An estimated 164,100 new cases of lung cancer will be diagnosed in 2000, and approximately 25% or 41,000 of these cases will be small-cell lung cancer (SCLC). Nearly one-third of the patients with SCLC present with limited-stage disease. This is defined as disease that is confined to one hemithorax without pericardial or pleural effusion and thus, encompassable by a single radiotherapy port. Limited-stage SCLC is potentially more curable than extensive disease. Prior to the use of chemotherapy, patients diagnosed with limited-stage SCLC survived an average of 3 months. With the advent of polychemotherapy, median survival is approximately 10 to 14 months, with 5-year survival ranging between 2% and 8%.
Of the currently available chemotherapeutic agents, several have been associated with response rates of 30% or more. These agents include cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan), doxorubicin(Drug information on doxorubicin) (Adriamycin), methotrexate(Drug information on methotrexate) (Folex, Mexate), etoposide (VePesid, VP-16), vincristine (Oncovin), and carboplatin(Drug information on carboplatin) (Paraplatin). Despite the known chemosensitivity of SCLC (with response rates of approximately 70% to 80% in all patients, and up to 50% complete responses with combination chemotherapy in patients with limited disease), the majority of patients diagnosed with limited-stage SCLC will die from recurrent disease. Over the past several years, investigators have attempted to improve upon this high relapse rate with different approaches.
Goldie and Coldman Hypothesis
The mathematical model described by Goldie and Coldman suggests that rapid alternation of noncross-resistant regimens might improve tumor-cell kill. The combination of cisplatin(Drug information on cisplatin) (Platinol) and etoposide(Drug information on etoposide) (PE) has been shown to be effective salvage therapy in SCLC patients treated with CAV (cyclophosphamide, doxorubicin, vincristine), with response rates approaching 50%. Additionally, a phase III study by the Southeastern Cancer Study Group randomized limited-disease SCLC patients to receive six cycles of CAV administered with or without two cycles of PE as consolidation therapy. Survival was significantly longer in the PE arm, 97.7 weeks vs 68 weeks, P = .0094. Because of these results, it is believed that CAV and PE may be noncross-resistant regimens.
Three randomized phase III trials in SCLC have attempted to prove this theory.[8-10] The first trial was conducted in Canada in 289 patients with extensive-disease SCLC.[8 ] Patients were randomized to receive either standard therapy consisting of CAV administered every 3 weeks for six courses or CAV alternating with PE every 3 weeks for six treatment cycles. The overall response rate (80% vs 63%, P < .002), and overall survival (9.6 vs 8.0 months, P = .03) favored the alternating regimen. Fukuoka et al conducted a randomized trial comparing CAV with PE and CAV alternating with PE. This trial included 288 eligible patients with both limited and extensive diseae. Patients with limited disease received thoracic radiation after completing chemotherapy.
Overall response rates were superior in the PE and CAV/PE arms compared to CAV alone, 78%, 76%, 55%, respectively (P < .005). Overall survival favored the alternating regimen, CAV/PE, as compared to either PE or CAV alone, 11.8 months, 9.9 months, and 9.9 months, respectively (P = .056). When the data were analyzed by stage, there was no difference in survival among patients with extensive disease (8 to 9 months). There was, however, a significant survival advantage for the alternating regimen in patients with limited disease when compared to either PB or CAV alone, 16.8 months, 11.7 months (P = .023), or 12.4 months (P = .14), respectively.
The Southeastern Cancer Study Group (SECSG) conducted a trial in patients with previously untreated extensive-disease SCLC. The 437 enrolled patients were randomized to receive either six cycles of CAV, four cycles of PE, or CAV alternating with PE (three cycles each). There was no difference in overall response rate, 51%, 61%, and 59%, respectively, or median survival, 8.3, 8.6, and 8.1 months, respectively.
Two phase II trials have established the activity of the VIP (cisplatin, ifosfamide(Drug information on ifosfamide), and etoposide) regimen.[11,12] Subsequently, the Hoosier Oncology Group conducted a randomized trial comparing VP-16 and cisplatin (VP) with or without ifosfamide (VIP) in patients with previously untreated extensive-disease SCLC. Between May 1989 and March 1993, 171 patients with chemotherapy-naive, extensive-disease SCLC were entered into the trial and 163 were evaluable for response. Responses were seen in 67% of patients treated with VP and 73% of patients treated with VIP (P = NS). Overall survival favored the VIP arm, 9.1 vs 7.3 months, and was statistically significant (P = .044). Myelosuppression was the most frequent toxicity, with grade 4 granulocytopenia occurring in 24% of patients treated with VP and 43% of patients treated with VIP. Miyamoto et al reported on a similar randomized trial comparing cisplatin and etoposide with or without ifosfamide in patients with both limited and extensive disease. This trial demonstrated no differences in response rate or overall survival, but the outcome may be equivocal because the study was small (N = 92) and included a mixed patient population.
The results of these studies suggest that for patients with extensive disease, there is no obvious survival advantage associated with any particular chemotherapy combination.
Short Intensive Weekly Therapy
Another treatment approach is the rapid sequencing of a regimen incorporating several active agents over a short period. One such regimen, CODE, consists of weekly treatments of cisplatin, vincristine (Oncovin), doxorubicin, and intravenous etoposide, with the myelosuppressive and nonmyelosuppressive agents alternated. The CODE regimen was designed to double the dose intensity of these agents in comparison with the more traditional regimen of CAV alternating with etoposide and cisplatin.
