is uniformly associated with activation of the MAPK/ERK signaling pathway.[5,6]

Clinically, LCH is a heterogenous disease that may involve a single organ (single-system LCH), which may be a single site (unifocal) or involve multiple sites (multifocal). It may also involve multiple organs (multisystem LCH). Multisystem LCH may involve a limited number of organs or be disseminated. Involvement of specific organs such as the liver, spleen, and hematopoietic system separates multisystem LCH into high-risk (multisystem risk-organ positive) and low-risk (multisystem risk-organ negative) groups, where risk indicates the risk of death from the disease.

References

1. Rodriguez-Galindo C, Allen CE: Langerhans cell histiocytosis. Blood 135 (16): 1319-1331, 2020. [PUBMED Abstract]
2. Emile JF, Abla O, Fraitag S, et al.: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127 (22): 2672-81, 2016. [PUBMED Abstract]
3. Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014. [PUBMED Abstract]
4. Allen CE, Merad M, McClain KL: Langerhans-Cell Histiocytosis. N Engl J Med 379 (9): 856-868, 2018. [PUBMED Abstract]
5. Willman CL, Busque L, Griffith BB, et al.: Langerhans’-cell histiocytosis (histiocytosis X)–a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994. [PUBMED Abstract]
6. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994. [PUBMED Abstract]

Cytogenetic and Genomic Studies

Genomics of LCH

BRAF, NRAS, and ARAF variants

The genomic basis of LCH was advanced by a 2010 report of an activating variant of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%).[17] Multiple subsequent reports have confirmed the presence of BRAF V600E variants in 50% or more of LCH cases in children.[2,18,19] Other BRAF variants that result in signal activation have been described.[18,20] ARAF variants are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.[21]

The presence of the BRAF V600E variant in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E variant by a sensitive quantitative polymerase chain reaction technique.[2] Circulating cells with the BRAF V600E variant could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The BRAF V600E allele was detected in circulating cell-free DNA in 100% of patients with risk-organ–positive multisystem LCH, 42% of patients with risk-organ–negative LCH, and 14% of patients with single-system LCH.[22]

The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the variant in the bone marrow of high-risk patients. In those with low-risk disease, the variant was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic variant occurs is critical in defining the extent of disease in LCH.

Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases,[23] while a later study of BRAF variants showed that 25% to 50% of adult patients with lung LCH had evidence of BRAF V600E variants.[23,24] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E variants and 40% had NRAS variants.[25] Approximately the same number of variants are polyclonal as are monoclonal. It has not been determined whether clonality and BRAF pathway variants are concordant in the same patients, which might suggest a reactive rather than a neoplastic condition in smoker’s lung LCH and a clonal neoplasm in other types of LCH.

In a study of 117 patients with LCH, 83 adult patients with pulmonary LCH underwent molecular analysis. Nearly 90% of these patients had variants in the MAPK pathway.[26][Level of evidence C3] Of the 69 patients who had their biopsy samples further analyzed using a next-generation sequencing panel of 74 genes, 36% had BRAF V600E variants, 29% had BRAF N486-P490 deletions, 15% had MAP2K1 variants or deletions, and 4% had NRAS variants. Only one patient had a KRAS variant. Additionally, 11 patients had their biopsy samples analyzed using whole-exome sequencing. An average of 14 variants were found per patient, which is markedly higher than the average of one variant found per pediatric patient.[27] There were no clinical correlates, including presence of a BRAF V600E variant and smoking status. Of the 117 patients with LCH, 60% experienced a relapse.

Enlarge

The RAS-MAPK signaling pathway (see Figure 1) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then the extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E variant of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[17,28]

In a mouse model of LCH, the BRAF V600E variant was shown to inhibit a chemokine receptor (CCR7)–mediated migration of dendritic cells, forcing them to accumulate in the LCH lesion.[29] This variant also causes an increased expression of BCL2L1, which results in resistance to apoptosis. This process leads to the cells being less responsive to chemotherapy. The BRAF V600E variant also causes growth arrest of hematopoietic progenitor cells and a senescence-associated secretory phenotype that further promotes accumulation of the pathological cells.[30]

Another mouse model with the BRAF V600E variant under control of Scl or Map17 gene promoters added additional insights into the biology of neurodegenerative LCH.[31] These studies confirmed the hematopoietic origin of CD11a-positive macrophages with BRAF V600E variants. This process disrupts the blood-brain barrier and causes loss of Purkinje cells and progressive neurodegeneration by resistance to apoptosis and production of senescent associated secretory proteins, which include inflammatory cytokines IL-1, IL-6, and matrix metalloproteinases. Treatment with a MAP kinase inhibitor and a senolytic agent (navitoclax) decreased the pathogenic cell numbers and led to clinical improvement in the mice.

In summary, LCH is now considered a myeloid neoplasm primarily driven by activating variants of the MAPK pathway. Fifty percent to 60% of the activating variants are caused by BRAF V600E variants, which are enriched in patients with multisystem risk organ–positive LCH and in patients with neurodegenerative-disease LCH.[32] Ongoing studies are assessing whether low-level variant detection in peripheral blood can be used as a minimal residual disease marker to assist in therapeutic decisions.

