The Role of Carboplatin in the Treatment of Small-Cell Lung Cancer
The Role of Carboplatin in the Treatment of Small-Cell Lung Cancer
Lung cancer is the leading cause of death due to cancer in the United States. Of the estimated 178,100 new cases that were expected to be diagnosed in 1997, approximately 17% to 25% will be small-cell lung cancer (SCLC). Unfortunately, due to its aggressive nature and rapid rate of proliferation, small-cell lung cancer is usually quite advanced at diagnosis.
The Veterans Administration Lung Group system for classifying small-cell lung cancer is preferred to TNM staging. This system classifies small-cell lung cancer into two stages, limited and extensive disease. In limited disease, tumor growth is confined to one hemithorax and its regional lymph nodes. Involvement beyond these limits is considered extensive disease. Ipsilateral pleural effusion and supraclavicular lymph node involvement are generally considered consistent with extensive disease, although this is controversial.
Combination cytotoxic therapies given at frequent intervals have yielded the best response rates in small-cell lung cancer patients. Overall response rates of 85% to 95% and 75% to 85% can be expected in patients with limited and extensive disease, respectively. Although small-cell lung cancer responds well to chemotherapy, disease will relapse in the majority of patients, who will die within 2 years of diagnosis. These poor survival rates are a result of the advanced disease stage at diagnosis, the high recurrence rates associated with local therapy, and the inability of combination chemotherapy to prolong survival significantly.
Cisplatin (Platinol), an active chemotherapeutic agent in the treatment of lung cancer, is routinely combined with etoposide (VePesid) to treat small-cell lung cancer. The use of cisplatin, however, is limited by toxicity and the need for aggressive hydration support. Adverse reactions associated with cisplatin include nausea and vomiting, nephrotoxicity, neurotoxicity, and ototoxicity.[2,6] This has led to the development and investigation of combination regimens that have more tolerable toxicity profiles. Carbo-platin (Paraplatin), an analogue of cisplatin, has similar activity and a more favorable toxicity profile and is easier to administer.[5,7]
Phase I and II trials of carboplatin as single-agent treatment for small-cell lung cancer resulted in overall response rates of approximately 60% for previously untreated patients and 17% for those who had received prior therapy. The dose-limiting toxicity of carboplatin is myelosuppression, particularly thrombocytopenia. Because carboplatin is associated with less toxicity than cisplatin and exhibits equivalent efficacy, carboplatin-based combination regimens are being used increasingly to treat small-cell lung cancer.
Approximately 70% of an administered carboplatin dose is excreted in the urine, and renal clearance of carboplatin correlates closely with the glomerular filtration rate (GFR). A clear relationship exists between carboplatin dose and hematologic toxicity. Accordingly, calculation of the carboplatin dose should be based on renal function to minimize toxicity and increase therapeutic efficacy.
The ability to predict the area under the concentration-time curve (AUC) following administration of carboplatin will allow consistent drug exposure for patients with either normal or impaired renal function. Calvert and colleagues have validated the use of a formula to calculate the carboplatin dose in adults based on GFR, measured with 51CrEDTA (ethylenediaminetetraacetic acid) clearance:
Of note, the Calvert formula calculates the total carboplatin dose in milligrams, not milligrams per square meter.
The AUC of carboplatin appears to relate more closely to both the therapeutic and the toxic effects of the drug than do doses calculated on the basis of body surface area. Therefore, the use of AUC dosing avoids subtherapeutic doses and minimizes overdosage. Moreover, using AUC rather than toxicity to measure carboplatin exposure minimizes the influence of previous or concurrent myelosuppressive therapy. Studies conducted before use of the Calvert formula became widespread did not administer standardized carboplatin doses to patients, as pharmaco-kinetics vary with age, performance status, and renal function. The importance of standardizing the carboplatin dose based on renal function cannot be overlooked in future trials.
A number of studies have been conducted to evaluate the combination of carboplatin and etoposide in treating small-cell lung cancer in previously untreated patients (Table 1[10-15]). Overall response rates ranged from 73% to 93% in patients with limited small-cell lung cancer and from 50% to 85% in those with extensive disease. Median survival durations ranged from 11 to 15.0 months for limited disease and from 4.6 to 12 months for extensive disease. In a study by the Hellenic Cooperative Oncology Group that compared carboplatin and etoposide with cisplatin and etoposide, the carboplatin-etoposide regimen was associated with less renal, neurologic, and gastrointestinal toxicity, and both combinations were equally effective.
