© 2007 Foundation for Promotion of Cancer Research
Complex Combination Biochemotherapy Regimen in Advanced Metastatic Melanoma in a Non-intensive Care Unit: Toxicity or Benefit?
Department of Dermatology and Allergy, Skin Cancer Centre, Charité – Universitätsmedizin Berlin, Berlin, Germany
For reprints and all correspondence: Maja Ann Hofmann, Department of Dermatology and Allergy, Skin Cancer Centre, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail: maja.hofmann{at}charite.de
Received September 13, 2006; accepted November 8, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: There is currently no chemotherapy or chemoimmunotherapy regimen that has shown impact on survival in patients with metastatic melanoma. Different biochemotherapy protocols showed promise with high response rates, but again without significant impact on survival.
Methods: We report the results of a retrospective analysis of a regimen consisting of dacarbazine, cisplatin, vindesine, interleukin-2 and interferon-
2b in 25 consecutively treated patients with regard to toxicity, efficacy and practicability. The treatment was performed on a regular dermatological ward.
Results: Grade III and IV toxicities were mainly haematological, with few cases of infection because of neutropenia seen. Best overall responses were CR 2/25, PR 2/25 and SD 9/25. The median progression free interval was 4 months (range 0–19) for all patients and the median survival time was 12 months (range 2–26). From a safety and practical point of view, there was no draw-back on treating patients in a non-intensive care unit. The median survival time is in the range of the one reported for monochemotherapy regimen. While there are some responding patients, the responses are short lived and go in parallel with high toxicity and impaired performance status.
Conclusion: This complex and highly toxic chemoimmunotherapeutic regimen should not be considered as standard therapy in patients with metastatic malignant melanoma.
Key Words: metastatic melanoma • survival • chemoimmunotherapy • toxicity
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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It is currently unclear whether any combination therapy for the treatment of metastatic melanoma is superior to standard single-agent dacarbazine (DTIC) in terms of response rates and overall survival time. Single-agent chemotherapy regimen have produced response rates of 10–20%. The alkylating agent DTIC is considered to be the most active drug for the treatment of metastatic melanoma with a response rate of approximately 15%. The majority of DTIC-induced responses are partial and transient (1, 2). In order to improve the chemotherapy response rates numerous clinical trials have been performed using combination chemotherapy. These regimen have produced higher response rates and prolongation of median survival, but could not demonstrate superiority to DTIC monotherapy (3–6).
Immunotherapy using high-dose interleukin-2 (IL-2) as a single agent has produced responses in up to 20% of melanoma patients (7–9). In some cases durable complete responses were achieved (9). Interferon- (IFN-) as a single agent has only marginal activity in metastatic melanoma, but the combination of IFN- and IL-2 has shown response rates of up to 40% (10–12). When combining IFN- with cytotoxic drugs, response rates of up to 50% have been observed (13). The same was found, when IL-2 was added to chemotherapy with even durable complete responses (CR) reported (14–20). Legha et al. (21) compared an alternating biochemotherapy regimen and a sequential biochemotherapy regimen using cisplatin, vinblastine, dacarbazine, IL-2 and IFN-. The sequential biochemotherapy regimen produced an overall response rate of 60% with 14 CRs out of 62 treated patients. Similar response rates have been reported using a concurrent biochemotherapy regimen in a monocentre trial (22). However, in a phase III trial comparing this biochemotherapy regimen with chemotherapy, the high number of CRs could not be confirmed. The biochemotherapy was significantly more toxic, but the median survival for biochemotherapy was 11.9 months, as compared to 9.2 months for chemotherapy (23).
We report our retrospectively analysed results with a similar concurrent biochemotherapy regimen as first described by Legha et al. (21) in patients with advanced metastatic melanoma on a regular dermatological ward.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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From August 1999 to January 2002, 25 patients were accrued to be treated with this combination regimen. Fifty more patients with metastatic melanoma were treated at the Charité Skin Cancer Centre during this period, but did not meet the eligibility criteria. The eligibility criteria included histologically confirmed, bidimensionally measurable metastatic stage IV melanoma, a life expectancy of at least 3 months, Eastern Cooperative Oncology Group performance status
2, adequate cardiac, respiratory, renal, hepatic and bone marrow function. All patients provided written informed consent before treatment.
Pre-treatment evaluation
Before treatment a complete medical history, physical examination and a complete staging examination consisting of contrast enhanced computed tomography (CT) scans of brain, thorax, abdomen and pelvis were performed. Laboratory evaluation included complete blood count (CBC), differential blood count, chemistry profile including liver and renal function, creatinine clearance, serum electrolytes, lactate dehydrogenase (LDH) and coagulation parameters.
