Sanjiv S. Agarwala

8505 Background: To assess the benefit of 4 weeks of HDI compared with observation (obs) in relation to the relapse free survival (RFS) and overall survival (OS) of patients (pts) with resectable intermediate and high-risk melanoma Methods: Pts with intermediate and high-risk melanoma defined as T3 (AJCC 6^th ed. >Breslow thickness 1.5mm (AJCC 7^th ed. >2.0mm) or any thickness with microscopically positive node disease (N1a-N2a) were randomized to receive postoperative adjuvant Interferon (IFN) alfa2b 20 MU/m2/day for 5 days/week X 4 weeks or observation. Primary endpoints of the trial were RFS and OS. A sample size of 1420 pts was chosen to detect a 15% relative increase in the median time-to-event for those not cured and a 7.5% absolute increase in the cure rate with 88% power at a 5% level of significance, using a two-sided log-rank test. Results: Between December 1998 and October 2010, 1150 pts were enrolled – 581 assigned to HDI and 596 to obs. The breakdown of stage at entry was as follows: T2N0: 22%, T3N0: 45%, T4N0: 14%, T1-4, N1a-2a:19%. Primary ulceration was present in 36% of pts. A third interim analysis of this trial was carried out in August 2010 with RFS data in 838 and OS data in 1091 pts. The 234 RFS events correspond to 69.0% information time, while the 134 OS events correspond to 74% information time. Median RFS for Obs was 7.3 years (95% CI 5.3, 9.8; n=413) while for IFN, RFS was 6.8 years (95% CI 5.1, 9.0; n=425). The 5-year survival rate for OBS was 0.85 (95% CI .81, .89; n=535) while for IFN induction-only the 5-year survival rate was 0.82 with (95% CI .78, .86; n=556). Accrual to the trial has therefore been terminated. Conclusions: Adjuvant HDI induction with only 4 weeks therapy neither improved RFS nor OS over observation for pts with intermediate and high-risk melanoma. This trial supports the importance of HDI treatment duration and argues that the approved 1 year Interferon regimen of induction followed by maintenance remains the standard of care for pts with T4N0 or node positive disease.

7549 Background: Multiagent biochemotherapy (BCT) has not been superior to chemotherapy alone in randomized trials. Previously tested BCT regimens have been criticized for the lower doses of IL-2 administered and the multiple chemotherapeutic agents, which have added to toxicity, but not to efficacy. Methods: We designed a unique BCT approach of single agent chemotherapy with TMZ given in an extended schedule (75 mg/m² per day for 3 weeks PO) followed by high-dose bolus IL-2 (600,000 U/Kg/dose, maximum 14 doses administered over 5 days). Cycles were repeated every 28 days with a two-week interval between even numbered cycles. Results: Eighteen patients (11 male, 7 female), age 27–74 (median 53) have been entered to date. All had AJCC stage IV melanoma (6 M1a, 3 M1b and 9 M1c) and had not previously received therapy for metastatic disease. Eight had received prior adjuvant interferon. A total of 50 cycles of therapy have been administered (median of 3.5 cycles per patient). The median number of doses was 9 (range 7–11) during cycle 1, and 7 (range 4–9) during cycle 2. Two patients did not receive any IL-2 and one had only 1 cycle of IL-2. Fifteen received at least 2 cycles, of which 14 are evaluable for response. All 18 patients are evaluable for toxicity. Grade 3 toxicities included hepatic (5), hematologic (2 leukopenia and 2 thrombocytopenia). No grade 3–4 cardiovascular or renal toxicities were noted. Overall response rate is 29% (2 complete lasting 3.8+ and 2.3+ months, 2 partial lasting 3.2+ and 2.5+ months). Responses were seen in both M1a and M1c disease. Nine patients had stable disease after 2 cycles and 4 of these have progressed. Median survival has not yet been reached. Conclusions: The combination of single agent extended-schedule TMZ with HDB IL-2 is a well-tolerated regimen that has shown promising activity in patients with stage IV melanoma. Accrual is on-going and long-term durability of the responses is being assessed. No significant financial relationships to disclose.

The First International Symposium on Melanoma and Other Cutaneous Malignancies, held in New York City on 23-25 April 2004, brought together researchers and clinicians from all over the world to discuss recent advances in the prevention, treatment and diagnosis of melanoma and other cutaneous malignancies. Discussion topics included primary and secondary prevention; advances in surgical therapy, including sentinel and elective lymph node dissection; the biology and pathogenesis of melanoma, including pathways of drug resistance; genomic analysis of melanoma, serum and tumour cell markers; with point and counterpoint sessions debating therapeutic controversies. The role of vaccines in the management of melanoma was discussed, including cell vaccines, dendritic cell-based vaccination and present research to improve the generation of melanoma vaccine-specific immunity. Adjuvant immunotherapy with high-dose IFN-alpha and an ongoing trial with biochemotherapy were debated. In addition, the role of chemotherapy and novel targeted agents in metastatic melanoma were discussed. Among the emerging agents and therapeutic targets presented were Bcl-2 antisense therapy, RAF kinases, heat-shock proteins, thalidomide and newer immunomodulatory drugs, cytotoxic T lymphocyte antigen-4 antibody and topical imiquimod. The symposium also provided an overview of existing and emerging agents and modalities in the management of patients with cutaneous T cell lymphomas, ocular melanoma and melanoma involving brain metastases. Sessions also included case-based learning and devoted ample time to providing 'how to' information for practising physicians.

