Extensive Small-Cell Lung Cancer: A Treatment Overview

ABSTRACT: New cases of lung cancer will be diagnosed in an estimated 164,100 Americans in 2000, and approximately 25% or 41,000 of those cases will be small-cell lung cancer (SCLC). Despite initial sensitivity to chemotherapy, only 10% of all patients with SCLC achieve significant long-term survival. Studies have yet to demonstrate a significant survival advantage for maintenance chemotherapy. In addition, it appears that chemotherapy is effective for only four to six cycles in the treatment of SCLC, and there is no defined role for dose escalation. In extensive disease, no chemotherapy combination has exhibited a definitive survival advantage although it appears that single-agent etoposide (VePesid, VP-16) may be inferior to combination intravenous chemotherapy. Several new agents with significant activity in SCLC await further study. [ONCOLOGY 14(Suppl 5):49-55, 2000]

Introduction

An estimated 164,100 new cases of lung cancer will be diagnosed in 2000,[1] 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.[2] 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%.[3]

Chemotherapy

Of the currently available chemotherapeutic agents, several have been associated with response rates of 30% or more. These agents include cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), methotrexate (Folex, Mexate), etoposide (VePesid, VP-16), vincristine (Oncovin), and carboplatin (Paraplatin).[4] 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 non–cross-resistant regimens might improve tumor-cell kill.[5] The combination of cisplatin (Platinol) and etoposide (PE) has been shown to be effective salvage therapy in SCLC patients treated with CAV (cyclophosphamide, doxorubicin, vincristine), with response rates approaching 50%.[6] 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.[7] Because of these results, it is believed that CAV and PE may be non–cross-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.[9] 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.[10] 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.

Three- vs Two-Drug Combinations

Two phase II trials have established the activity of the VIP (cisplatin, 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.[13] 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.[14] 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.[15] 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.[16] In this study, 228 patients with extensive-disease SCLC were randomized either to the CODE plus granulocyte colony-stimulating factor (G-CSF, 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.[17]

Dose Intensity

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.[20] 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 (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 (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.[23] 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.[24] 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.

Newer Active Agents

Although improvements have been made in the treatment of SCLC, the overall results remain disappointing, with only a small percentage of patients achieving significant long-term survival. Newer agents are still clearly needed. Several agents with significant activity in SCLC (Table 2)[25-36] were studied in the 1990s.[27,30,31] Smyth et al studied docetaxel in 28 previously treated patients with SCLC.[27] Docetaxel was administered every 3 weeks at a dose of 100 mg/m². Responses were seen in seven patients for an overall response rate of 25%. The principal toxicities were neutropenia (grade 4) and asthenia in 71% and 65% of the patient population, respectively.

Two studies evaluated paclitaxel (Taxol) in extensive-disease SCLC.[30,31] The ECOG studied 36 patients with previously untreated extensive-disease SCLC.[30] Paclitaxel 250 mg/m² was administered as a continuous intravenous infusion over 24 hours every 3 weeks with G-CSF given for hematopoietic support. Responses were seen in 34% of patients. Grade 4 leukopenia developed in 56% of patients. The North Central Cancer Treatment Group reported on a similar trial with paclitaxel 250 mg/m² administered as a 24-hour infusion.[31] Responses were seen in 15 of 37 evaluable patients (41%) and an additional 10 patients with evaluable disease only (ie, confirmable by chest x-ray) had significant tumor-burden reduction for an overall response rate of 68%. Grade 4 leukopenia occurred in association with 19% of the doses.

Gemcitabine

Gemcitabine (Gemzar) is a new pyrimidine antimetabolite analog of deoxycytidine. Cormier et al studied gemcitabine in 29 patients with previously untreated SCLC.[28] Patients received gemcitabine 1,000 to 1,250 mg/m² weekly for 3 weeks. Cycles were repeated every 4 weeks. Seven of 26 evaluable patients responded, for an overall response rate of 27%. Toxicity was mild with grade 3/4 myelosuppression associated with 18% of treatment cycles, and grade 3/4 thrombocytopenia associated with only 1 of 72 treatment cycles.

Topotecan

Topotecan (Hycamtin) is a semisynthetic camptothecin analog and thus a topoisomerase-I inhibitor. Two studies have evaluated topotecan in patients with SCLC.[32,33] Wanders et al reported on a multicenter trial in patients with previously treated SCLC.[32] Topotecan was administered at a dose of 1.5 mg/m² daily for 5 days. Cycles were repeated every 21 days. Responses were seen in 12 of 57 evaluable patients for an overall response rate of 21%. Not surprisingly, an increased response rate of 33% (9 of 27 patients) was observed in patients who had responded to first-line chemotherapy and relapsed more than 3 months after treatment. Toxicity was primarily hematologic, with leukopenia (grade 3/4) seen in 80% of the treatment cycles. Grade 3/4 thrombocytopenia was associated with 29% of treatment cycles and 54% of patients treated.

