Cisplatin (Platinol)-based chemotherapy has been the foundation of the treatment of lung cancer for over 2 decades. Several new classes of agents, or analogs of existing drugs, that have single-agent activity comparable to cisplatin(Drug information on cisplatin) have recently been introduced. Two classes of new drugs that have significant activity in both small-cell and non-small-cell lung cancer are the camptothecins and the taxanes.
Taxanes preferentially bind to microtubules, inhibiting dynamic reorganization of the microtubular network, leading to the arrest of cells in the G2/M phase of the cell cycle. Both paclitaxel(Drug information on paclitaxel) (Taxol) and docetaxel(Drug information on docetaxel) (Taxotere) are drugs active against non-small-cell lung cancer, and each produces a single-agent response rate of approximately 20%.
The Eastern Cooperative Oncology Group (ECOG) performed a randomized study comparing cisplatin/etoposide to cisplatin/paclitaxel. Patients were randomized to three arms: control (cisplatin/etoposide), paclitaxel 135 (cisplatin and paclitaxel as a 24-hour infusion at 135 mg/m2 per cycle), and paclitaxel 250 (cisplatin and paclitaxel as a 24-hour infusion at 250 mg/m2 per cycle with granulocyte colony-stimulating factor [G-CSF] support). Survival was better in both paclitaxel-containing arms than in the control arm, but the difference reached standard levels of statistical significance only if results of the two paclitaxel-containing groups were combined (1-year survival of 39% vs 32%, P = .048).
Patient tolerance and preservation of quality of life were fairly comparable with the different regimens. Preliminary results of a study comparing the combination of carboplatin(Drug information on carboplatin) (Paraplatin)/paclitaxel to cisplatin/etoposide reported comparable survival. Febrile neutropenia developed less frequently in the patients treated with carboplatin/paclitaxel, but myalgia and neuropathy were more common.
The Southwest Oncology Group (SWOG) has reported the preliminary results of a study that compared carboplatin/paclitaxel to cisplatin/vinorelbine (Navelbine). No difference in survival was noted. However, fewer patients dropped out of the carboplatin/paclitaxel arm due to toxicity, suggesting that this regimen was better tolerated. The ECOG has also conducted a large study (E1594) comparing four of the newer platinum-containing regimens. This study compared the combinations of cisplatin/paclitaxel to cisplatin/gemcitabine (Gemzar) to cisplatin/docetaxel to carboplatin/paclitaxel.
A total of 1,163 patients were treated, and survival was comparable in the four arms. The median survival ranged from 7.4 to 8.2 months, and 1-year survival ranged from 31% to 36%. Taken together, these studies suggest that platinum-containing chemotherapy regimens that include one of the newer drugs, such as a taxane, offer advantages to regimens that contain older agents (ie, etoposide(Drug information on etoposide)). Whether or not there are clinically important differences if a platinum drug is combined with a taxane or with another one of the newer drugs, such as gemcitabine(Drug information on gemcitabine), has not been established.
For patients who have received prior platinum-containing chemotherapy, docetaxel is one of the few agents that have demonstrated activity. Shepherd and colleagues randomized previously treated patients (one or more regimens) to docetaxel or to best supportive care. Overall, both survival (time to progression and median survival) and quality of life were better in the patients who received treatment with docetaxel. A study by Fossella and coworkers randomized 373 previously treated patients to docetaxel 100 (docetaxel at 100 mg/m2 per cycle), docetaxel 75 (docetaxel at 75 mg/m2 per cycle), or a control arm of vinorelbine or ifosfamide(Drug information on ifosfamide) (Ifex). Previous treatment with paclitaxel was permitted, and 37% of the patients had received this drug as part of their prior therapy.
Based on an intention-to-treat analysis, survival at 1 year in the docetaxel 75 group (32%) was superior to the other two arms (21% and 19% in the docetaxel 100 and control group [P = .025 vs control], respectively). In both docetaxel arms progression-free survival and quality of life were improved. An analysis attempting to adjust for the effects of poststudy treatment suggested a survival advantage for both docetaxel arms.
