Elsevier

Lung Cancer

Volume 43, Issue 1, January 2004, Pages 83-91
Lung Cancer

Cisplatin versus carboplatin in combination with mitomycin and vinblastine in advanced non small cell lung cancer. A multicenter, randomized phase III trial

https://doi.org/10.1016/S0169-5002(03)00280-0Get rights and content

Abstract

Background: In advanced not selected NSCLC chemotherapy achieved an advantage of approximately 1–2 months on median survival versus best supportive care. Chemotherapy seems to improve symptoms control, even if randomised studies with quality of life as first endpoint are lacking and often chemotherapy toxicity compromises the frail cost/benefit ratio. The aim of the present study is to evaluate the impact on QoL, substituting cisplatin, a pivot drug in NSCLC therapy, with carboplatin, an analogue with an improved toxicity profile. The combination of cisplatin with Mitomycin and Vinblastine was one of the most frequently used in the palliative setting at the time of design of our study. Methods: Patients were randomized to receive MVP regimen (Mitomycin-C 8 mg/m2 d1, Vinblastine 4 mg/m2 d 1–8, Cisplatin 100 mg/m2 d1) or MVC regimen (Mitomycin-C 8 mg/m2 d1, Vinblastine 4 mg/m2 d 1–8, Carboplatin 300 mg/m2 d1) every 3 weeks. The QoL was evaluated by the Spitzer QL-Index and by the EORTC QLQ-C30+LC 13 questionnaires before chemotherapy, after one cycle, after three cycles, and then every 6 weeks in the first 6 months and every 3 months thenafter. Results: From September 1994 to July 1997, 153 consecutive patients were randomized to MVP (75 patients) or MVC arm (78 patients). Despite difficulties in carrying out and analysing QoL items in such patients, the global QoL evaluated by the Spitzer's questionnaire suggested an advantage for MVC regimen (P=0.05) and a significant difference was observed in global health subdomain (P=0.04). The disease-related symptoms improved with time, and the benefits lasted for the entire treatment period. When evaluated with the EORTC questionnaire there was significantly less nausea and vomiting (P=0.0001), appetite loss (P=0.01), insomnia (P=0.03), constipation (P=0.01) and peripheral neuropathy (P=0.01) in favour of MVC, and a trend for less hair loss (P=0.05). The advantage lasted for all the duration of chemotherapy. No differences were observed in global quality of life subdomain (P=0.40) between the two regimen. QoL was the first endpoint and the statistical power was inadequate to assess other parameters. However, we reported a response rate of 43.1 and 38.6%, respectively, in MVP and MVC arm (P=0.59) and a median survival of 10.2 and 7.2 months, respectively, for cisplatin and carboplatin arm (P=0.39). Conclusions: The carboplatin containing regimen (MVC) has a significant better toxicity profile than the cisplatin containing (MVP) regimen as proven both by the EORTC questionnaires and by the WHO toxicity data reported by physicians. No significant differences in terms of response rate, time to progression and overall survival were observed between the two regimen. The two chemotherapy regimen showed a similar effectiveness in symptom palliation when evaluated with C30 addendum of EORTC QOL questionnaire. With the Spitzer's questionnaires a trend towards an improved quality of life index was observed during treatment with the carboplatin combination in comparison to the cisplatin combination. This difference, however, was not observed when the global quality of life was evaluated with the EORTC patients compiled questionnaires. A carboplatin containing regimen with better toxicity profile and a similar potentiality for symptoms control offers an option in comparison to similar cisplatin containing combinations in the palliative treatment of advanced NSCLC.

Introduction

The role of primary chemotherapy in advanced non small cell lung cancer (NSCLC) remains controversial. A meta analysis of 52 randomized clinical trials [1] showed a small benefit with cisplatin-based chemotherapy versus best supportive care (BSC) with an absolute survival improvement of 10% at 1 year and a 6 week increase in median survival.

Quality of life (QoL) assessment becomes extremely important given the small survival advantage and the toxicity of chemotherapy. The main question is whether a small gain in survival time is enough to justify the side effects of chemotherapy.