Purpose: Temozolomide is a well-tolerated oral alkylating agent with activity in the CNS. A multicenter, open-label, phase II study was conducted to assess the safety and efficacy of temozolomide in patients with brain metastases from metastatic melanoma (MM) who did not require immediate radiotherapy. Patients and Methods: Eligible patients had histologically confirmed MM to the brain, and no prior radiotherapy or radiosurgery for brain metastases. Previously untreated patients received temozolomide at 200 mg/m²/d × 5 days; previously treated patients received 150 mg/m²/d × 5 days every 28 days. Treatment continued for 1 year or until disease progression or unacceptable toxicity. Results: Of 151 patients enrolled, 117 had received no prior systemic chemotherapy, and 34 had received prior chemotherapy for MM. Among previously untreated patients, 25% had more than four brain lesions, eight (7%) achieved an objective response (one complete and seven partial), and 34 (29%) had stable disease in brain metastases. Median overall survival was 3.5 months. Among previously treated patients, 21% had more than four brain lesions, one had a partial response, and six (18%) had stable disease in brain metastases. Median overall survival was 2.2 months. Temozolomide was well tolerated, with four (3%) patients discontinuing because of adverse events. Grade 3/4 hematologic toxicities included thrombocytopenia (3%), neutropenia (2%), and leukopenia (1%). Headache (9%) and vomiting (8%) were the most common nonhematologic grade 3/4 adverse events. Conclusion: Temozolomide was well tolerated and demonstrated activity in the treatment of brain metastases from MM. Further evaluation of temozolomide combination therapy is warranted.

BACKGROUND: The local and systemic effects of bacillus Calmette–Guerin (BCG) have been known for decades. To investigate the adjuvant effect of BCG on resected American Joint Committee on Cancer (AJCC) Stage I–III melanoma, the Eastern Cooperative Oncology Group conducted a large trial to study the use of BCG alone or a combination of BCG and dacarbazine between 1974 and 1978.METHODS: A total of 734 patients were randomized to 4 clinical groups consolidated into 2 cohorts. Cohort I compared BCG with observation and Cohort II compared BCG with a combination of BCG and dacarbazine. The primary end points were survival time and time to disease progression.RESULTS: Within Cohort I, no statistically significant difference in disease‐free survival (DFS) (P = 0.84) or overall survival (OS) (5‐year survival 67% vs. 62%; P = 0.40) was observed between BCG treatment and observation. Within Cohort II, the addition of dacarbazine to BCG did not improve DFS (P = 0.74) or OS (P = 0.81) compared with BCG alone. Toxicity was mild to moderate in both cohorts. Although toxicity with this agent is mild, the use of BCG is associated with the development of punctate abscesses in greater than two‐thirds of patients treated.CONCLUSIONS: In what to our knowledge is the largest ever trial to test the role of BCG as adjuvant therapy for melanoma, no benefit for BCG was observed for patients with AJCC Stage I–III disease. The mature results of the current trial projected to 30 years confirmed the negative results of previous smaller studies utilizing this agent. Cancer 2004. © 2004 American Cancer Society.

The two most widely investigated immunotherapy drugs for melanoma are interferon (IFN)-α and interleukin-2 (IL-2). The role of IFNα-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse has recently been established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. Recombinant IL-2 (rIL-2) has an overall response rate of 15–20% in metastatic melanoma and is capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has recently approved the use of high-dose bolus administration of rIL-2 for the therapy of patients with metastatic melanoma. Results of combination chemotherapy and immunotherapy regimens containing rIL-2 and IFNα (biochemotherapy) are promising, but conclusions regarding an advantage for this therapy in terms of survival must await the completion of ongoing randomized trials. The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. In the setting of adjuvant therapy, to date, no vaccine has demonstrated a survival benefit in comparison with either observation or IFNα. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNα.

BACKGROUND: Metastatic melanoma (MM) is associated with a high risk of central nervous system (CNS) metastases, and current chemotherapy does not adequately treat or protect patients with MM against CNS metastases. Therefore, the authors initiated a Phase I study to determine the pharmacokinetics and safety profile of temozolomide (TMZ), a novel oral alkylating agent known to cross the blood‐brain barrier, in combination with interferon α‐2b (IFN‐α2b).METHODS: Twenty‐three patients with MM were enrolled in this single‐center, open‐label study. Patients with CNS metastasis were excluded. One cohort (n = 6 patients) received oral TMZ (200 mg/m² per day) for 5 days every 28‐day cycle plus subcutaneous IFN‐α2b (5 million International Units [MIU]/m² per day, 3 times per week). A second cohort (n = 17 patients) received TMZ 150 mg/m² per day on the same schedule plus escalating doses of IFN‐α2b (5.0 MIU/m² per day, 7.5 MIU/m² per day, and 10 MIU/m² per day 3 times per week).RESULTS: The most common adverse events were fatigue, fever, nausea/emesis, anxiety, and diarrhea. Most toxicity was mild to moderate in severity. The primary dose‐limiting toxicity was thrombocytopenia. The maximum tolerated dose was either TMZ 150 mg/m² plus IFN‐α2b 7.5 MIU/m² or TMZ 200 mg/m² plus IFN‐α2b 5.0 MIU/m². Four patients (17%) had objective responses (one complete response and three partial responses), and four patients had stable disease. The median survival was 9 months. The pharmacokinetics of TMZ were not affected by coadministration of IFN‐α2b.CONCLUSIONS: TMZ can be combined safely with IFN‐α2b. This regimen demonstrated clinical activity in patients with MM and merits further investigation to define its effect on the incidence of brain metastases. Cancer 2003;97:121–7. © 2003 American Cancer Society.DOI 10.1002/cncr.11041

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst [1]. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro [2], inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC) [3]. Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia...

The malignant melanoma session at the Chemotherapy Foundation Symposium XVIII comprised four presentations focusing on immunotherapeutic approaches for the treatment of melanoma.