Treatment schedule
The dose and schedule of the biochemotherapy regimen are described in Table 1. The treatment was started on day 1 and restarted at day 28. Patients were admitted to hospital for 6 days. Therapy was administered on a regular dermatology ward by trained physicians and nursing staff. Before each therapy cycle the patients underwent placement of a central venous catheter, which was removed at the end of each cycle. Dacarbazine (850 mg/m2) was given on day 1 as 1 h infusion before giving vindesine (1.6 mg/m2) as a bolus injection. On day 2, 3, 4, 5 cisplatin (20 mg/m2) was infused over 2 h before vindesine (1.6 mg/m2) bolus injection. IL-2 (9 MU/m2) was infused continuously on days 2–5, IFN-2b (5 MU/d) was given s.c. on days 1–5.
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Dose modification criteria
In general, in patients with grade 3 or 4 toxicity according to common toxicity criteria, the treatment was interrupted and withheld until the toxicity grade reached 1 or 2.
Response assessment
Response by means of CT scans was assessed 8 weeks after start of therapy and thereafter at intervals of 8 weeks. A bone scan was performed only in patients with suspected or known bone metastases. Standard response criteria were used. CR (complete response) was defined as the complete disappearance of all clinical and radiological evidence of metastatic disease. PR (partial response) was defined as a > 30% decrease in the sum of the products of the perpendicular diameters of all bidimensionally measurable lesions, SD (stable disease) as no new lesions and no increase of > 25%, PD (progressive disease) was defined as a > 25% increase in the sum of the areas of all lesions or the appearance of a new lesion. Response duration was measured from the time of SD, PR or CR.
Statistical methods
The statistical analyses were performed with SPSS 11.5 (LEAD Techn., Chicago, IL). Survival curves were plotted using the product limit method of Kaplan and Meier.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient characteristics
We report the results of 25 consecutive patients with disseminated melanoma treated in our department with a concurrent biochemotherapy protocol. The characteristics of the 25 patients are listed in Table 2. Fifteen patients were men and 10 were women, the median age was 53 years. The patients received a total of 101 therapy cycles. Most of the patients (18/25) had more than two sites of metastatic disease. Fifteen out of the 25 patients had received prior first-line therapy. Accordingly, nine patients received chemotherapy or chemoimmunotherapy, five patients immunotherapy and one patient cutaneous radiotherapy.
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Toxicities
The toxicity evaluation is summarized in Table 3. Grade 1 and 2 toxicities were seen in most patients. The most common toxicities were nausea, vomiting and fever. Lethargy was seen in 16/25 patients. Grade 4 leukopenia occurred in seven patients, grade 4 neutropenia in five patients. Neutropenic fever was seen in one patient. Other grade 4 toxicities were thrombocytopenia (1/25) and anaemia (2/25). The main grade 3 toxicities were: thrombocytopenia (3/25), anaemia (1/25), hypotonia (2/25), oedema (2/25) and rise of liver transaminases (4/25).
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Dose modification
Dose reduction was necessary in 15/25 patients. The most often reduced chemotherapeutic agent was vindesine (15/25), whereas IL-2 was the most often reduced immunotherapeutic agent (6/25). Accordingly, IL-2 dosage was reduced because of hypotonia grade III (two patients) and hypotonia grade II and oedema grade III in one patient. A 50% dosage reduction of IL-2 was necessary in three patients because of grade II oedema and grade I hypotonia, furthermore in one patient in conjunction with a reduction of the complete regimen. IFN was reduced in three patients, in two of them because of a general fatigue syndrome and in the other in conjunction with a 50% reduction of the other compounds. Dacarbazine was only reduced in one patient. Table 4 details the characteristics of dose modification.
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Tumour response and survival
In 7/25 (28%) tumour response was not evaluable, either because the patients refused further therapy (n = 4) or treatment was stopped because of severe toxicities (n = 3). Complete remission was verified in 2/25 patients (8%), partial remission in 2/25 (8%) and stable disease in 9/25 (36%) patients. Five of 25 patients (20%) had disease progression. In patients with prior chemotherapy 2/8 patients (25%) had PR, 2/8 (25%) SD and in 3/8 (37.5%) PD was seen. One of eight patients was not evaluable. The progression free time for all patients was estimated with Kaplan–Meier plots. The median duration of response was 4 months (range 0–19) with the longest response duration being 19 months. The median survival time from start of therapy was 12.0 months (range 2–26) for all 25 patients (Fig. 1).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The medical literature contains multiple phase II studies employing numerous chemotherapeutic drug combinations, with or without immunotherapy (1,14–16). The aim of the studies was to improve survival times and the durability of tumour responses and to determine if the combination treatment regimen of chemotherapy and immunotherapy were superior to single-agent DTIC therapy.