Only few studies evaluated the impact of chemotherapy not only on survival but also on QoL of patients. Cullen [2] showed an improvement in survival and in QoL in patients treated with the Mitomycin, Ifosfamide and Cisplatin (MIP) combination in comparison with BSC only. Similar results were reported by Thongprasert [3] comparing two schemes of chemotherapy, ifosfamide, epirubicin and cisplatin (IEP) and Mitomycin, Vinblastine and Cisplatin (MVP), in comparison with only BSC. In this randomized trial MVP doubled median survival (8.1 vs. 4.1 months) and quadrupled 1 year survival (39.3 vs. 13%) in comparison with BSC. Moreover, improvement in QoL scores were seen in the chemotherapy arms only, not in the BSC arm.

QoL is the result of the difficult balance between the advantage of chemotherapy on disease and symptom control and the disadvantage of side effects of chemotherapy itself. Carboplatin is an analogue of cisplatin with an improved toxicity profile [4]. It has lower neurotoxicity, nephrotoxicity and nausea and vomiting toxicity compared with cisplatin. Moreover alopecia, that is a main psycological point, with a great impact on QoL, is uncommonly induced by carboplatin contrary to cisplatin.

Although carboplatin has a similar mechanism of action and preclinical spectrum of activity as cisplatin, it is still unclear whether it has an equivalent efficacy for all disease types.

The role of carboplatin, alone or in combination, is not yet well defined in NSCLC. The results of two randomized trials comparing carboplatin to cisplatin based combinations, showed no difference in terms of response rate and survival, while the toxicity was considerably less in the carboplatin arm [5], [6].

In our preliminary Phase II study, which included stage IIIB and IV patients or patients relapsing after previous surgery, a chemotherapy regimen with Mitomycin, Vinblastine and Carboplatin (MVC) appeared feasible in an outpatient setting, with good patient compliance, low toxicity profile, promising response rate (38.6%) and median duration of response of 9.8 months [7].

However, the effectiveness of carboplatin as a substitute of cisplatin in improving QoL has never been adequately tested in NSCLC at the time of design of our study.

Section snippets

Patient eligibility

From September 1994 to July 1997, 153 patients with advanced (stage IIIB with pleura effusion or involvement of supraclavicular lymphnodes) or metastatic (stage IV) NSCLC entered the study. Eligibility criteria included: histologically confirmed NSCLC; Karnofsky performance status >50; age ≤70 years; life expectancy ≥3 months; ability to understand and fill-in QoL questionnaire; measurable or evaluable disease; adequate hematological (WBC≥4.0×109 per l, Platelets≥100×109 per l and Hemoglobin≥10

Results

From September 1994 to July 1997, a total of 153 patients were recruited in the trial; 75 patients were randomized to the MVP arm and 78 to the MVC arm.

The clinical characteristics of the 153 patients are summarised in Table 1. The most important prognostic factors were quite equally distributed in the two arms and well balanced.

Also the baseline QoL characteristics, evaluated with the Spitzer's scales and the EORTC scales resulted well balanced between the two arms (Table 2, Table 3).

When we

Discussion

The impact of chemotherapy on quality of life in advanced NSCLC is a crucial question but there are a lot of problems in designing and conducting trials on this issue.

We have chosen to use the physician compiled Spitzer's questionnaire and the patients compiled EORTC QLQ-C30 and QLQ-LC 13 questionnaires to compare the physician's and the patient's attitude in evaluating chemotherapy-induced modifications of QoL.

The main finding of our study was that with the Spitzer's questionnaires the global

Conclusions

From our study the carboplatin-containing MVC regimen showed a better toxicity profile than the cisplatin-containing MVP regimen.

On the other hand, MVP seems to be slightly superior in response rate, time to progression and overall survival although our data did not show a statistically significant advantage.

The two chemotherapy regimens showed a similar effectiveness in symptom palliation when evaluated with C 30 addendum of EORTC QoL questionnaire. The better toxicity profile of MVC may have

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