Non-small-cell lung cancer: which platinum for gemcitabine?

Cisplatin-based chemotherapy remains the backbone in the treatment of non-small-cell lung cancer (NSCLC), with significantly improved survival and better quality of life [1]. Platinum based doublets, with new drugs like Gemcitabine, Vinorelbine and Taxanes, are superior to single agent chemotherapy and should be preferred in first line treatment of patients with advanced NSCLC, according to current American Society of Clinical Oncology (ASCO) guidelines [2]. Gemcitabine (2,2-difluorodeoxicytidine) has shown good clinical activity against NSCLC, with synergism with cisplatin in preclinical studies [3]; the combination cisplatin-gemcitabine is today one of the reference treatments in NSCLC, showing superiority when compared with cisplatin doublets and triplets using other drugs like etoposide, mitomycin, vindesine and ifosfamide. Several phase II and phase III trials with these combinations achieved response rates of 28–54 %, with improvement in time to progression and survival [4–10]. Relevant toxicity, namely myelosuppression with trombocytopenia, emesis, neurotoxicity, nephrotoxicity and the need for hydration are the main limits associated with the use of cisplatin; because of these side effects many medical oncologists remain sceptical about the utilization of this drug to treat patients with advanced NSCLC [11]. Carboplatin, an analogous of cisplatin, shows similar mechanism of action, but has different pharmacokinetics and toxicities, that make of it, in some way, a different drug [12]. In particular, a less non hematological toxicity and an increased convenience in an outpatient setting are balanced by a higher myelosuppression, particularly thrombocytopenia, which limits its combination with other drugs at a full dose. Because of a good activity with an easier administration and a milder non hematological toxicity, Carboplatin has often replaced Cisplatin in few malignancies, such as ovarian and breast cancer [13–16]. In NSCLC, several phase II studies have evaluated the combination of Gemcitabine-Carboplatin, using 3 weeks as well as 4 weeks schedule [17–23], with encouraging results in terms of response rate and survival. Only one study compared 21-day and 28-day schedules; response rate and survival were similar, with a significant reduction of thrombocytopenia in the patients receiving the 21-day schedule [19]. Oxaliplatin is the newer platinum compound entered in clinical practice; in a phase II study in patients with NSCLC it showed activity as single agent, with an overall response rate of 16%. Given its synergy with Gemcitabine, the combination Gem-Ox was evaluated in few phase II studies, achieving a response rate in the range of 16–43% [24–26]. Toxicity, hematological and non hematological, was mild, also in elderly and pretreated patients. Although Cisplatin-based chemotherapy is currently considered to be the standard treatment in advanced NSCLC, many attempts to circumvent Cisplatin induced toxicity, replacing it with Carboplatin, have been made. Go et al. [27], reviewed the comparative pharmacology and clinical activity of Cisplatin and Carboplatin in several tumors. Prospective randomized trials were identified for ovarian (n = 12), germ cell (n = 4), NSCLC (n = 1), SCLC (n = 3) and Head and Neck (n = 4) cancers. In those trials Carboplatin was found to be inferior to Cisplatin in germ cell, head and neck and esophageal cancer; conclusions were that Carboplatin does not possess equivalent activity to Cisplatin in all platinum-sensitive tumors. On the other hand, comparisons between Cisplatin and Carboplatin in NSCLC have been based on limited data. Recently a meta-analysis of randomized clinical trial comparing Cisplatin to Carboplatin in patients with advanced NSCLC has been published [28]. Eight phase III trials (2948 patients) were identified in which doublets with Carboplatin were compared to doublets with Cisplatin; five of these trials investigated drug regimens containing a platinum plus a new agent (two studies with Gemcitabine, two with Paclitaxel and one with Docetaxel). The response rate to Cisplatin-based chemotherapy was superior to that of Carboplatin-based chemotherapy in all eight single trials. s y m p o s iu m