Author: RR

Adjuvant and Salvage Radiotherapy after Prostatectomy American Society of Clinical Oncology Clinical Practice Guideline Endorsement

RR

SUMMARY: The American Society of Clinical Oncology (ASCO) recently endorsed the Clinical Practice Guidelines recommended by the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO), on Adjuvant and Salvage Radiotherapy after Prostatectomy. These guidelines target Medical and Radiation Oncologists, Primary care providers, Urologists, other health care providers and address patient counseling, use of radiotherapy in the adjuvant and salvage settings, definition of biochemical recurrence and restaging evaluation. The following are the ASCO Key Recommendations for Adjuvant and Salvage Radiotherapy after Prostatectomy:

1. Patients who are being considered for management of localized prostate cancer with radical prostatectomy should be informed of the potential for adverse pathologic findings that portend a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery.

2. Patients with adverse pathologic findings, including seminal vesicle invasion, positive surgical margins, and extraprostatic extension, should be informed that adjuvant radiotherapy, compared with radical prostatectomy only, reduces the risk of biochemical Prostate Specific Antigen (PSA) recurrence, local recurrence, and clinical progression of cancer. They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of two randomized controlled trials that addressed these outcomes indicated a benefit, but the other trial did not demonstrate a benefit defined as reduced risk of metastasis and death.

3. Physicians should “OFFER” adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy, including seminal vesicle invasion, positive surgical margins, or extraprostatic extension, because of demonstrated reductions in biochemical recurrence, local recurrence and clinical progression.

4. Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death resulting from the disease. Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate.

5. Clinicians should define biochemical recurrence as a detectable or increasing PSA value after surgery that is more than 0.2 ng/mL, with a second confirmatory level more than 0.2 ng/mL.

6. A restaging evaluation in a patient with a PSA recurrence may be considered although it is not clear at this time which imaging modalities to use, as all imaging modalities have limited sensitivity and specificity in the low PSA range.

7. Physicians should “OFFER” salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy, in whom there is no evidence of distant metastatic disease.

8. Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when administered at lower levels of PSA (less than 1 ng/ml). Salvage radiotherapy in this patient population with a short PSA doubling time, has been shown to improve overall survival.

9. Patients should be informed of the possible short and long term urinary, bowel, and sexual adverse effects of radiotherapy as well as of the potential benefits of controlling disease recurrence.

This endorsement was made with certain qualifying statements, clarifying certain aspects of these guidelines.

a) The word “OFFER” should be interpreted as having a detailed discussion with the patient about the risks and benefits of adjuvant radiation.

b) Even though 0.2 ng/mL is considered a reasonable cut point for PSA recurrence, the benefits of using this cut point versus other cut points remains unclear.

c) Patient’s who have the greatest benefit in absolute risk reduction from adjuvant RT, are those with adverse pathologic findings as noted in the guidelines, with a high risk of recurrence or clinical progression.

In conclusion, the decision to administer adjuvant or salvage radiotherapy should be made by the patient and multidisciplinary treatment team, after discussing the risks and benefits of such intervention. Freedland SJ, Rumble RB, Finelli A, et al. J Clin Oncol 2014;32:3892-3898

OPDIVO® (Nivolumab)

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The FDA on December 22, 2014 granted accelerated approval to OPDIVO® for the treatment of patients with unresectable or metastatic melanoma and disease progression following YERVOY® (Ipilimumab) and if BRAF V600 mutation positive, a BRAF inhibitor. OPDIVO® is a product of Bristol-Myers Squibb Company.

LYNPARZA® (Olaparib)

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The FDA on December 19, 2014 approved LYNPARZA® capsules as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) (as detected by an FDA-approved test) advanced ovarian cancer, who have been treated with three or more prior lines of chemotherapy. Concurrent with this action, FDA approved the BRACAnalysis CDx® (Myriad Genetics) for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes. LYNPARZA® capsules is a product of AstraZeneca Pharmaceuticals LP.

SOMATULINE® Depot Injection (Lanreotide)

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The FDA on December 16, 2014 approved SOMATULINE® Depot Injection for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. SOMATULINE® Depot Injection was previously approved for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. SOMATULINE® Depot Injection is a product of Ipsen Pharma.

CYRAMZA® (Ramucirumab)

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The FDA on December 12, 2014 approved CYRAMZA® for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA®. CYRAMZA® injection for intravenous infusion is a product of Eli Lilly and Company.