Other RAS-MAPK pathway alterations

Because RAS-MAPK pathway activation (elevated phosphor-ERK) can be detected in all LCH cases, including those without BRAF variants, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:

• MAP2K1 variants. Whole-exome sequencing on biopsy samples of BRAF-altered versus BRAF–wild-type LCH tissue revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 variants, while no BRAF-altered specimens had MAP2K1 variants.[28] The variants in MAP2K1 (which codes for MEK1) were activating, as indicated by their induction of ERK phosphorylation.[28]

  Another study showed MAP2K1 variants exclusively in 11 of 22 BRAF–wild-type cases.[33] One study showed that MAP2K1 and other variants associated with pediatric and adult LCH were mutually exclusive of BRAF variants.[34] The authors found a variety of variants in other pathways (e.g., JNK, RAS-ERK, and JAK-STAT) in pediatric and adult patients with BRAF V600E or MAP2K1 variants. Another study evaluated the kinase alterations and myeloid-associated variants in 73 adult patients with LCH.[35] They reported a median of two variants per adult patient, as opposed to children who usually have only one variant. BRAF V600E was found in 31%, BRAF indel in 29%, and MAP2K1 in 19% of patients with LCH. A variety of other protein kinase and related pathways were found in 89% of adult patients with LCH. MAP2K1 variants were exclusive of BRAF variants.

• In-frame BRAF deletions and FAM73A::BRAF gene fusions. In-frame BRAF deletions and in-frame FAM73A::BRAF gene fusions have occurred in the group of BRAF V600E and MAP2K1 variant–negative cases.[27]

In summary, studies support the universal activation of ERK in LCH. ERK activation in most cases of LCH is explained by BRAF and MAP2K1 alterations.[17,27,28] Altogether, these variants in the MAP kinase pathway account for nearly 80% of the causes of the universal activation of ERK in LCH.[17,27,28] The remaining cases have a range of variants that include small deletions in BRAF, BRAF gene fusions (discussed above), as well as variants in ARAF, MAP3K1, NRAS, ERBB3, PI3CA, CSF1R, and other rare targets.[34,32][Level of evidence C1]

Clinical implications

Clinical implications of the described genomic findings include the following:

• LCH is included in a group of other pediatric tumors with activating BRAF variants, such as select nonmalignant conditions (e.g., benign nevi) [36] and low-grade malignancies (e.g., pilocytic astrocytoma).[37,38] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[36,39]
• In some pediatric studies, BRAF V600E variants have been associated with more severe multisystem disease, treatment failure, increased reactivations, and an increased risk of neurodegeneration (see below).[40] These clinical correlates were recently investigated for non-BRAF V600E variants in an international study. Similar to the BRAF V600E cohort, all patients with multisystem risk organ–positive LCH had detectable variants in peripheral blood mononuclear cells. Of seven patients with multisystem risk organ–negative LCH, four had detectable variants. No patients with single-system disease had detectable variants in peripheral blood mononuclear cells. The authors concluded that other MAPK pathway variants are associated with risk status, similar to BRAF V600E variants.[32]

  BRAF V600E variants can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of melanoma in adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcomes compared with treatment using a BRAF inhibitor alone.[41,42]

  Several case reports and two case series have also demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[43–48] However, the long-term role of this therapy is complicated because most patients will relapse when the inhibitors are discontinued. For more information, see the sections on Treatment of recurrent, refractory, or progressive high-risk disease: multisystem LCH and Targeted therapies for the treatment of single-system and multisystem disease.

• Circulating BRAF V600E–altered cells have been found in 59% of patients who developed neurodegenerative-disease LCH, compared with 15% of patients who did not develop neurodegenerative-disease LCH. Detectable altered circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–altered cells.[13]
• With additional research, the observation of the BRAF V600E variant (or potentially MAP2K1 variants) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease.[2] Additionally, for patients who have a somatic variant, persistence of circulating cells with the variant may be useful as a marker of residual disease.[2]

