Rationale for superseding
There is no evidence demonstrating equivalent efficacy for day 8 dosing of carboplatin vs the day 1 schedule. Whilst a small phase II study did demonstrate fewer dose adjustments with day 8 carboplatin, no difference in outcomes were noted,r and carboplatin/gemcitabine regimens across several malignancies have continued to administer carboplatin on day 1. For this reason the Medical Oncology Reference Committee has superseded this protocol.
The key data regarding the efficacy of this regimen comes from 3 phase III trials with 900 patients (not previously treated) with advanced NSCLC. These studies compared gemcitabine/carboplatin versus gemcitabine alone, gemcitabine/carboplatin v gemcitabine/cisplatin, and gemcitabine/carboplatin v mitomycin/ifosfamide/cisplatin.
Results show that gemcitabine/carboplatin efficacy was equivalent or superior to that achieved with single agent gemcitabine or other platinum based treatments. The regimen was well tolerated overall and available data show improved quality of life. Gemcitabine/carboplatin appears a viable option in first line treatment of advanced NSCLC.r
Cisplatin vs. Carboplatin
A meta-analysis of abstracted data by Hotta et alr compared the results of 9 trials involving 2698 patients between cisplatin based combination chemotherapy (1489 patients) against carboplatin based chemotherapy (1479 patients) in first line treatment of advanced NSCLC. It showed that cisplatin based chemotherapy achieved higher objective response rates (OR 1.36/ P<0.01) but showed no overall survival advantage (HR 1.05, P=.515). Toxicity was not uniformly comparable but there were no significant differences in treatment related deaths.
Optimal chemotherapy doublet
The predictive influence of histological subtypes on outcomes has been shown in recent studies. In a combined analysis of individual patient data from three phase III trials in first line treatment of NSCLC, Treat et alr demonstrated a difference in overall survival between patients with non-squamous and squamous histology to different chemotherapy combinations. In patients with non-squamous histology, pemetrexed/cisplatin conferred superior median overall survival (11 months) compared with other regimens including gemcitabine/carboplatin (8.3 months). However, in patients with squamous histology, vinorelbine/cisplatin conferred the best median overall survival outcome and gemcitabine/cisplatin was superior to pemetrexed/ cisplatin.
A combination of carboplatin and gemcitabine showed a significant improvement in 1 year survival and a reduction in risk of death in comparison to single agent gemcitabine. Intent to treat analysis showed a longer median time to disease progression.
The results of gemcitabine/carboplatin versus gemcitabine arm among the 291 patients evaluable for response are summarised in the table below.
|1 year survival
|2 year survival
|Overall median survival
|Median time to disease progression
NR: not reported
© Seminars of Oncology 2003
A combination of carboplatin and gemcitabine showed a significant improvement in 1 year survival and a reduction in risk of death in comparison to single agent gemcitabine.
Intent to treat analysis showed a longer median time to disease progression.
Results of gemcitabine/carboplatin versus gemcitabine arm, 291 patients included.r
Myelosuppression is the dose limiting toxicity of carboplatin. Thrombocytopenia occurs more commonly. Anaemia is more often seen in those patients with prolonged exposure to carboplatin. Although there were higher haematological toxicities with carboplatin/gemcitabine compared to gemcitabine alone, most resolved quickly with no major clinical sequelae.r
|Non-Haematological grades 3&4
|| 26.1 %
|| 28.4 %
Grade 3 (%)
| Grade 4 (%)
|| Grade 3 (%)
|| Grade 4 (%)