Ian Quirt

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

BACKGROUND An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium.

CCI‐779 is an analog of the immunosuppressive agent, rapamycin, that has demonstrated activity against melanoma in preclinical models and shown clinical benefit in patients with breast and renal carcinoma. CCI‐779 is not immunosuppressive when administered on an intermittent schedule, and its toxicity is modest, consisting of nausea, diarrhea, hypertriglyceridemia, thrombocytopenia, asthenia, and follicular dermatitis.

Outcome and prognostic factors in soft tissue sarcoma in the adult.

PURPOSE To evaluate the outcome, patterns of failure and prognostic factors in this rare disease in adult patients treated at a single institution in the modern era. METHODS AND MATERIALS The records of all patients (389 cases) with soft tissue sarcoma in the extremities, torso (excluding retroperitoneum), and head and neck managed between 1980 and 1988 were reviewed. A curative (radical) approach was used in 321 patients of whom 10% were recurrent lesions. The local management consisted of surgery alone in 54 cases, surgery and radiotherapy in 250 and radiotherapy alone in 17. Adjuvant chemotherapy was used as a policy for high grade lesions in the initial five years of the study (98 cases), but was omitted subsequently. RESULTS Extremity lesions fared more favourably compared to head and neck and torso lesions (p = 0.02) with respect to survival. Extremity and torso lesions had significantly better local control (p < 0.0001) than in the head and neck where local failure was a common cause of death. A multiple Cox regression analysis revealed that resection margins, local extension of tumor, age at diagnosis, and grade correlated with local relapse and distant relapse was also associated with local extension, high grade and in addition, large lesions. Size appeared especially predictive for distant failure, the most common cause of death. Distant failure was not influenced by the use of adjuvant chemotherapy. Patients treated for recurrence in this series had significantly worse survival due to increased distant failure despite similar local control to primary cases. CONCLUSION This series highlights the overall problem of distant failure in this disease. It also reaffirms the importance of obtaining local control both in the head and neck, where uncontrolled local disease is the major cause of death, and in general since local relapse appears to increase the risk of distant failure. It appears that the current staging systems should be reviewed in the light of the apparent effect of different prognostic factors.

Systematic Review of Systemic Adjuvant Therapy for Patients at High Risk for Recurrent Melanoma

The authors examined the role of systemic adjuvant therapy in patients with high‐risk, resected, primary melanoma. Outcomes of interest included overall survival, disease‐free survival, adverse effects, and quality of life. A systematic review of the literature was conducted to locate randomized controlled trials, practice guidelines, meta‐analyses, and reviews published between 1980 and 2004. Thirty‐seven randomized controlled trials, 2 meta‐analyses, and 1 systematic review were identified that investigated interferon, levamisole, vaccine, or chemotherapy as adjuvant therapy. For high‐dose interferon‐α, the results from 3 randomized trials conducted by the Eastern Cooperative Oncology Group were pooled, and a meta‐analysis of 2‐year death rates yielded a risk ratio of 0.85 (95% confidence interval, 0.73–0.99; P = .03). Five randomized trials comparing low‐dose interferon‐α with observation only after surgery did not detect a statistically significant improvement in overall survival. A meta‐analysis of 4 levamisole trials did not demonstrate a significant survival benefit for levamisole over control; similarly, no survival benefit was demonstrated by data from randomized controlled trials with vaccines (9 trials) or with chemotherapy (10 trials). In this review of the available literature, no systemic adjuvant therapy was identified that conferred a significant overall survival benefit in patients with high‐risk, resected, primary melanoma. However, high‐dose interferon should be considered in the treatment of these patients, because such therapy is associated with a significant improvement in disease‐free survival and a reduction in 2‐year mortality. Until the results of ongoing trials are available, the authors could not state with confidence whether such therapy benefits patients with microscopically detected, sentinel lymph node‐positive disease. Cancer 2006.

Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung.

One hundred fifty-three patients with limited and 167 with extensive small cell carcinoma of the lung (SCCL) were evaluable for response to treatment with six courses of chemotherapy (cyclophosphamide, doxorubicin, and vincristine), irradiation to intrathoracic disease, and prophylactic cranial irradiation (PCI). No maintenance chemotherapy was given. Fifty-two percent of patients with limited disease (LD) and 10% of extensive disease patients (ED) achieved a complete response. The median survival times for LD and ED patients were 49 and 34 weeks, respectively. These results were compared to a previous experience with 147 patients who were treated with three courses of similar induction chemotherapy and thoracic irradiation, as well as one year of maintenance chemotherapy (CCNU, procarbazine, and methotrexate) but without PCI. Although the use of PCI was found to reduce the frequency of brain metastases as the site of first relapse, detailed comparisons of response rates and survival showed no significant differences between the two study populations. Prolonged maintenance chemotherapy of the type used in the first study does not favorably influence outcome after intensive induction therapy for SCCL.