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2. Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014. [PUBMED Abstract]
3. Hyman DM, Diamond EL, Vibat CR, et al.: Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders. Cancer Discov 5 (1): 64-71, 2015. [PUBMED Abstract]
4. Emile JF, Abla O, Fraitag S, et al.: Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127 (22): 2672-81, 2016. [PUBMED Abstract]
5. Picarsic J, Jaffe R: Nosology and Pathology of Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am 29 (5): 799-823, 2015. [PUBMED Abstract]
6. Ginhoux F, Merad M: Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88 (4): 387-92, 2010 May-Jun. [PUBMED Abstract]
7. Durham BH, Roos-Weil D, Baillou C, et al.: Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood 130 (2): 176-180, 2017. [PUBMED Abstract]
8. Hutter C, Kauer M, Simonitsch-Klupp I, et al.: Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells. Blood 120 (26): 5199-208, 2012. [PUBMED Abstract]
9. Berres ML, Allen CE, Merad M: Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases. Adv Immunol 120: 127-61, 2013. [PUBMED Abstract]
10. Badalian-Very G, Vergilio JA, Fleming M, et al.: Pathogenesis of Langerhans cell histiocytosis. Annu Rev Pathol 8: 1-20, 2013. [PUBMED Abstract]
11. Geissmann F, Lepelletier Y, Fraitag S, et al.: Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 97 (5): 1241-8, 2001. [PUBMED Abstract]
12. Chikwava K, Jaffe R: Langerin (CD207) staining in normal pediatric tissues, reactive lymph nodes, and childhood histiocytic disorders. Pediatr Dev Pathol 7 (6): 607-14, 2004 Nov-Dec. [PUBMED Abstract]
13. McClain KL, Picarsic J, Chakraborty R, et al.: CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer 124 (12): 2607-2620, 2018. [PUBMED Abstract]
14. Yu RC, Morris JF, Pritchard J, et al.: Defective alloantigen-presenting capacity of ‘Langerhans cell histiocytosis cells’. Arch Dis Child 67 (11): 1370-2, 1992. [PUBMED Abstract]
15. Senechal B, Elain G, Jeziorski E, et al.: Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med 4 (8): e253, 2007. [PUBMED Abstract]
16. Sengal A, Velazquez J, Hahne M, et al.: Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH. Blood 137 (13): 1777-1791, 2021. [PUBMED Abstract]
17. Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010. [PUBMED Abstract]
18. Satoh T, Smith A, Sarde A, et al.: B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 7 (4): e33891, 2012. [PUBMED Abstract]
19. Sahm F, Capper D, Preusser M, et al.: BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 120 (12): e28-34, 2012. [PUBMED Abstract]
20. Héritier S, Hélias-Rodzewicz Z, Chakraborty R, et al.: New somatic BRAF splicing mutation in Langerhans cell histiocytosis. Mol Cancer 16 (1): 115, 2017. [PUBMED Abstract]
21. Nelson DS, Quispel W, Badalian-Very G, et al.: Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 123 (20): 3152-5, 2014. [PUBMED Abstract]
22. Héritier S, Hélias-Rodzewicz Z, Lapillonne H, et al.: Circulating cell-free BRAF(V600E) as a biomarker in children with Langerhans cell histiocytosis. Br J Haematol 178 (3): 457-467, 2017. [PUBMED Abstract]
23. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003. [PUBMED Abstract]
24. Roden AC, Hu X, Kip S, et al.: BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 38 (4): 548-51, 2014. [PUBMED Abstract]
25. Mourah S, How-Kit A, Meignin V, et al.: Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis. Eur Respir J 47 (6): 1785-96, 2016. [PUBMED Abstract]
26. Jouenne F, Chevret S, Bugnet E, et al.: Genetic landscape of adult Langerhans cell histiocytosis with lung involvement. Eur Respir J 55 (2): , 2020. [PUBMED Abstract]
27. Chakraborty R, Burke TM, Hampton OA, et al.: Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood 128 (21): 2533-2537, 2016. [PUBMED Abstract]
28. Chakraborty R, Hampton OA, Shen X, et al.: Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124 (19): 3007-15, 2014. [PUBMED Abstract]
29. Hogstad B, Berres ML, Chakraborty R, et al.: RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med 215 (1): 319-336, 2018. [PUBMED Abstract]
30. Bigenwald C, Le Berichel J, Wilk CM, et al.: BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology. Nat Med 27 (5): 851-861, 2021. [PUBMED Abstract]
31. Wilk CM, Cathomas F, Török O, et al.: Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders. Immunity 56 (12): 2790-2802.e6, 2023. [PUBMED Abstract]
32. Milne P, Abhyankar H, Scull B, et al.: Cellular distribution of mutations and association with disease risk in Langerhans cell histiocytosis without BRAFV600E. Blood Adv 6 (16): 4901-4904, 2022. [PUBMED Abstract]
33. Brown NA, Furtado LV, Betz BL, et al.: High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 124 (10): 1655-8, 2014. [PUBMED Abstract]
34. Durham BH, Lopez Rodrigo E, Picarsic J, et al.: Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med 25 (12): 1839-1842, 2019. [PUBMED Abstract]
35. Chen J, Zhao AL, Duan MH, et al.: Diverse kinase alterations and myeloid-associated mutations in adult histiocytosis. Leukemia 36 (2): 573-576, 2022. [PUBMED Abstract]
36. Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436 (7051): 720-4, 2005. [PUBMED Abstract]
37. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008. [PUBMED Abstract]
38. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008. [PUBMED Abstract]
39. Jacob K, Quang-Khuong DA, Jones DT, et al.: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17 (14): 4650-60, 2011. [PUBMED Abstract]
40. Héritier S, Emile JF, Barkaoui MA, et al.: BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol 34 (25): 3023-30, 2016. [PUBMED Abstract]
41. Larkin J, Ascierto PA, Dréno B, et al.: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371 (20): 1867-76, 2014. [PUBMED Abstract]
