Abstract
Background: The treatment results of metastatic melanoma are miserable if the tumor has spread beyond the soft tissue and lung, in particular, if dacarbazine (DTIC)-based therapy has failed. Platinum analogs and vinca alkaloids have shown some activity in melanoma. Interleukin-2 (IL-2) may augment the efficacy of chemotherapy. Patients and Methods: A prospective phase II pilot study was conducted to evaluate the efficacy and tolerability of a regimen which contained carboplatin (450 mg/m2 on day 1), vinorelbine (30 mg/m2 on day 1) and IL-2 (9 MU subcutaneously once daily on days 2-5 and 9-12) in metastatic melanoma. Twenty-two patients (11 men, 11 women; median age 56 years) were eligible, of whom 13 had cutaneous, 6 ocular and 3 unknown primary melanoma. Seventeen patients (77%) had liver metastases and an equal number had received prior chemotherapy and/or interferon-alfa for recurrent disease. Results: One partial response was recorded, yielding a response rate of 4.5% . Nine patients had stable disease for a median of 6.0 months (range 3.0-8.6 months). The median time to progression for all patients was 1.8 months (range 0.7-8.6 months) and the median survival was 7.2 months (range 1.4-42.0 months). Toxicity was moderate but manageable. Myelosuppression was the most significant adverse event. Conclusion: This regimen may offer clinical benefit for melanoma patients with poor prognosis as second-line therapy after DTIC has failed.
Metastatic melanoma remains a challenge for oncologists despite recent developments in medical oncology. Dacarbazine (DTIC), which is still the standard agent in melanoma, produces an average response rate of 17% and a median survival of around 7 months (1). Polychemotherapy regimens have often yielded higher response rates than single agents but they have not improved survival in randomised studies (2). The cytokines interferon (IFN)-alfa and interleukin-2 (IL-2) have shown some activity in melanoma (2, 3). High-dose intravenous IL-2 has produced durable responses in metastatic melanoma: at a long-term follow-up update, 5-year survival was 10% (3). The toxicity of high-dose IL-2, however, limits its wider use. Less toxic, lower doses of IL-2 administered subcutaneously have been incorporated into various chemotherapy plus IFN-alfa regimens with some benefit in terms of response rate (2).
Besides DTIC, vinca alkaloids and platinum compounds have shown some anti-melanoma activity (4). There are only few reports on a newer vinca alkaloid, vinorelbine, in metastatic melanoma. Single agent studies have produced negative results (5, 6) but combined with paclitaxel (7), tamoxifen (8), IL-2 (9), or docetaxel plus granulocyte-macrophage colony-stimulating factor (GM-CSF) (10), response rates ranging from 9 to 50% have been reported in small phase II first- or second-line studies. Responses in unfavourable metastatic locations, such as abdominal viscera, have also been occasionally observed with vinorelbine (7, 8). Carboplatin has been studied less than cisplatin in melanoma. Over the last decade, response rates ranging from zero to 29% have been reported with carboplatin-containing combinations in metastatic melanoma (11-16). With regimens containing vinorelbine or carboplatin some second-line activity has also been reported (9, 10, 13, 15, 16).
We carried out a prospective phase II pilot study to assess the efficacy and tolerability of a regimen which contained carboplatin, vinorelbine and subcutaneous IL-2 in melanoma patients who had progressed on previous systemic treatment or in chemo-naive patients with unfavourable metastatic load.
Patients and Methods
Patient eligibility. The main inclusion criteria for the study were i) cytologically or histologically verified metastatic melanoma with cutaneous, subcutaneous tissue, lymph node and/or lung or pleural disease that had progressed on previous systemic treatment(s); ii) other metastases irrespective of previous treatment(s), if any. Other inclusion criteria were measurable or evaluable disease, age ≤65 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, a life expectancy of at least 3 months and adequate bone marrow, liver and renal functions. The main exclusion criteria were metastases confined to the soft tissue and/or lung in chemo-naive patients, central nervous system involvement, severe other illness or any illness which required chronic immunosuppressive treatment and any other metastasizing malignancy treated within the previous five years.
