Paclitaxel/Carboplatin with Paclitaxel/Cisplatin in Patients with Advanced Non-Small-Cell Lung Cancer
Abstract & Commentary
Synopsis: This is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.
Source: Rosell R, et al. Ann Oncol. 2002;13:1539-1549.
Cisplatin has been a backbone of chemotherapy combinations in non-small-cell lung cancer (NSCLC), and several combinations of cisplatin-based chemotherapy are used in the current treatment of this disease. In the United States, carboplatin has been used extensively in place of cisplatin, but there have been very few randomized trials comparing these drugs.1 There have been a number of studies and meta-analyses that document the importance of platinum compounds.2 The substitution of carboplatin for cisplatin has been studied in other malignancies, particularly ovarian cancer. The drugs are not equivalent in all situations. The present study is a randomized, multicenter European trial comparing paclitaxel/carboplatin vs paclitaxel/cisplatin. The major end point is objective response rate with secondary end points of survival, toxicity, quality of life, and the analysis of prognostic factors including histology.
There had been some question for many years whether chemotherapy is beneficial in patients with advanced NSCLC. There are conclusive studies that have shown a definite survival advantage in patients receiving chemotherapy compared to best supportive care. This includes cisplatin-containing regimens, vinorelbine compared to fluorouracil plus leucovorin and docetaxel as a second-line agent.3-7 The current study was undertaken to determine the relative benefits of the 2 platinum compounds. The trial included untreated patients with NSCLC with stage IIIB or IV disease, and ECOG PS 0-2 with measurable (or nonmeasurable but assessable) disease. Six hundred sixteen patients were randomized. Patients on the paclitaxel/cisplatin arm received on day 1 paclitaxel (200 mg/m2 for 3 h) followed by cisplatin (80 mg/m2 for 30 min) and patients randomized to paclitaxel/carboplatin received the same dose of paclitaxel followed by carboplatin (AUC 6 for 30 min). Treatment was administered in 21-day cycles. Patient characteristics were well balanced and 17% of patients had PS of 2. The overall results are shown in the Table. Greater than 80% of patients received 90% of the schedule paclitaxel dose intensity. There were similar results with the platinum drugs. The only significant difference in toxicity was thrombocytopenia in the carboplatin-containing arm. There were no significant differences in global health status or in the functional scales, which are global indices of quality of life. The differences in survival were small but statistically significant, leading Rosell et al to conclude that the cisplatin-containing arm is superior. In the accompanying editorial, Soria and Le Chevalier indicate that carboplatin is probably a slightly inferior drug to cisplatin in NSCLC. However they also state there are many circumstances in which carboplatin would be an acceptable alternative (ie, renal insufficiency, hearing loss, pre-existing neuropathy, etc).8
There have now been a number of trials attempting to compare cisplatin with carboplatin in NSCLC. A series of ECOG trials in the 1980s demonstrated carboplatin superiority.9 In a recent 4-arm ECOG trial, the response rate and survival did not differ significantly between patients receiving paclitaxel/cisplatin and those in any of the other 3 arms (cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel).10 In this European randomized trial cisplatin was superior. The differences in these trials could be patient selection, histology (squamous vs adeno), dose of carboplatin, length of paclitaxel infusion (3 vs 24 h), dose of paclitaxel or supportive care. It seems that the differences between the 2 agents are minimal and may be insignificant in terms of survival. The real differences are in the toxicity profiles. The treating physician must decide on which agent to use based on their patient’s tolerance and in particular comorbid illnesses. It is questionable whether further studies comparing these 2 drugs should be performed. There are currently trials evaluating nonplatinum-containing combinations.11 It seems that a therapeutic ceiling is being reached with standard chemotherapy. Overall the trials seem to indicate an approximate 1-year survival in advanced NSCLC of about 30%. Newer treatment strategies are needed to overcome the limits of our current drug therapy.
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