The Second ASH CHOOSING WISELY® Campaign Five Hematologic Tests and Treatments to Question

RR

SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged medical societies to identify 5 tests, procedures or treatments, within each specialty's clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care. The 2014 Task Force was comprised of 13 individuals representing a broad spectrum of hematologic expertise including malignant, benign, adult, and pediatric specialists. The five final recommendations of the 2014 ASH Choosing Wisely Campaign are summarized below. Practicing hematologists should give due consideration to these recommendations which are evidence based and cost effective.

ASH recommendation #1: In patients with a first VTE (Venous ThromboEmbolism) provoked by a major, transient VTE risk factor such as surgery, trauma, or an intravascular catheter, do not treat with an anticoagulant for more than 3 months. There is a low risk of VTE recurrence after three months in this setting and anticoagulation for VTE continued beyond three months may be associated with increased bleeding risk, particularly in the elderly and those with comorbidities. This recommendation is not applicable to patients with non-major, transient VTE risk factors such as travel-associated immobility, pregnancy or hormone use. Women who experience a first VTE during pregnancy should receive anticoagulation until at least six weeks post-partum, for a minimum total duration of three months or longer. VTEs occurring in the context of estrogen supplements are associated with a low recurrence rate following discontinuation of hormonal therapy/oral contraceptives and three months of anticoagulation may be adequate. However, the optimal duration of anticoagulation for VTEs provoked by hormones or by travel remains unclear and should be determined on a on a case-by-case basis.

ASH recommendation #2: Routine transfusion of PRBC for chronic anemia or uncomplicated pain crises in patients with sickle cell disease is not recommended as these patients who are predominantly African Americans, are at an especially higher risk for alloimmunization to minor blood group antigens, which can result in delayed-hemolytic transfusion reactions, as well as difficulty finding compatible blood when necessary. The baseline hemoglobin values range between 7 and 10g/dL in stable patients with severe sickle cell disease and these patients are often able to tolerate a 1-2g/dL decreases in their hemoglobin values following IV hydration. Further, data does not strongly support that episodic red cell transfusion reduces pain during acute vaso-occlusive crises. Moreover, iron overload from repeated transfusions can cause significant morbidity and mortality in patients with sickle cell disease.

ASH recommendation #3: Unlike in other lymphoproliferative diseases, routine surveillance CT scans are not recommended in patients with asymptomatic, early stage chronic lymphocytic leukemia (CLL). Both the Rai and Binet staging systems are based on physical exam findings and complete blood counts and prognosis can be assessed with molecular mutational analyses. CT scans are therefore not necessary and can be potentially harmful, by exposing patients to radiation and may also trigger additional workup to evaluate incidental findings (Cascade effect), that may not be of importance.

ASH recommendation #4: Do not test or treat for suspected Heparin-Induced Thrombocytopenia (HIT) in patients with a Low pretest probability of HIT. The 4Ts is a pretest scoring system for HIT and incorporates 4 components of HIT which include magnitude of thrombocytopenia, timing of thrombocytopenia with respect to heparin exposure, thrombosis or other sequelae of HIT and likelihood of other causes of thrombocytopenia. The 4Ts score is the sum of the values for each of the 4 categories. A score of 0-3 is classified as Low, 4-5 as Intermediate and 6-8 as High pretest probability for HIT. The negative predictive value of a Low 4T’s score is close to 100% in adults. Further, Enzyme ImmunoAssays (EIA) for HIT have a high false positive rate and a positive EIA HIT test results in a patient with a Low 4T’s score is much more likely to represent a false positive value than true positive. Confirmatory testing with serotonin release assays are not easily available and can be expensive. Misdiagnosing HIT can harm patients by denying them a heparin preparation in the future and the use of alternative, expensive anticoagulants such as Argatroban in these thrombocytopenic patients can be associated with a higher risk of bleeding. For these reasons, testing for HIT is only cost-effective when the pre-test probability of HIT is greater than 8%, which corresponds to an Intermediate or High 4T’s score

ASH recommendation #5: Do not treat patients with Immune Thrombocytopenic Purpura (ITP) in the absence of bleeding or a very low platelet count. ITP is often a temporary condition in children and resolves without treatment and treatment is not recommended in childhood ITP unless there is bleeding or risk factors for bleeding. ITP in adults is usually a chronic disease with remissions and exacerbations and patients with a platelet count of 30,000/microL or more and with no bleeding, can be observed without intervention. Steroids can impair glucose metabolism, increase infection risk, cause adrenal suppression and in children can cause growth impairment. Splenectomy is associated with perioperative risks and small risk of life threatening infections. Rituximab can cause Hepatitis B reactivation and TPO receptor agonists are only cost-effective in the setting of severe ITP, refractory to other treatment interventions.

