Cisplatin versus carboplatin in combination with mitomycin and vinblastine in advanced non small cell lung cancer. A multicenter, randomized phase III trial
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
References (23)
- et al.
Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy
Lung Cancer
(1999) - et al.
Survival advantage for carboplatin 500 mg/m2 substituting cisplatin 120 mg/m2 in combination with vindesine and mitomycin-C in patients with stage IIIB and IV squamous cell bronchogenic carcinoma. A randomized phase III study in 221 patients
Lung Cancer
(1997) - et al.
Measuring the quality of life of cancer patients: a concise QL-index for use by physicians
J. Chronic Dis.
(1981) - et al.
The EORTC QLQ-LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials
Eur. J. Cancer
(1994) - et al.
Quality of life in patients with lung cancer. A review of literature from 1970 to 1995
Chest
(1998) - et al.
Is cisplatin still the best platinum compound in non-small cell lung cancer
Ann. Oncol.
(2002) - et al.
Phase III randomised trial comparing paclitaxel/carboplatin with cisplatin/carboplatin in patients with advanced non small cell lung cancer: a cooperative multinational trial
Ann. Oncol.
(2002) Chemotherapy in non small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials
Br. Med. J.
(1995)- et al.
Mitomycin, ifosfamide and cisplatin in unresectable non small cell lung cancer: effects on survival and quality of life
J. Clin. Oncol.
(1999) Review of therapeutic trials of carboplatin in lung cancer
Semin. Oncol.
(1989)
A randomized study comparing ciplatin or carboplatin with etoposide in patients with advanced non small cell lung cancer: European Organization for research and Treatment of Cancer protocol 07861
J. Clin. Oncol.
Cited by (62)
Chemotherapy-induced peripheral neuropathy: Symptomatology and epidemiology
2018, Bulletin du CancerWhat can platinum offer yet in the treatment of PS2 NSCLC patients? A systematic review and meta-analysis
2015, Critical Reviews in Oncology/HematologyHow are palliative care cancer populations characterized in randomized controlled trials? A literature review
2014, Journal of Pain and Symptom ManagementAssessment of quality of life in advanced non-small-cell lung cancer: An overview of recent randomized trials
2012, Cancer Treatment Reviews