42. Long GV, Stroyakovskiy D, Gogas H, et al.: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386 (9992): 444-51, 2015. [PUBMED Abstract]
43. Eckstein OS, Visser J, Rodriguez-Galindo C, et al.: Clinical responses and persistent BRAF V600E+ blood cells in children with LCH treated with MAPK pathway inhibition. Blood 133 (15): 1691-1694, 2019. [PUBMED Abstract]
44. Donadieu J, Larabi IA, Tardieu M, et al.: Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol 37 (31): 2857-2865, 2019. [PUBMED Abstract]
45. Kolenová A, Schwentner R, Jug G, et al.: Targeted inhibition of the MAPK pathway: emerging salvage option for progressive life-threatening multisystem LCH. Blood Adv 1 (6): 352-356, 2017. [PUBMED Abstract]
46. Lee LH, Gasilina A, Roychoudhury J, et al.: Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. JCI Insight 2 (3): e89473, 2017. [PUBMED Abstract]
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48. Váradi Z, Bánusz R, Csomor J, et al.: Effective BRAF inhibitor vemurafenib therapy in a 2-year-old patient with sequentially diagnosed Langerhans cell histiocytosis and Erdheim-Chester disease. Onco Targets Ther 10: 521-526, 2017. [PUBMED Abstract]
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50. Annels NE, Da Costa CE, Prins FA, et al.: Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis. J Exp Med 197 (10): 1385-90, 2003. [PUBMED Abstract]
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145. Rosso DA, Amaral D, Latella A, et al.: Reduced doses of cladribine and cytarabine regimen was effective and well tolerated in patients with refractory-risk multisystem Langerhans cell histiocytosis. Br J Haematol 172 (2): 287-90, 2016. [PUBMED Abstract]
146. Rodriguez-Galindo C, Jeng M, Khuu P, et al.: Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 51 (5): 703-6, 2008. [PUBMED Abstract]
147. Abraham A, Alsultan A, Jeng M, et al.: Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer 60 (6): E19-22, 2013. [PUBMED Abstract]
148. Donadieu J, Larabi IA, Tardieu M, et al.: Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol 37 (31): 2857-2865, 2019. [PUBMED Abstract]
149. Tardieu M, Néron A, Duvert-Lehembre S, et al.: Cutaneous adverse events in children treated with vemurafenib for refractory BRAFV600E mutated Langerhans cell histiocytosis. Pediatr Blood Cancer 68 (9): e29140, 2021. [PUBMED Abstract]
150. Mohapatra D, Gupta AK, Haldar P, et al.: Efficacy and safety of vemurafenib in Langerhans cell histiocytosis (LCH): A systematic review and meta-analysis. Pediatr Hematol Oncol 40 (1): 86-97, 2023. [PUBMED Abstract]
151. Whitlock JA, Geoerger B, Dunkel IJ, et al.: Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv 7 (15): 3806-3815, 2023. [PUBMED Abstract]
152. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PUBMED Abstract]
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154. Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003. [PUBMED Abstract]
155. Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001. [PUBMED Abstract]
156. Caselli D, Aricò M; EBMT Paediatric Working Party: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008. [PUBMED Abstract]
157. Kudo K, Maeda M, Suzuki N, et al.: Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis. Int J Hematol 111 (1): 137-148, 2020. [PUBMED Abstract]
158. Veys PA, Nanduri V, Baker KS, et al.: Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol 169 (5): 711-8, 2015. [PUBMED Abstract]
159. Ziogas IA, Kakos CD, Wu WK, et al.: Liver Transplantation for Langerhans Cell Histiocytosis: A US Population-Based Analysis and Systematic Review of the Literature. Liver Transpl 27 (8): 1181-1190, 2021. [PUBMED Abstract]
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167. Sakamoto K, Morimoto A, Shioda Y, et al.: Long-term complications in uniformly treated paediatric Langerhans histiocytosis patients disclosed by 12 years of follow-up of the JLSG-96/02 studies. Br J Haematol 192 (3): 615-620, 2021. [PUBMED Abstract]
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170. Nanduri V, Tatevossian R, Sirimanna T: High incidence of hearing loss in long-term survivors of multisystem Langerhans cell histiocytosis. Pediatr Blood Cancer 54 (3): 449-53, 2010. [PUBMED Abstract]
171. Nanduri VR, Lillywhite L, Chapman C, et al.: Cognitive outcome of long-term survivors of multisystem langerhans cell histiocytosis: a single-institution, cross-sectional study. J Clin Oncol 21 (15): 2961-7, 2003. [PUBMED Abstract]
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173. Egeler RM, Neglia JP, Puccetti DM, et al.: Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer 71 (3): 865-73, 1993. [PUBMED Abstract]
174. Egeler RM, Neglia JP, Aricò M, et al.: The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society. Hematol Oncol Clin North Am 12 (2): 369-78, 1998. [PUBMED Abstract]
175. Castro EC, Blazquez C, Boyd J, et al.: Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature. Pediatr Dev Pathol 13 (3): 225-37, 2010 May-Jun. [PUBMED Abstract]
176. Feldman AL, Berthold F, Arceci RJ, et al.: Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 6 (6): 435-7, 2005. [PUBMED Abstract]
177. Rodig SJ, Payne EG, Degar BA, et al.: Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol 83 (2): 116-21, 2008. [PUBMED Abstract]
178. Bagnasco F, Zimmermann SY, Egeler RM, et al.: Langerhans cell histiocytosis and associated malignancies: A retrospective analysis of 270 patients. Eur J Cancer 172: 138-145, 2022. [PUBMED Abstract]
179. Goyal G, Parikh R, Richman J, et al.: Spectrum of second primary malignancies and cause-specific mortality in pediatric and adult langerhans cell histiocytosis. Leuk Res 126: 107032, 2023. [PUBMED Abstract]