A physical examination, performance status, complete blood counts, blood chemistry and electrocardiogram were recorded at baseline and before each treatment cycle. Staging was based on clinical and radiological examinations, which included chest radiography, body computed tomography scan, bone scan and additional imaging, when indicated. Blood counts and liver and renal function tests were repeated in the second week of the treatment cycle.
The protocol was approved by the Ethical Committee and all patients provided written informed consent to participate in the study.
Treatment schedule. The treatment regimen consisted of carboplatin 450 mg/m2 and vinorelbine 30 mg/m2 (maximum dose 60 mg), both on day 1 intravenously (i.v.). Recombinant human IL-2 (Proleukin® Chiron Corporation, Emeryville, California, USA) was administered at a dose of 9 million international units (MU) subcutaneously (s.c.) once daily on days 2 to 5 and 9 to 12. The cycle was 3 weeks.
In cases of no disease progression after 2 cycles, the treatment was to be continued up to 4 cycles, unless a patient refused or toxicity warranted treatment interruption. If the patient had a response or stable disease (SD) after 4 treatment cycles, maintenance treatment with IL-2 was to be pursued to a maximum of 4 cycles. The maintenance treatment consisted of IL-2 at 9 MU once daily s.c. on days 1 to 4 and 8 to 11 of a 28-day cycle.
Assessment of efficacy. The primary end-points were response rate (RR) and tolerability; the secondary end-points included time to progression (TTP) and overall survival (OS). Response was analysed every 6-8 weeks according to the RECIST criteria (17) in all eligible patients. Toxicity assessments were performed at every cycle according to the Common Terminology Criteria for Adverse Events (CTCAE v3.0) (http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm).
In the statistical analysis, descriptive statistics and the Kaplan-Meier method were used. TTP was calculated from the initiation of treatment to the date of progression and OS from the treatment start to the date of death or last follow-up.
Results
Twenty-three patients with American Joint Committee on Cancer (AJCC) stage IV melanoma and poor prognostic features were enrolled for the present multicenter study during April 2004 and October 2006. One patient was subsequently deemed ineligible due to concomitant metastatic carcinoid tumor. The patient characteristics of the 22 eligible patients are shown in Table I. The male/female ratio was 11/11 and the median age 56 years (range 27-63 years). Six patients had an ocular primary tumor. Out of 22 patients, only 3 had metastases confined to the soft tissue or lung, while 17 had liver metastases and 2 had other abdominal involvement. The majority had received prior DTIC-containing chemotherapy for recurrent metastatic disease.
At the time of analysis, all patients had progressed and 20 patients had died. One patient (4.5%, 95% CI 0.8-21.8%) with nodal, liver, bone and adrenal involvement from unknown primary melanoma achieved a partial response (PR) with TTP of 4.5 months. Nine patients (40.9%, 95% CI 23.3-61.3%) had stable disease (SD) which lasted for a median of 6.0 months (range 3.0-8.6 months, 95% CI 1.4-10.5 months). Six of them had a cutaneous primary tumor, two had uveal melanoma and one had melanoma of an unknown origin. Twelve patients (54.5%, 95% CI 34.7-73.1%) had PD. The median TTP for the entire patient population was 1.8 months (range 0.7-8.6 months, 95% CI 0-3.7 months). TTP exceeded 6 months in 4 patients. The median OS for all patients was 7.2 months (range 1.4-42.0 months, 95% CI 3.5-10.9 months) and for patients with SD, 18.2 months (range 4.2-42.0 months, 95% CI 14.5-21.9 months). Nine patients survived for over one year.
The median number of administered cycles (treatment and maintenance) per patient was 2 (range 1-8). The patient with PR received 6 cycles and the patients with SD received a median of 6 cycles (range 2-8 cycles). Dose reductions and/or treatment delays with chemotherapeutic agents occurred in 17 patients and with IL-2 in 9 patients.