Single-agent DTIC is generally well tolerated. The major side effects are nausea and vomiting. The combination therapy regimen are associated with a significantly higher number of side effects. Legha et al. (21) described for the sequential biochemotherapy more severe side effects as in immunotherapy or in chemotherapy. In our patients most of the severe toxicities were haematological ones. Only a minority of patients suffered from reversible grade II or III toxicities which affected renal or liver function. Overall toxicities are increased compared with DTIC alone. A similar toxicity profile has been reported for other polychemoimmunotherapy regimen, but in our patient group about 20% of the patients refused further therapy because of severe side effects significantly impaired quality of life. Regarding the immunotherapy, more severe side effects are known for IL-2 when compared to IFN- (24). Because of severe hypotension and oedema in the context with the capillary leak syndrome a dose reduction of IL-2 was more often necessary. As IFN- was applied in this regimen only in a low dose of 5 MU/d, the more severe side effects were expected for IL-2. Aside from this a prolongation of hospital stay because of multiple toxicities is associated with higher health care expenditures.
Because of the significant toxicity a superiority of the polychemoimmunotherapy with regard to tumour response and survival is necessary to justify the routine use. High response rates were observed by combining chemotherapy and immunotherapy (14,17,25). The sequence of application of the dual components of chemotherapy and immunotherapy seems to play a role in achieving high response rates. Using an alternating biochemotherapy regimen, response rates failed in contrast to the sequential biochemotherapy programme (21). Using a similar sequential biochemotherapy regimen Richards et al. (14) reported response rates of 57% with 24% CR in a group of 42 patients. A sequential biochemotherapy regimen of cisplatin in combination with IL-2 and IFN- resulted in response rates of 54% and a CR rate of 13% among 39 patients (17). A more convenient schedule of drug administration in which chemotherapy was used concurrently with immunotherapy showed an overall objective response rate of 64%, 21% achieved a CR and 43% a PR (22). Although a majority of responses was stable diseases (36%), an objective response rate of 16% was observed with a CR rate of 8% in our patients. The overall survival data suggest that about 50% of the patients benefit from therapy compared with those with progressive disease. These results corroborate the findings reported in the patients treated with this therapy regimen so far (22,25,26). The durability of responses was disappointingly low. The median progressive free time was 3 months, whereas 5 months was reported by Legha et al. (22). As yet no long-term survivors have been seen. The rate of durable responses with immunochemotherapy is about 10% in contrast to 4% with the use of high-dose IL-2 alone and 1–2% with chemotherapy alone (9,22,27). The length of our treatment cycles (28 days) in contrast to 21 days and the non-application of the IFN- in the treatment intervals perhaps leads to the reduction in long-term survivors.
Despite acceptable response rates in this therapy regimen, there is no clear evidence that immunochemotherapy provides a definitive improvement in overall survival. Despite a low rate of objective responses the overall median survival of 12 months was comparable to the 11.8 months reported by Legha (22). These survival times are superior to those of 6–10 months achieved with chemotherapy or immunotherapy alone (12,28–30). When CVD (cisplatin, vindesine and dacarbazine) plus IL-2 and IFN- was compared in a phase III trial, no significant survival benefit was seen in patients treated with biochemotherapy (23).
In single-agent therapy with DTIC alone median survival times are about 8–10 months (6,31). Even in randomized phase III studies comparing chemoimmunotherapy versus chemotherapy or immunotherapy alone impressive response rates were seen, but no advantage in durable CRs or in overall survival (27,32). Meta-analysis comparing single-agent DTIC versus combination chemotherapy with or without immunotherapy from numerous randomized trials revealed no difference in overall survival (1, 33).
In conclusion, chemotherapy with dacarbazine, vindesine and cisplatin in combination with IL-2 and IFN- is invariably accompanied by substantially increased and potentially hazardous toxicity. To date DTIC monotherapy is well tolerated and appears to deliver clinical improvements similar to the polychemoimmunotherapies. Although the administration in a non-intensive care unit is practicable, in a palliative setting the patients comfort should be considered. Therapeutic approaches with less toxicity and regimen with a benefit on overall survival are desired in the treatment of advanced malignant melanoma. Our presented data, in combination with the existing reports can perhaps serve for designing urgently needed studies in patients with advanced malignant melanoma with regard to achieving a survival benefit.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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