The natural history of disease in adults with Langerhans cell histiocytosis (LCH) is poorly understood. Pulmonary LCH is the exception to this finding. Delays of many months or years commonly occur before adults are diagnosed, and they have long-term issues with chronic pain and fatigue. There are other differences from childhood LCH, including frequency of various bone sites of disease. It also appears that multisystem high-risk LCH in adults may be less aggressive than high-risk disease in children. A consensus group reported on the evaluation and treatment of adult patients with LCH.[1] However, treatment discussions continue, particularly regarding optimal first-line therapy.

A multicenter retrospective review of 219 adult patients (aged >18 years) with LCH was conducted to assess long-term outcomes. The median follow-up was 74 months. The 5-year disease-free survival rate was 58%, and the overall survival (OS) rate was 88%. About one-third of deaths were LCH-related and occurred within 5 years of diagnosis. Second cancers occurred in 16.4% of cases (both hematologic and solid tumors). Deaths that occurred 5 or more years after diagnosis were predominantly non-LCH related (i.e., second cancers, chronic obstructive pulmonary disease, and cardiovascular disease). Compared with the general U.S. population, patients with LCH had a higher standard mortality ratio (SMR) if diagnosed before age 55 years (SMR, 5.94) or had multisystem disease (SMR, 4.12).[2]

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86. Hazim AZ, Ruan GJ, Ravindran A, et al.: Efficacy of BRAF-Inhibitor Therapy in BRAFV600E -Mutated Adult Langerhans Cell Histiocytosis. Oncologist 25 (12): 1001-1004, 2020. [PUBMED Abstract]
87. Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012. [PUBMED Abstract]
88. Sander CS, Kaatz M, Elsner P: Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide. Dermatology 208 (2): 149-52, 2004. [PUBMED Abstract]
89. Crickx E, Bouaziz JD, Lorillon G, et al.: Clinical Spectrum, Quality of Life, BRAF Mutation Status and Treatment of Skin Involvement in Adult Langerhans Cell Histiocytosis. Acta Derm Venereol 97 (7): 838-842, 2017. [PUBMED Abstract]

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.

Recurrent gestational trophoblastic neoplasia (GTN) is cancer that has recurred (come back) after it has been treated. The cancer may come back in the uterus or in other parts of the body.

Gestational trophoblastic neoplasia that does not respond to treatment is called resistant GTN.

For information about the treatments listed below, see the Treatment Option Overview section.

For more information from the National Cancer Institute about gestational trophoblastic tumors and neoplasia, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

Gestational trophoblastic disease (GTD) is a broad term encompassing both benign and malignant growths arising from products of conception in the uterus.[1]

References

1. Ngan HY, Kohorn EI, Cole LA, et al.: Trophoblastic disease. Int J Gynaecol Obstet 119 (Suppl 2): S130-6, 2012. [PUBMED Abstract]
2. Altieri A, Franceschi S, Ferlay J, et al.: Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 4 (11): 670-8, 2003. [PUBMED Abstract]
3. Altman AD, Bentley B, Murray S, et al.: Maternal age-related rates of gestational trophoblastic disease. Obstet Gynecol 112 (2 Pt 1): 244-50, 2008. [PUBMED Abstract]
4. Gestational trophoblastic neoplasms. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 691-7.

Gestational trophoblastic disease (GTD) may be classified as follows:[1]

Choriocarcinoma, PSTT, and ETT are often grouped under the heading gestational trophoblastic tumors.

References

1. Altieri A, Franceschi S, Ferlay J, et al.: Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 4 (11): 670-8, 2003. [PUBMED Abstract]
2. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990. [PUBMED Abstract]
3. Feltmate CM, Genest DR, Goldstein DP, et al.: Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47 (5): 337-41, 2002. [PUBMED Abstract]
4. Schmid P, Nagai Y, Agarwal R, et al.: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374 (9683): 48-55, 2009. [PUBMED Abstract]
5. Shih IM, Kurman RJ: Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 22 (11): 1393-403, 1998. [PUBMED Abstract]
6. Palmer JE, Macdonald M, Wells M, et al.: Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53 (7): 465-75, 2008. [PUBMED Abstract]

References

1. Ngan HYS, Seckl MJ, Berkowitz RS, et al.: Diagnosis and management of gestational trophoblastic disease: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 86-93, 2021. [PUBMED Abstract]
2. Gestational trophoblastic neoplasms. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 691-7.

Most hydatidiform moles (HMs) are benign and are treated conservatively by dilation, suction evacuation, and curettage. However, since they carry a risk of persistence or progression to malignant gestational trophoblastic disease (GTD), they must be followed carefully with weekly serum human chorionic gonadotropin (hCG) levels to normalization. Monthly follow-up for 6 months is generally recommended, although the duration of this phase of follow-up is not based on empiric study.[1]

Prompt institution of therapy for GTD and continuing follow-up at very close intervals until normal beta-hCG titers are obtained is the cornerstone of management. When chemotherapy is instituted, the interval between courses should rarely exceed 14 to 21 days, depending on the regimen used. It is recommended that patients receive one to three courses of chemotherapy after the first normal beta-hCG titer, depending on the extent of disease. The modified World Health Organization (WHO) Prognostic Scoring System (see Table 1) should be used, and combination chemotherapy should be initiated when warranted by the patient’s score. If a diagnosis of GTD is made, routine work-up includes the following:

Treatment of GTD depends on the risk category determined by the modified WHO Prognostic Scoring System as adapted by the Fédération Internationale de Gynécologie et d’Obstétrique (see Table 1). Since the very rare placental-site trophoblastic tumors and the even more rare epithelioid trophoblastic tumors are biologically distinct entities, their management is discussed separately.