Two phase II studies have examined the role of single-agent paclitaxel in patients with previously untreated extensive-stage small-cell lung cancer.[10,11] The ECOG reported a response rate of 34%, but life-threatening grade 4 leukopenia occurred in 56% of the patients. A second trial, conducted by the North Central Cancer Treatment Group (NCCTG), administered paclitaxel on a similar schedule, but with the addition of G-CSF. The response rate was similar (53%), and the incidence of severe leukopenia was reduced to 14%.
One study has examined the activity of paclitaxel in patients refractory to chemotherapy, defined as a relapse within 3 months of the completion of previous therapy. Nearly half of the patients enrolled in this study had received prior platinum-containing chemotherapy. In 21 assessable patients, 7 achieved a partial response, for an objective response rate of 29%. There were two early deaths and two toxic deaths in the trial, and the median survival of assessable patients was 100 days. This study suggests that paclitaxel is a useful, active drug in the management of refractory small-cell lung cancer.
When combined with cisplatin, paclitaxel has shown substantial activity in small-cell lung cancer. A phase II study by Nair et al in chemotherapy-naive patients assessed paclitaxel at an initial dose of 135 mg/m2, later escalated to 175 mg/m2, with cisplatin at 75 mg/m2. Patients that developed progressive disease were crossed over to cisplatin and etoposide. Fifteen of 21 (71%) evaluable patients in the lower paclitaxel arm and 39 of 44 (89%) evaluable patients in the higher paclitaxel arm demonstrated a response to treatment.
Docetaxel has been evaluated in small-cell lung cancer in a small number of phase II trials. The National Cancer Institute of Canada evaluated docetaxel in chemotherapy-naive patients with extensive disease at a dose of 75 mg/m2 every 3 weeks. Twelve patients were evaluable for response, of which only one demonstrated a partial response (12-week duration), resulting in a disappointing response rate of 8%. A subsequent SWOG study utilized a higher dose of docetaxel at 100 mg/m2 every 3 weeks. In 46 eligible patients with untreated extensive-stage small-cell lung cancer, a response rate of 26%, with a median survival of 9 months, was reported. In 34 previously treated patients, a European Organization for Research and Treatment of Cancer (EORTC) study reported a response rate of 25%.
In previously untreated patients, irinotecan(Drug information on irinotecan) (Camptosar, CPT-11) has demonstrated a single-agent response rate of 15% to 32%. Response rates in previously treated patients have been comparable to other chemotherapy drugs and ranged from 0% to 14%. The main toxicities were neutropenia and diarrhea. Pulmonary toxicity, presumably due to a hypersensitivity reaction, occurred in 8% of patients in one phase II study. Similar to the results in studies of colorectal cancer, both the weekly schedule of administration of irinotecan and the single dose every 3 weeks appear to yield comparable activity and side effects.
The combination of irinotecan and cisplatin has been reported to show significant antitumor activity in untreated patients, with response rates ranging between 31% and 55%.[17,19,20] Dose reductions are common when irinotecan is given on a weekly schedule and cisplatin is administered once every 4 weeks. Schedules in which cisplatin is given in divided doses weekly together with irinotecan may be better tolerated and are equally effective.
Two randomized phase III studies from Japan have compared the combination of cisplatin and irinotecan to a standard regimen in patients with previously untreated non-small-cell lung cancer. In the study by Masuda and colleagues, 398 patients were randomized to cisplatin/irinotecan, irinotecan alone, or a control arm consisting of cisplatin and vindesine(Drug information on vindesine); 378 were evaluable for response, survival, and toxicity. In a study by Niho and coworkers, 203 eligible patients were evaluated for responses and toxicity to cisplatin/irinotecan or cisplatin/vindesine regimens. Although no differences in survival were detected individually in these studies, an analysis that combined the data showed that patients treated with cisplatin/irinotecan had a significantly better survival at 1 year than patients treated with the controlled regimen.