The toxicity was moderate but manageable (Table II). Constitutional symptoms, myelosuppression, nausea and subcutaneous injection site reactions were the most frequent adverse events. In addition, elevations of liver transaminases or alkaline phosphatase were frequent, but mostly mild and transient. No capillary leak syndrome attributable to IL-2 was documented. The dose-limiting toxicity was hematological, neutropenia in particular. IL-2 frequently caused lymphopenia followed by rebound lymphocytosis, and eosinophilia was also common. Any (worst) grade 3 toxicity occurred in 9 patients and grade 4 in 8 patients. Grade 4 toxicities included neutropenia, thrombocytopenia, gastrointestinal bleeding associated with thrombocytopenia and anemia, and hyponatremia. One patient had the study treatment discontinued due to severe obstipation and fatigue. There were no toxic deaths.
Discussion
In the present prospective phase II study, we analyzed the efficacy and feasibility of a combination of carboplatin, vinorelbine and subcutaneous IL-2 in patients with advanced melanoma. The vast majority of our patients (77%) had liver involvement (all ocular melanoma patients and 69% of the others). Two thirds of the patients had been previously treated with DTIC-containing chemotherapy for stage IV disease. Therefore, albeit the RR for the present regimen was no greater than 4.5%, the SD rate of 41% with a median duration of 6 months and median survival of 18.2 months deserves some attention. Presently, there is no standard second-line therapy for patients with disseminated cutaneous melanoma, and even less so for those with the ocular counterpart. In previous reports, RR of 0-26% and SD in around 20% of patients have been obtained in pretreated melanoma patients with combinations that contain vinorelbine or carboplatin (5, 9, 13, 15, 16). Those studies, however, included fewer patients with liver metastases than did our study (5, 9, 13, 16). Furthermore, our series included 5 patients with uveal melanoma, a disease which is even more resistant to systemic therapies than is cutaneous melanoma (18). Interestingly, in our series, two patients with uveal melanoma who achieved SD, one with liver metastases and the other with liver plus lung involvement, were still alive at 31.2 and 42 months, respectively. The latter patient was continuing on low-dose IFN-alfa after three lines of chemotherapy, including the study treatment.
Patient characteristics.
Toxicity of treatment.
In the present study on patients with poor prognosis, the median TTP in the entire study population of 1.8 months is slightly inferior to other reports on pretreated melanoma patients with TTP of 2-3 months, while the median OS of approximately 7 months falls within the category of 6-9 months reported in second-line studies (5, 9, 15, 16). In previously published literature, an interesting combination which aims at increasing the platinum dose but avoiding severe side-effects is a combination of carboplatin and cisplatin. The regimen has produced 14-26% response rates, 20-50% SD rates and a median survival of 8-12.5 months in pretreated melanoma patients (19, 20).
In the present study, the main toxicity was hematological, particularly neutropenia. This was not unexpected since carboplatin and vinorelbine both are myelotoxic. The most frequent non-hematological toxicities were, as expected, subcutaneous injection site reactions, flu-like symptoms, fatigue and gastrointestinal effects. In our study, mild metabolic hepatotoxicity, attributable to vinorelbine, was also common. Vinca alkaloids are eliminated mainly by the biliary system while platinum agents are primarily excreted by the kidneys (21).
On more novel agents, preliminary data on a multi-kinase inhibitor, sorafenib, combined with carboplatin and paclitaxel were not impressive in the second-line setting, but sorafenib combined with DTIC in chemo-naive patients appears more promising (4, 22). A novel immunotherapeutic approach, namely monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA4), is an interesting avenue (23). Meanwhile, considering that only few agents have any effect in advanced melanoma, cytokines continue to have some role in melanoma therapy. Local treatment modalities combined with systemic treatment should not be neglected either (24). Selected patients with metastatic disease may benefit from aggressive surgery (25).
In conclusion, the present regimen offered clinically meaningful disease stabilization in melanoma patients with an unfavourable tumor load albeit at the cost of moderate toxicity. This regimen may be a second-line treatment option for DTIC-resistant patients.
Acknowledgements
The study was supported by the Pirkanmaa Hospital District Research Fund.
- Received September 17, 2008.
- Revision received December 17, 2008.
- Accepted January 14, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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