References

1. Sita-Lumsden A, Short D, Lindsay I, et al.: Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009. Br J Cancer 107 (11): 1810-4, 2012. [PUBMED Abstract]
2. Muller CY, Cole LA: The quagmire of hCG and hCG testing in gynecologic oncology. Gynecol Oncol 112 (3): 663-72, 2009. [PUBMED Abstract]

Treatment of hydatidiform mole (HM) is within the purview of the obstetrician/gynecologist and is not discussed separately here. However, following the diagnosis and treatment of HM, patients should be monitored to rule out the possibility of metastatic gestational trophoblastic neoplasia. In almost all cases, this can be performed with routine monitoring of serum beta human chorionic gonadotropin (beta-hCG) to document its return to normal. An effective form of contraception is important during the follow-up period to avoid the confusion that can occur with a rising beta-hCG as a result of pregnancy.

Chemotherapy is necessary when there is the following:

Chemotherapy is ultimately required for persistence or neoplastic transformation in about 15% to 20% of patients after evacuation of a complete HM but for fewer than 5% of patients with partial HM. Chemotherapy is determined by the patient’s modified World Health Organization score.

In women with complete HM, risk of persistence or neoplastic transformation is approximately doubled in the setting of certain characteristics, which include the following:

Studies have shown that a single course of prophylactic dactinomycin or methotrexate can decrease the risk of a postmolar gestational trophoblastic disease (GTD).[1–3] However, there is concern that chemoprophylaxis increases tumor resistance to standard therapy in the women who subsequently develop GTD.[1] Therefore, this practice is generally limited to countries in which a large number of women do not return for follow-up.

References

1. Kim DS, Moon H, Kim KT, et al.: Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole. Obstet Gynecol 67 (5): 690-4, 1986. [PUBMED Abstract]
2. Limpongsanurak S: Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 46 (2): 110-6, 2001. [PUBMED Abstract]
3. Uberti EM, Fajardo Mdo C, Ferreira SV, et al.: Reproductive outcome after discharge of patients with high-risk hydatidiform mole with or without use of one bolus dose of actinomycin D, as prophylactic chemotherapy, during the uterine evacuation of molar pregnancy. Gynecol Oncol 115 (3): 476-81, 2009. [PUBMED Abstract]

There is no consensus on the best chemotherapy regimen for initial management of low-risk gestational trophoblastic neoplasia (GTN), and first-line regimens vary by geography and institutional preference. Most regimens have not been compared head-to-head, and the level of evidence for efficacy is often limited to C2 except as noted below. Even if there are differences in initial remission rate among the regimens, salvage with alternate regimens is very effective, and the ultimate cure rates are generally 99% or more. The initial regimen is generally given until a normal beta human chorionic gonadotropin (beta-hCG) (for the institution) is achieved and sustained for 3 consecutive weeks (or at least for one treatment cycle beyond normalization of the beta-hCG). A salvage regimen is instituted if any of the following occur:

The use of chemotherapy in the first-line management of low-risk GTN has been assessed in a Cochrane Collaboration systematic review.[1] In that systematic review, four randomized controlled trials were identified.[2–5]

Three of the randomized trials [3–5] compared the same two commonly used regimens:

These three trials included a total of 392 patients. In all three trials, patients who received pulsed dactinomycin had better primary complete response rates without the need for additional salvage therapy (relative risk [RR] of cure, 3.00; 95% confidence interval [CI], 1.10–8.17), even though the magnitude of benefit showed substantial heterogeneity (I2 statistic = 79%).[3–5][Level of evidence B1] Fewer courses of dactinomycin therapy were needed to achieve complete response and cure. As expected, salvage chemotherapy was nearly uniformly successful, because almost all low-risk GTN patients are ultimately cured, irrespective of the initial chemotherapeutic regimen. There were no statistically significant differences in most toxicities, including the following:

There was a statistically significant increase in dermatologic toxicity, including alopecia, associated with dactinomycin. However, in the largest study,[5] there was more low-grade gastrointestinal toxicity, grade 2 nausea, grade 1 to 2 vomiting, and grades 1 to 3 neutropenia in the dactinomycin group. These values were statistically significant. In this study, patients with choriocarcinoma and risk scores of 5 to 6 had worse complete response rates to initial treatment with single-agent therapy. Methotrexate was virtually ineffective.[5]

The fourth randomized trial was very small and included 45 patients. The study compared a 5-day regimen of dactinomycin (10 μg/kg) with an 8-day regimen of methotrexate (1 mg/kg) and leucovorin (0.1 mg/kg) on alternate days. There was a statistically significant decrease in risk of failure to achieve primary cure without the need for salvage therapy in the dactinomycin arm (RR, 0.57; 95% CI, 0.40–0.81).[2][Level of evidence B1] There was less alopecia associated with methotrexate but more hepatic toxicity.

The Cochrane systematic review also summarized the evidence from four nonrandomized trials, but comparisons across studies are difficult. The regimens evaluated in those studies are included in the lists below.[1][Level of evidence C2]

Commonly used treatment regimens include the following:

Other regimens in less-common use include the following:[1]

The unusual patient with a tumor that becomes refractory to single-agent chemotherapy is treated with one of the combination regimens described below for high-risk GTN. For more information, see the Treatment of High-Risk Gestational Trophoblastic Neoplasia (FIGO Score ≥7) section.

