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Small cell lung cancer

Chemotherapy

Commonly used combination chemotherapy regimens currently used to treat SCLC include cyclophosphamide, doxorubicin, and vincristine (CAV); cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide (PE). PE has been compared with CAV or CAV alternating with PE in two randomized trials. Investigators for the Southeastern Cancer Study Group showed no difference in response rates (51%, 61%, and 59%, respectively) or median survival (8.3, 8.6, and 8.1 months, respectively).

Carboplatin has also been shown to be highly active against SCLC and less toxic than cisplatin.  In one randomized trial, the combination of carboplatin and etoposide (CE) was compared to PE in treating 143 SCLC patients evaluable for response. Among 82 limited-disease patients, there was a 76% overall response rate, including a 44% CR in the PE treatment arm.

The Search for New Agents

Since the development of these active drugs and their addition to combination regimens, > 15 years have passed in trying to optimize SCLC therapy. However, even novel therapeutic programs using these agents--including maintenance therapy with more cycles of drugs, administering higher drug doses, or using drugs in alternating sequences--have been disappointing, yielding no change in survival rates.

Topotecan

Topotecan is the most extensively studied compound to date for the treatment of SCLC. Phase I testing identified myelosuppression as the dose-limiting toxicity and 1.5 mg/m² IV over 30 min for 5 days every 21 days.

Currently, single-agent topotecan is being evaluated as part of a phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG). In this trial, untreated patients with extensive-stage SCLC receive four cycles of PE and are then randomized to four cycles of topotecan or observation. Results are awaited. Combination trials incorporating topotecan into active regimens are also underway. Two institutions are performing a phase I trial of topotecan with PE, and a promising regimen of topotecan plus paclitaxel is discussed below.

Taxanes

Two phase II studies established the efficacy of paclitaxel in SCLC. In an ECOG study, Ettinger and colleaguesadministered paclitaxel, 250 mg/m² by 24-h infusion, to achieve a 53% response rate (11 of 32 untreated patients) and an 11-month median survival. The North Central Cancer Treatment Group conducted a similar trial and reported a 68% response rate in 37 patients and a median survival of 7.3 months. Grade 4 leukopenia was the major toxicity seen in both studies.

To improve on the results with single-agent paclitaxel, several groups have combined paclitaxel with the platinum agents, cisplatin or carboplatin. Untreated extensive-stage SCLC to treatment with paclitaxel, 135 mg/m² or 175 mg/m² , plus cisplatin, 75 mg/m² on day 1. Fifteen of 21 evaluable patients receiving the lower dose of paclitaxel responded (71%), as did 39 of 44 patients (89%) on the higher dose arm. Median survival was 8.5 months vs 9.5 months and 1-year survival was 24% vs 38% on the low-dose and higher-dose paclitaxel arms, respectively, suggesting a dose-response effect for paclitaxel. Only one patient (2%) receiving the high-dose paclitaxel regimen experienced grade 4 neutropenia. Georgiadis et al conducted a dose-escalating trial of a 96-h infusion of paclitaxel plus cisplatin in patients with advanced lung cancer. Four of six patients (67%) with SCLC achieved an objective response. The maximally tolerated dose without growth factor support was paclitaxel, 120 mg/m² , with cisplatin, 80 mg/m².

Gemcitabine

Gemcitabine is a new potent antimetabolite shown to be active against SCLC. Cormier and coworkers used gemcitabine, 1,000 to 1,250 mg/m² administered weekly for 3 of 4 weeks, to treat 29 previously untreated patients with SCLC.

Vinorelbine

Vinorelbine, a semisynthetic vinca alkaloid, has been evaluated as a single agent for the treatment of SCLC by five investigators, as show. Depierre et al administered vinorelbine, 30 mg/m² weekly, to 30 patients with untreated advanced disease, achieving a PR in 8 of 30 patients (27%). Myelosuppression was observed in 12 patients (40%) as was the dose-limiting toxicity; 3 patients experienced grade 3 or grade 4 constipation. In a smaller trial by Tummarello and coworkers, vinorelbine, 25 mg/m² weekly, yielded no responses among six previously untreated patients.

Irinotecan

Irinotecan is a camptothecin derivative similar to topotecan with single-agent activity in SCLC. Negoro and coworkers treated 35 patients (27 had received previous therapy) with irinotecan, 100 mg/m² weekly. Nine previously treated patients (33%) and four of eight untreated patients (50%) responded.

One Japanese phase II combination trial (investigators brochure) examined irinotecan, 80 mg/m² on days 1, 8, and 15; and cisplatin, 60 mg/m² on day 1, every 28 days.

MMP Inhibitors

The MMP inhibitors are a new class of drugs that break down extracellular matrix and disrupt tissue architecture that is associated with tumor progression. Specific MMPs, MMP-2 and MMP-9, have been isolated in lung tumors. MMP inhibitors have been shown to inhibit tumor invasion in vitro and in vivo and block tumor-induced neovascularization.

Two MMP inhibitors are being examined in SCLC as maintenance therapy in phase III clinical trials. Responding patients with limited- or extensive-stage SCLC are randomly assigned to an oral MMP inhibitor or placebo treatment. In one study, patients take the medication for a maximum of 18 months, while the other study allows patients to take the medication until the cancer progresses. In phase I testing, MMPs are extremely well tolerated, with the major side effects being myalgias, arthralgias.