Treatment of Stages IIIB and IV, Non Small Cell Lung Cancer With Alternating Cycles of Carboplatin/Taxol and Carboplatin/Gemcitabine.

Lung cancer is the leading cause of cancer death in men and women in the USA, and account for 28% of all cancer deaths in 2002 (1). In stage IV and some patients with stage III disease chemotherapy is widely used with the primary aim of prolonging survival and /or palliating symptoms. A meta analysis of clinical studies that randomized patients between the best supportive care and chemotherapy concluded that Cisplatin based chemotherapy resulted in a potential gain in the median survival and an increase of the 1-year survival rate compared to the supportive care alone (2). Combination chemotherapy regimens (Platinum/Taxanes, Platinum/Gemcitabine, Platinum/Vinca alkaloids) have demonstrated a response rate of 30-50% with median survival of approximately 10 months, one year survival rates around 40%, and 2 year survival of only 10 % in patients with advanced Non Small Cell Lung Cancer (NSCLC) (3,4). Therefore it is important to continue to search for new agents/combinations that can be used to improve the overall prognosis of these patients.

Rationale for using alternating cycles of chemotherapies:

Emergence of progressive or recurrent disease is a consequence of selection and overgrowth of pre-existent, drug resistant cells during treatment. Based on the mechanism of somatic cell mutation, Goldie and Coldman (5,6) proposed a model for the emergence of drug resistant cells in tumors. Their model proposed that alternating non-cross-resistant combinations would prevent the overgrowth of resistant cancer cells and improve the probability of tumor control or cure. Their recommendation assumed that the two non-cross-resistant regimens were of equal or similar efficacy and that the drugs contained in the two combinations could not be administered together in one single regimen.

There are few instances in Clinical Oncology where two regimens of similar efficacy exist for the same tumor type. Since apparently equivalent chemotherapy regimens exist for the treatment of NSCLC, the Goldie and Coldman hypothesis could also be tested in this tumor type. Historically, SWOG conducted a phase III trial randomizing patients between FOMi (5-Fluorouracil/Vincristine/MitomycinC), CAP (Cyclophosphamide/Doxorubicin/Cisplatin) and a third arm FOMi/CAP, which alternated the two combinations. Response rates were 26%, 17% and 22%, respectively, and were not statistically significantly different (P=0 .247). Survival was reported as 20, 24 and 23 weeks, respectively. Statistically survival of FOMi/CAP treated patients was superior to FOMi treated (P=0.024) but not CAP treated (P=0.23) patients (7). Since then, several studies have attempted to improve upon the response rate and survival in advanced NSCLC by using regimens with alternating cycles of non-cross-resistant therapy (8,9,10,11). These regimens yielded overall response rate of 21-49%, median survival of 20-48 wks with acceptable toxicity.

Though several studies have been done to evaluate clinical response in lung cancer using alternating chemotherapies, none of these studies have evaluated clinical response with alternating Paclitaxel and Gemcitabine based treatment which are two of the most effective chemotherapy regimens in use currently. In studies of Platinum combinations that included one of these agents, results were better than those achieved with Platinum alone or combined with earlier generation agents such as Vindesine or Etoposide (12). Current evidence suggests that combinations of Paclitaxel or Gemcitabine with Cisplatin or Carboplatin are among the most active palliative treatments for advanced NSCLC. With combination of Cisplatin and Gemcitabine a response rate in phase II trials ranged from 30-54%, with median survival times of approximately 8-15 months and I year survival rates from 34-61% (13,14). Myelosuppression was the major toxicity, while Cisplatin associated nonhematologic gastrointestinal, renal and neurologic effects were also problematic. Attempts to reduce toxicity associated with the Cisplatin/ Gemcitabine regimen have included replacing Cisplatin with Carboplatin, a platinum analog possessing similar efficacy and hematologic effects, but lacking the non hematologic toxicity commonly experienced with Cisplatin therapy (15,16). Furthermore Carboplatin can be administered with no need for prehydration to avoid renal toxicity.