References

1. Alazzam M, Tidy J, Hancock BW, et al.: First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev (1): CD007102, 2009. [PUBMED Abstract]
2. Lertkhachonsuk AA, Israngura N, Wilailak S, et al.: Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer 19 (5): 985-8, 2009. [PUBMED Abstract]
3. Gilani MM, Yarandi F, Eftekhar Z, et al.: Comparison of pulse methotrexate and pulse dactinomycin in the treatment of low-risk gestational trophoblastic neoplasia. Aust N Z J Obstet Gynaecol 45 (2): 161-4, 2005. [PUBMED Abstract]
4. Yarandi F, Eftekhar Z, Shojaei H, et al.: Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynaecol Obstet 103 (1): 33-7, 2008. [PUBMED Abstract]
5. Osborne RJ, Filiaci V, Schink JC, et al.: Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol 29 (7): 825-31, 2011. [PUBMED Abstract]
6. Khan F, Everard J, Ahmed S, et al.: Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: efficacy, acute and long-term effects. Br J Cancer 89 (12): 2197-201, 2003. [PUBMED Abstract]
7. Hitchins RN, Holden L, Newlands ES, et al.: Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987. Eur J Cancer Clin Oncol 24 (6): 1041-6, 1988. [PUBMED Abstract]

Multiagent chemotherapy is standard for the initial management of high-risk gestational trophoblastic neoplasia (GTN). A systematic literature review revealed only one randomized controlled trial (and no high-quality trials)—conducted in the 1980s—comparing multiagent chemotherapy regimens for high-risk GTN.[1] In the trial, only 42 women were randomly assigned to either a CHAMOMA regimen (i.e., methotrexate, leucovorin, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin) or MAC (i.e., methotrexate, dactinomycin, and chlorambucil).[2] There was substantially more life-threatening toxicity in the CHAMOMA arm and no evidence of higher efficacy. However, there were serious methodological problems with this trial. It was reportedly designed as an equivalency trial, but owing to the small sample size, the trial was inadequately powered to assess equivalence. In addition, the characteristics of the patients randomly assigned to the two study arms were not reported (although the authors stated that there were no major differences in the patient populations assigned to each arm), nor was the method of randomization or allocation concealment described.

There are no randomized trials comparing regimens in common use to establish the superiority of one over another. Therefore, the literature does not permit firm conclusions about the best chemotherapeutic regimen.[1][Level of evidence C2] However, since EMA/CO (i.e., etoposide, methotrexate, and dactinomycin/cyclophosphamide and vincristine) is the most commonly used regimen, the specifics are provided in Table 2 below.[3–5]

Cycles are repeated every 2 weeks (on days 15, 16, and 22) until any metastases present at diagnosis disappear and serum beta-human chorionic gonadotropin (beta-hCG) has normalized, then the treatment is usually continued for an additional three to four cycles.

Results of a large, consecutive case series of 272 patients with up to 16 years of follow-up showed a complete remission rate of 78% using this regimen, and these results are consistent with other case series in the literature that employed EMA/CO.[3] More than two-thirds of the women who did not have a complete response or subsequently had disease recurrence could be salvaged with cisplatin-containing regimens (with or without resection of metastases), yielding a long-term cure rate of 86.2% (95% confidence interval, 81.9%–90.5%).[3][Level of evidence C1] Moreover, routinely when the addition of cisplatin plus etoposide was added to EMA/CO, a 9% improvement was reported in the survival results of these high-risk patients.[6] Among the women who had an intact uterus, about 50% retained their fertility. Patients with documented brain metastases received higher doses of systemic methotrexate as part of the EMA component of EMA/CO (1 g/m2 intravenously [IV] for 24 hours, followed by leucovorin rescue, 15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with brain metastases received an increased dose of systemic methotrexate of 1 g/m2 for 24 hours followed by leucovorin (15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with lung metastases received cranial prophylaxis with irradiation and intrathecal methotrexate 12.5 mg every 2 weeks with the CO (i.e., cyclophosphamide and vincristine) cycles.

Examples of other regimens that have been used include the following:[1]

Brain metastases are associated with poor prognosis, particularly when liver metastases are also present.[7–9] However, even patients with brain metastases may achieve long-term remission in 50% to 80% of cases.[3,4,9] Patients with central nervous system (CNS) metastases receive additional therapy simultaneously with the initiation of systemic chemotherapy. Some centers use whole-brain irradiation (30 Gy in 2 Gy fractions) with or without intrathecal methotrexate.[7] However, some investigators omit the cranial radiation, relying on replacement of the standard dose of methotrexate in the EMA/CO regimen with the higher dose of 1,000 mg/m2 IV for 24 hours on the first day, as noted above, to achieve therapeutic CNS levels.[9]

References

1. Deng L, Yan X, Zhang J, et al.: Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev (2): CD005196, 2009. [PUBMED Abstract]
2. Curry SL, Blessing JA, DiSaia PJ, et al.: A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in “poor prognosis” metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 73 (3 Pt 1): 357-62, 1989. [PUBMED Abstract]
3. Bower M, Newlands ES, Holden L, et al.: EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 15 (7): 2636-43, 1997. [PUBMED Abstract]
4. Escobar PF, Lurain JR, Singh DK, et al.: Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol Oncol 91 (3): 552-7, 2003. [PUBMED Abstract]
5. Lurain JR, Singh DK, Schink JC: Management of metastatic high-risk gestational trophoblastic neoplasia: FIGO stages II-IV: risk factor score > or = 7. J Reprod Med 55 (5-6): 199-207, 2010 May-Jun. [PUBMED Abstract]
6. Alifrangis C, Agarwal R, Short D, et al.: EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol 31 (2): 280-6, 2013. [PUBMED Abstract]
7. Small W, Lurain JR, Shetty RM, et al.: Gestational trophoblastic disease metastatic to the brain. Radiology 200 (1): 277-80, 1996. [PUBMED Abstract]
8. Crawford RA, Newlands E, Rustin GJ, et al.: Gestational trophoblastic disease with liver metastases: the Charing Cross experience. Br J Obstet Gynaecol 104 (1): 105-9, 1997. [PUBMED Abstract]
9. Newlands ES, Holden L, Seckl MJ, et al.: Management of brain metastases in patients with high-risk gestational trophoblastic tumors. J Reprod Med 47 (6): 465-71, 2002. [PUBMED Abstract]