Hicks LK, Bering H, Carson KR, et al. Prepublished online December 3, 2014; doi:10.1182/blood-2014-09-599399

A phase 3 randomized, open-label study of nivolumab (anti-PD-1;BMS-936558; ONO-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy

RR

SUMMARY: The FDA on December 22, 2014 granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients with unresectable or metastatic melanoma whose disease has progressed following YERVOY® (Ipilimumab) and if BRAF V600 mutation positive, a BRAF inhibitor. It is estimated that in the US, approximately 76,000 new cases of melanoma will be diagnosed and close to 8000 individuals will die of the disease in 2014. The incidence of melanoma has been on the rise for the past three decades. Unlike other malignancies, the role of chemotherapy for the treatment of melanoma has been limited. Treatment of advanced melanoma with immunotherapy using a cytokine, Interleukin-2 (IL-2) produced by T cells during an immune response, was first explored in the mid 1970’s. Durable responses were noted in a very small percentage of patients but this was associated with significant toxicities. This however opened the doors for the development a novel immunotherapeutic approaches, with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. The first immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab), an antibody that blocks Immune checkpoint protein/receptor CTLA- 4, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® in previously conducted studies demonstrated durable antitumor activity and promising overall survival (OS) in pretreated patients. CheckMate-037 is an open label, randomized, phase III study, in which 370 patients with unresectable or metastatic melanoma, received OPDIVO® 3 mg/kg IV every 2 weeks (N=268) or investigator’s choice of chemotherapy, which included either Dacarbazine or a combination of Carboplatin plus Paclitaxel given every 3 weeks (N=102). Treatment was continued until disease progression or unacceptable toxicity. Eligible patients were required to have disease progression following YERVOY® (Ipilimumab) and a BRAF inhibitor if BRAF V600 mutation positive. The primary endpoints were ORR and overall survival. Early findings (Objective Response Rate-ORR) in the first 120 patients who were treated with OPDIVO® and in 47 patients treated with chemotherapy and had a minimum 6 months follow up (planned interim analysis), was presented at the 2014 ESMO Congress. The Objective Response Rate (ORR) was 32% in the OPDIVO® group and 11% in the chemotherapy group. The median time to response was 2.1 months in the OPDIVO® group and 3.5 months with chemotherapy. The majority, (95%) of responses at 6 months were ongoing in the OPDIVO® group and the median duration of response was not reached. The most common (greater than or equal to 20%) adverse reaction in the OPDIVO® group was rash. Grade 3 and 4 adverse events were seen in 2-5% of patients receiving OPDIVO® and included abdominal pain, hyponatremia, elevated liver enzymes and increased lipase. Clinically significant immune-mediated adverse reactions were pneumonitis, colitis, hepatitis, nephritis, and thyroid dysfunction. OPDIVO® is a new and novel treatment option for patients with advanced melanoma and is a welcome addition, as we try to better understand tumor immunology. Weber JS, Minor DR, D'Angelo S, et al. ESMO 2014, LBA3_PR

Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years a systematic review and meta-analysis

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SUMMARY: The American Cancer Society estimates that in 2014, 18,860 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,460 patients will die of the disease. Acute Myeloid Leukemia in general is a disease of the elderly and the average age of a patient with AML is about 66 years. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy. The Fms-Like Tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the cell surface (transmembrane) and plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. The most common FLT3 mutation is the FLT3-ITD (Internal Tandem Duplication) mutation caused by tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia free and overall survival. These mutations are detected using Polymerase Chain Reaction (PCR) based molecular diagnostic DNA testing. The authors in this meta-analysis examined the prognostic significance of three mutations frequently noted in patients with cytogenetically normal Acute Myeloid Leukemia. These mutations included FLT3-ITD, mutated NPM1 (Nucleophosmin) and mutations of the CCAAT enhancer-binding protein alpha (CEBPA) gene. This systematic review and meta-analysis included 1942 patients from multiple electronic databases from 2000 to March 2012. It was noted that FLT3-ITD was associated with the worse prognosis, with inferior Overall Survival (OS) and Relapse Free Survival (RFS), whereas mutations in NPM1 and CEBPA genes were associated with a favorable prognosis. The discovery of new molecular mutations in AML patients with normal cytogenetics may help predict outcomes and provide valuable information to facilitate risk-adapted therapy. Port M, Böttcher M, Thol F, et al. Ann Hematol. 2014;93:1279-1286