In a promising Canadian pilot study, Murray et al reported a 94% overall response rate (40% CR) in 48 patients (all less than 66 years old) with extensive-disease SCLC. Median survival was 61 weeks. The principal toxicities were grade 4 granulocytopenia in 56% of patients and anemia requiring blood transfusions in 58% of patients. There were four incidents of neutropenic fever. Nonhematologic toxicities included grade 2/3 mucositis in 12% of patients and grade 2 or greater neurologic complications in 16% of patients. There were two treatment-related deaths, one from neutropenic fever and the second from pneumonia in a non-neutropenic patient.
However, a larger phase III trial conducted in Japan failed to confirm a survival advantage with the CODE regimen. In this study, 228 patients with extensive-disease SCLC were randomized either to the CODE plus granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim), [Neupogen]) arm or the standard arm of CAV alternating with PE. Overall response rates (85.3% and 76.7%, respectively) and survival (11.9 months and 10.6 months, respectively) were not statistically different between the two treatment arms. A confirmatory Canadian/United States trial included 220 patients randomized between CODE and CAV/PE. The study closed prematurely due to an excess number of toxic deaths in the CODE arm (8.2% vs 0.9%). There was no statistical difference in overall survival between the two arms, 0.98 years vs 0.91 years, P = NS.
In order to improve the resistance of SCLC to chemotherapy administered after the first four to six cycles, investigators have designed trials to test the hypothesis that higher doses of chemotherapy, particularly in the first one to four cycles, may improve survival.
This approach was investigated in seven randomized trials (Table 1).[18-24] In the late 1970s and 1980s, five studies evaluated either doxorubicin-based or alkylating agent-based chemotherapy,[18-22] and only one of these studies demonstrated a survival advantage in favor of the dose-intensive arm. That study, conducted by the Eastern Cooperative Oncology Group (ECOG), randomized 349 patients with limited- or extensive-disease SCLC to receive either standard therapy with cyclophosphamide 700 mg/m² on days 1 and 22, Lomustine(Drug information on lomustine) (CCNU) 70 mg/m² on day 1, and methotrexate 15 mg/m² twice weekly during weeks 2, 3, and 5, 6 or to receive the same regimen with an increased dose of cyclophosphamide (1,500 mg/m²). All responding patients on the standard arm received maintenance therapy with doxorubicin, vincristine, and procarbazine(Drug information on procarbazine) (Matulane) alternating with a low-dose version of the induction regimen.
In a second randomization designed to test the role of maintenance therapy, only half the patients in the dose-intensive arm received maintenance therapy. Survival was improved in the dose-intensive arm, 41 weeks vs 36 weeks (P = .04). This difference was most pronounced in the group of patients with limited disease, where survival was 56 vs 42 weeks (P = .02). Toxicity, particularly hematologic toxicity, was more pronounced in the dose-intensive arm, with life-threatening and lethal toxicities reported as 53% vs 7% and 4% vs 1%, respectively (P < .0001).
Two randomized trials of cisplatin-based chemotherapy in limited-disease SCLC have been published with conflicting results.[23,24] A French study randomized 105 patients to receive a chemotherapy regimen consisting of cisplatin, cyclophosphamide, doxorubicin, and etoposide. All patients received doxorubicin 40 mg/m² and etoposide 75 mg/m² on days 1 to 3. The standard regimen consisted of cisplatin 80 mg/m² and cyclophosphamide 900 mg/m² divided over 4 days in addition to the doxorubicin and etoposide combination. The dose-intensive arm consisted of cisplatin 100 mg/m² and cyclophosphamide 1,200 mg/m² divided over 4 days plus doxorubicin and etoposide. Chemotherapy doses differed for the first cycle of treatment only. All patients received the identical standard arm dose for cycles 2 through 6 as well as identical chest radiotherapy. With a median follow-up of 33 months, the 2-year survival rate for patients in the higher-dose chemotherapy arm was 43% vs 26% for those in the standard arm. There was no difference in the patterns of toxicity between the two arms.
Another study, conducted at the National Cancer Institute (NCI), randomized 90 patients with extensive-disease SCLC to receive standard-dose or high-dose cisplatin and etoposide for cycles 1 and 2. The standard-dose arm consisted of cisplatin (P) 80 mg/m² on day 1 and etoposide (E) 80 mg/m² on days 1 to 3 every 3 weeks. The high-dose arm consisted of cisplatin 135 mg/m² divided over 5 days and etoposide 80 mg/m² on days 1 to 5. Cycles were repeated every 3 weeks. All patients received standard-dose PE in cycles 3 and 4. Patients in complete remission continued to receive PE in cycles 5 through 8. All other patients received CAV or a drug program based on in vitro drug sensitivity testing from tumor cell lines established for individual patients. The authors reported no difference in overall median survival between the two arms, 10.7 months for the standard arm and 11.4 months for the high-dose arm, P = .68. Toxicities including leukopenia (P < .0001), febrile neutropenia (P = .01), thrombocytopenia (P < .000l), and weight loss (P = .02) were seen more commonly in the high-dose arm.
Currently, there are no data demonstrating the superiority of higher-dose over standard-dose chemotherapy. However, several studies may have detected a survival advantage associated with high-dose chemotherapy in patients with limited disease. Future studies aimed at testing this hypothesis should be conducted in this patient population.