Because placental-site trophoblastic tumors (PSTTs) are rare, reports of therapeutic results are confined to relatively small case series with accrual extending for very long time periods. Therefore, few reliable comparisons among surgical approaches or chemotherapeutic regimens can be made. Nevertheless, there are distinctions in underlying biology between PSTTs and the other gestational trophoblastic tumors—particularly resistance to chemotherapy—that justify specific treatment strategies, such as the following:

In part because of the inherent chemoresistance of PSTTs, resection of tumors is often considered in addition to chemotherapy regimens used for high-risk gestational trophoblastic neoplasias. In retrospective series, adjuvant surgery, such as hysterectomy, excision of lung metastases, or removal of obstructing abdominal lesions, has been associated with favorable disease control. However, it is not clear which component of the favorable outcomes is attributable to the surgery or to patient selection factors.[2,3][Level of evidence C2]

References

1. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990. [PUBMED Abstract]
2. Schmid P, Nagai Y, Agarwal R, et al.: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374 (9683): 48-55, 2009. [PUBMED Abstract]
3. Feltmate CM, Genest DR, Goldstein DP, et al.: Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47 (5): 337-41, 2002. [PUBMED Abstract]

Epithelioid trophoblastic tumors (ETTs) are exceedingly rare, and there is little information to guide therapy. However, these tumors are similar in behavior and prognosis to placental-site trophoblastic tumors, so it is reasonable to manage them similarly. For more information, see the Treatment of Placental-Site Trophoblastic Tumor section. Few ETTs are malignant in nature, but they are not very responsive to systemic therapy. A variety of chemotherapy regimens have been used.[1]

References

1. Palmer JE, Macdonald M, Wells M, et al.: Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53 (7): 465-75, 2008. [PUBMED Abstract]

Recurrent disease indicates failure of prior chemotherapy unless initial therapy was surgery alone. One study found recurrence of disease in 2.5% of patients with nonmetastatic disease, 3.7% of patients with good-prognosis metastatic disease, and 13% of patients with poor-prognosis metastatic disease.[1] Nearly all recurrences occur within 3 years of remission (85% before 18 months). A patient whose disease progresses after primary surgical therapy is generally treated with single-agent chemotherapy unless one of the poor-prognosis factors that requires combination chemotherapy supervenes. Relapse after failure of prior chemotherapy automatically places the patient in the high-risk category. These patients should be treated with aggressive chemotherapy.

Reports of combination chemotherapy come from small retrospective case series. Long-term disease-free survival, in excess of 50%, is achievable with combination drug regimens.[2][Level of evidence C2] A variety of regimens have been reported that include combinations of the following:[3–7]

A select group of patients with chemotherapy-resistant and clinically detectable gestational trophoblastic neoplasia may benefit from salvage surgery.[8][Level of evidence C2]

References

1. Mutch DG, Soper JT, Babcock CJ, et al.: Recurrent gestational trophoblastic disease. Experience of the Southeastern Regional Trophoblastic Disease Center. Cancer 66 (5): 978-82, 1990. [PUBMED Abstract]
2. Newlands ES: The management of recurrent and drug-resistant gestational trophoblastic neoplasia (GTN). Best Pract Res Clin Obstet Gynaecol 17 (6): 905-23, 2003. [PUBMED Abstract]
3. Matsui H, Iitsuka Y, Suzuka K, et al.: Salvage chemotherapy for high-risk gestational trophoblastic tumor. J Reprod Med 49 (6): 438-42, 2004. [PUBMED Abstract]
4. Xiang Y, Sun Z, Wan X, et al.: EMA/EP chemotherapy for chemorefractory gestational trophoblastic tumor. J Reprod Med 49 (6): 443-6, 2004. [PUBMED Abstract]
5. Lurain JR, Nejad B: Secondary chemotherapy for high-risk gestational trophoblastic neoplasia. Gynecol Oncol 97 (2): 618-23, 2005. [PUBMED Abstract]
6. Wan X, Xiang Y, Yang X, et al.: Efficacy of the FAEV regimen in the treatment of high-risk, drug-resistant gestational trophoblastic tumor. J Reprod Med 52 (10): 941-4, 2007. [PUBMED Abstract]
7. Wang J, Short D, Sebire NJ, et al.: Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE). Ann Oncol 19 (9): 1578-83, 2008. [PUBMED Abstract]
8. Lehman E, Gershenson DM, Burke TW, et al.: Salvage surgery for chemorefractory gestational trophoblastic disease. J Clin Oncol 12 (12): 2737-42, 1994. [PUBMED Abstract]
9. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
10. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
11. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
12. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
13. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
14. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
15. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
16. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

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.

Treatment of Recurrent or Chemoresistant Gestational Trophoblastic Neoplasia

Added Fluorouracil Dosing as a new subsection.

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.