Schiller et al, reporting for the ECOG, evaluated topotecan in 48 patients with previously untreated SCLC.[33] Topotecan was administered at a dose of 2.0 mg/m² daily for 5 days. The first 13 patients did not receive G-CSF support and the next 35 did. Cycles were repeated every 21 days. Responses were seen in 19 patients, for a response rate of 39%. Of patients treated without G-CSF, 92% developed grade 3/4 neutropenia, compared to 29% who received G-CSF. The incidence of neutropenic fever was similar, 11% and 8%, respectively.

von Pawel et al reported on the results of a randomized phase III trial comparing topotecan to CAV in patients with relapsed SCLC. Topotecan was administered at a dose of 1.5 mg/m² daily for 5 days with cycles repeated every 3 weeks. A total of 211 patients were randomized between the two arms. There was no difference in response rate, 24.3% vs 18.3%, P = .285, or median survival, 25 weeks vs 24.7 weeks, P = .795. Symptoms improved significantly in the topotecan arm, P £ .034.[34]

Vinorelbine and Irinotecan

Vinorelbine (Navelbine) is a new semisynthetic vinca alkaloid that was selected for its high affinity in preventing tubulin polymerization. There have been two studies evaluating vinorelbine in patients with previously treated SCLC.[35,36] Jassem et al reported on 26 patients treated with vinorelbine 30 mg/m² weekly.[35] All patients responded to first-line therapy and were off treatment for at least 3 months. Responses were seen in 4 of 25 evaluable patients for a response rate of 16%. Neutropenia (grade 3/4) was the predominant toxicity, occurring in 32% of patients. Furuse et al reported on 24 patients with previously treated SCLC. Patients were treated with vinorelbine 25 mg/m² weekly.[36] Responses were seen in three patients, for a response rate of 12.5%. Neutropenia (grade 3/4) occurred in 17 of 24 patients.

Irinotecan (Camptosar, CPT-11) is a derivative of camptothecin, an inhibitor of the nuclear enzyme topoisomerase I. The enzyme topoisomerase-I creates single-stranded breaks in DNA during DNA replication. There have been two studies evaluating irinotecan in patients with SCLC.[25,26] Negoro et al evaluated 35 patients, 27 of whom had received prior therapy. Responses were seen in 9 previously treated patients (33%) and 4 of 8 previously untreated patients (50%).[25] Principal toxicities were neutropenia and diarrhea. Masuda et al studied 16 previously treated patients with SCLC; 15 patients were assessable. Irinotecan 100 mg/m2 was administered weekly with doses adjusted for toxicity.[26] Responses were seen in seven of 15 evaluable patients for a response rate of 47%. Principal toxicities were diarrhea and neutropenia. Two patients suffered from grade 3 or 4 pulmonary toxicity, and one subsequently died.

Newer Combinations

The next logical step was to combine these newer active agents with some of the more established agents. The study of new agents and combinations has not advanced as rapidly in SCLC as it has in the treatment of non–small-cell lung cancer (NSCLC). This may be related, in part, to the smaller number of patients diagnosed with SCLC.

Paclitaxel

Paclitaxel is currently being evaluated in combination with cisplatin and etoposide.[37,38] Kelly et al reported the results of a Southwest Oncology Group (SWOG) phase II study of the combination of cisplatin 80 mg/m² plus etoposide 80 mg/m² administered intravenously on day 1 and 160 mg/m² administered orally on days 2 and 3.[37] G-CSF (5mg/kg) was given subcutaneously on days 4 through 14. Cycles were repeated every 21 days. There were 88 patients (28% were ECOG performance status of 2) entered into the study, with 82 evaluable for response and 83 evaluable for toxicity. Responses were seen in 56% of patients, including 12% complete responses. Median survival was 11 months, with 43% of patients alive at 1 year. Grade 4 neutropenia occurred in 35% of patients. While the incidence of neutropenic fever was not specifically noted, the incidence of grade 5 neutropenia was reported as 7%. Grade 2/3 peripheral neuropathy occurred in 22 (26.5%) and 2 patients (2.4%), respectively.[37]

Glisson et al treated 41 patients with extensive-disease SCLC with the combination of cisplatin 75 mg/m² on day 1, etoposide 80 mg/m² on days 1 to 3, and paclitaxel 130 mg/m² (3-hour infusion) on day 1.[38] The authors reported an overall response rate of 90%, including 165 complete responses among 38 assessable patients. Grade 4 neutropenia occurred in 47% of 188 treatment cycles, resulting in neutropenic fever in 9% of treatment cycles. Fatal neutropenic sepsis developed in 2 patients, and significant nonhematologic toxicity (³ grade 3) occurred in only 5% of all courses, with fatigue, peripheral neuropathy, and nausea/vomiting seen most frequently.[38]

Topotecan has been evaluated in combination with paclitaxel in patients with untreated extensive-disease SCLC. Jacobs et al reported the results of their phase II trial of paclitaxel 135 mg/m2 infused over 24 hours on day 1 plus topotecan 1.0 mg/m2 given intravenously on days 1 through 5.[39] Primary prophylaxis was provided by G-CSF. Cycles were repeated every 3 weeks. The major toxicity was myelosuppression, with grade 4 myelosuppression occurring in 27 of 28 patients. Responses were seen in 17 of 28 evaluable patients (60%) including 6 complete responses (21%). Median survival was 54 weeks.[39]

Conclusions

Irinotecan has been shown to be active when used in combination with cisplatin and/or etoposide in untreated patients with SCLC. Studies incorporating this combination are listed in Table 3 and are discussed in more detail in this supplement by Dr. Fukuoka on page 57.[40-43]

Numerous other studies are ongoing in an attempt to define the role of these new agents in combination chemotherapy for patients with SCLC.

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