The Hellenic Cooperative Oncology Group Comparative Study
A randomized phase III trial compared the efficacy and toxicity of etoposide and cisplatin vs etoposide and carboplatin in previously untreated small-cell lung cancer patients who were younger than 75 years. The diagnosis was confirmed histologically or cytologically and eligible patients had a World Health Organization performance status of less than 3. Disease stage was classified as limited or extensive according to the Veterans Administration Lung Group criteria.
TreatmentPatients were randomized to receive etoposide 100 mg/m² intravenously (IV) on days 1 through 3 plus either cisplatin 50 mg/m² IV on days 1 and 2 or carboplatin 300 mg/m² IV on day 1. Treatment cycles were administered every 3 weeks to a maximum of six cycles. Patients with limited disease received thoracic irradiation with the fourth cycle. Limited-stage disease patients who achieved a complete response received prophylactic cranial irradiation.
ResponseOverall response rate in patients with limited disease was 73% with etoposide and cisplatin and 86% with etoposide and carboplatin; patients with extensive disease in these treatment groups had overall response rates of 50% and 64%, respectively (Table 1). Complete response rates were also comparable between the two treatment arms based on disease stage.
The median duration of survival did not depend on the treatment regimen (12.5 months for the etoposide-cisplatin group and 11.8 months for patients given etoposide and carboplatin). Disease stage and performance status, however, correlated strongly with survival. The median survival time was 14.1 months for patients with limited disease and 10.4 months for those with extensive disease (P < .05). The proportion of patients with limited disease and extensive disease who survived more than 2 years was 26% and 7%, respectively. For performance status 0-1 and 2-3, median length of survival was 12.9 months and 8.6 months, respectively (P < .05).
ToxicityIn addition, patients who received etoposide and carboplatin experienced significantly less toxicity, both nonhematologic and hematologic (Table 2). Nausea and vomiting, nephrotoxicity, neurotoxicity, leukopenia, infection, mucositis, and allergic reactions were reported less frequently for patients in the carboplatin arm than for those in the cisplatin arm. Carboplatin was also easier to administer and resulted in fewer hospitalizations. Dose intensity was similar for both the carboplatin and the cisplatin regimens.
ConclusionThe results of this trial provide a rationale for the use of etoposide and carboplatin over etoposide and cisplatin, based on the similar efficacy and decreased toxicity of the etoposide-carboplatin regimen.
Toxicity Findings in Other Trials
Other trials using etoposide and carboplatin to treat small-cell lung cancer reported similar toxicity profiles. Leukopenia and thrombocytopenia were reported most frequently and were dose limiting and dose dependent.
In a study in which carboplatin 125 mg/m²/day combined with etoposide 200 mg/m²/day was administered for 3 days, grade 3 and grade 4 leukopenia and thrombocytopenia were reported in 81% and 76% of patients, respectively. Four patients died of myelosuppression. Only 19% of patients reported grade 3 or grade 4 nausea and vomiting, however, and no neurotoxicity occurred.
In contrast to the high rates of myelosuppression with carboplatin given on 3 consecutive days, when carboplatin 300 mg/m² was administered on day 1, the rates of grade 3 and grade 4 leukopenia and thrombocytopenia were 20% and 16%, respectively. Similarly, when carboplatin 450 mg/m² was administered on day 1, the incidence of grade 3 and grade 4 leukopenia and thrombocytopenia was 8% and 11%, respectively.
Higher doses of carboplatin are also associated with increased hematologic toxicity. Approximately two thirds of patients receiving carboplatin 600 mg/m² on day 1 developed grade 3 and grade 4 leukopenia and/or thrombocytopenia. In a dose-escalation trial, the maximum tolerated dose of carboplatin was 650 mg/m² for patients younger than 70 years and 450 mg/m² for those 70 years or older. As discussed, the use of AUC dosing may help reduce hematologic side effects.