Olaparib Monotherapy in Patients with Advanced Cancer and a Germline BRCA1/2 Mutation

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SUMMARY:The FDA on December 19, 2014 approved LYNPARZA® (Olaparib) as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) advanced ovarian cancer who had been treated with three or more prior lines of chemotherapy. It is estimated that in the United States, approximately 22,000 women will be diagnosed with ovarian cancer in 2014 and a little over 14,000 women will die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. They also account 15 percent of ovarian cancers in addition to other cancers such as colon and prostate. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal. The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2, repair damaged DNA. LYNPARZA® is a PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations. The approval of LYNPARZA® was based on a single arm phase II trial in which 137 platinum resistant ovarian cancer patients with measurable germline BRCA mutations were enrolled. The BRCA mutation status was verified retrospectively in 97% of the patients with available blood samples from the phase II study, using the BRACAnalysis CDx® test. These patients had received three or more lines of prior chemotherapy. Treatment consisted of LYNPARZA® administered orally twice a day and was continued until disease progression or unacceptable toxicity. The primary endpoint was Objective Response Rate (ORR). The Overall Response Rate was 34% and the median response duration was 7.9 months. In a larger cohort of patients reported by the authors (ovarian cancer cohort, N=193) the median Progression Free Survival was 7 months, 55% of patients were progression free at 6 months, the median Overall Survival was 16.6 months and 64.4% of patients were alive at 12 months. The most common adverse reactions associated with LYNPARZA® were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and abdominal pain/discomfort. This ground breaking therapy with LYNPARZA® is first of a new class of drugs, for treating ovarian cancer and along with the BRACAnalysis CDx® companion diagnostic test, is a significant milestone for patients with difficult-to-treat advanced ovarian cancer, with germline BRCA mutations. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. [published online November 3, 2014]. J Clin Oncol. doi:10.1200/JCO.2014.56.2728.

Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa) An ECOG-led phase III randomized trial

RR

SUMMARY: Prostate cancer is the most common cancer in American men, excluding skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, over 230,000 new cases of prostate cancer will be diagnosed in 2014 and close to 30,000 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy and TAXOTERE® (Docetaxel) has been shown to improve Overall Survival (OS) of metastatic prostate cancer patients, who had progressed on androgen deprivation therapy. It is not clear however, whether ADT is more effective with or without TAXOTERE®, when treating patients with metastatic prostate cancer. To address this further, a randomized phase III trial (E3805) was conducted to assess the benefit of upfront treatment with a combination of chemotherapy and hormonal therapy, in patients with metastatic hormone sensitive prostate cancer. Seven hundred and ninety (N=790) patients with newly diagnosed metastatic prostate cancer were randomly assigned to receive either Androgen Deprivation Therapy alone (N=393) or ADT plus TAXOTERE® (N=397). Androgen Deprivation Therapy consisted of either Luteinizing Hormone Releasing Hormone (LHRH) agonist therapy, LHRH antagonist therapy, or surgical castration. Chemotherapy consisted of TAXOTERE®, started within 4 months of starting ADT, dosed at 75 mg/m2 given every 3 weeks for a maximum of six cycles. The median age of patients was 63 years and approximately two-thirds of patients had high-volume disease, with either extensive liver or bone metastases. The primary endpoint of this study was Overall Survival. At a median follow up of 29 months, the median Overall Survival was 42.3 months in the ADT group and 52.7 months in the ADT plus TAXOTERE® group (HR=0.63; P<0.0006). This benefit was even more significant in patients with high volume disease (32.2 vs 49.2 months for ADT and ADT plus TAXOTERE® respectively, HR=0.62; P<0.0012). At 12 months, the proportion of patients with PSA levels less than 0.2 ng/mL was 9.4% in the ADT alone group vs 19.7% in the ADT plus TAXOTERE® group (P < 0.0001). The median time to clinical progression was 19.8 months in the ADT alone group vs 32.7 months in the ADT plus TAXOTERE® group (P < 0.0001). The authors concluded that this is the first study to demonstrate survival benefit in patients with newly diagnosed metastatic prostate cancer. This survival benefit with Androgen Deprivation Therapy and TAXOTERE® is even more so, in patients with high volume disease and should be considered standard treatment for those patients who are fit to receive TAXOTERE® based therapy. Sweeney C, Chen Y, Carducci MA, et al. 2014 ASCO Annual Meeting; LBA2