Neurologic disorders in patients with small cell lung cancer

In a series of 641 patients with small cell lung cancer, 189 (29.5%) had at least one neurologic disorder either at the time of presentation or during the subsequent clinical course of the cancer. The total number of neurologic disorders was 210, which included brain metastases (75.7%), meningeal carcinomatosis (6.7%), intramedullary metastases (2.4%), epidural metastases (11.0%), hyponatremia producing CNS symptoms (3.3%), and Eaton‐Lambert syndrome (1.0%). The most common signs and symptoms were motor dysfunction and confusion. The overall survival of patients with any neurologic disorder was compared to that of patients without neurologic problems. There was no difference between the survival curves for the first year and a half, but patients without neurologic complications had a greater probability of long‐term survival (log‐rank P = 0.03). There were no statistically significant differences when this comparison was made according to stage of disease. When a neurologic disorder related to cancer occurred, the survival time from the date of that diagnosis was usually short. The neurologic disorder was the immediate cause of death in the majority of cases. In patients who achieved a complete remission, the administration of prophylactic cranial irradiation (PCI) significantly reduced the risk of developing brain metastases as the initial site of the relapse (log‐rank P = 0.0034). After adjustment for performance status and extent of disease, the survival of complete responders treated with and without PCI was not significantly different. We conclude that neurologic complications are a frequent and serious problem in patients with SCLC.

Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

Purpose: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. Patients and methods: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m2 IV over 1 hour daily × 3 days every 3 weeks. Patients were assessed for response every 2 cycles. Results: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8–9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received ≥90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. Conclusions: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.

0‐7‐21 radiotherapy in nodular melanoma

Fifty‐four patients from August 1975 to March 1980 were treated with high dose per fraction (0‐7‐21) radiotherapy for malignant. The patients were subdivided into three clinical subtypes of disease: microscopic residual melanoma following surgery (22 patients), gross residual melanoma following surgery (nine patients), and recurrent melanoma (23 patients). Eighteen of 22 (82%) of patients treated for microscopic residual disease have been free of local recurrence to date. Ten of the 18 are alive and free of disease for up to 44 months following irradiation. Seven of nine (78%) patients treated for gross residual tumor have had no recurrence or progression of tumor in the irradiated volume, five of the nine achieved a complete remission and three are alive and free of disease at ten, 13, and 42 months, respectively. Twenty‐three patients with recurrent melanoma were irradiated. Nine achieved a complete remission (39%) of tumor in the irradiated volume and three are alive and free of disease at up to 56 months following irradiation treatment. Three major complications of irradiation have been seen in the 54 patients treated. It is concluded that nodular melanoma is not a radioresistant tumor, large dose per fraction radiotherapy produces a high response rate of patients with measurable diseased which is prolonged in some patients. The indications for radiotherapy in nodular melanoma are discussed and prospective studies of irradiation in melanoma are proposed.

Is Bone Marrow Examination in Small-Cell Lung Cancer Really Necessary?

Of 403 patients with small-cell lung cancer, we identified by aspiration, biopsy, or both 67 with bone marrow involvement and found the two procedures to be complementary in detecting marrow involvement. The mean surface area of the positive biopsy specimens was significantly greater than that of a randomly selected group of negative biopsy specimens, suggesting that the larger the specimen, the greater the chance of detecting tumour. Patients with marrow involvement had only a slightly worse prognosis compared with other patients who had extensive disease. Only 7 of the 403 patients (1.7%) had extensive disease based on marrow involvement alone. Because bone marrow examination rarely changes the stage of cancer in noninvasively assessed patients, and has no impact on the tolerance of chemotherapy and only a small effect on length of survival, we do not recommend this procedure in the routine staging of small-cell lung cancer.

Phase II study of marimastat (BB-2516) in malignant melanoma: a clinical and tumor biopsy study of the National Cancer Institute of Canada Clinical Trials Group.

AbstractObjectives: To determine thetolerability and efficacy of daily oralmarimastat (BB-2516 in patients withmetastatic melanoma and to determine thematrix metalloproteinase (MMP) activity,tumour necrosis, peri- and intra-tumoralfibrosis and tumor inflammation in pre- and post-treatmenttumor biopsies. Patients and methods: Patients withmeasurable metastatic melanoma who hadreceived no more than one priorchemotherapy regimen and lesions accessiblefor biopsy were eligible. The first 18 weretreated with 100 mg p.o. twice daily and thenext 11 received a reduced dose of 10 mgp.o. twice daily because of musculoskeletaltoxicity. Response was assessed accordingto standard criteria. Results: Twenty-nine patients were entered and 28 wereeligible. Five had early progression (< 4 weeks oftherapy), 2 experienced a partial responsespersisting for 3.2 months and 3.6 months, 5had stable disease and 16 progressivedisease. Eleven patients had both pre- andpost-treatment biopsies. In 3, no tumortissue was present in one or the otherbiopsy. Two patients showed a clearincrease in peri-tumoral fibrosis and twoothers showed an increase in tumornecrosis, but no consistent pattern inhistologic changes was seen. In onepatient, who later developed a PR,apoptosis was increased. Conclusion: Marimastat has onlylimited activity in patients withmetastatic malignant melanoma. However,the observation of two partial responseswas interesting given that this agent mighthave been expected to cause tumor stasisrather than regression. Additional studieswill be required to determine if thedevelopment of peri-tumoral fibrosis ortumor necrosis antedates a clinicalresponse to marimastat.