The Role of Carboplatin in the Treatment of Small-Cell Lung Cancer

ABSTRACT: Lung cancer is the leading cause of death due to cancer in the United States, and approximately 178,100 new cases were estimated to occur last year. Small-cell lung cancer (SCLC) accounts for approximately 17% to 25% of all lung cancers. Due to its aggressive nature and rapid proliferation rate, small-cell lung cancer is usually widespread at diagnosis. Therefore, chemotherapy is the cornerstone of therapy for this disease. Cisplatin (Platinol) is an active chemotherapeutic agent used to treat small-cell lung cancer, but its toxicity, including nausea and vomiting, nephrotoxicity, neurotoxicity, and ototoxicity, has led to the investigation of combination regimens with different toxicity profiles. Carboplatin (Paraplatin), a derivative of cisplatin, has far less nonhematologic toxicity, although myelosuppression may be slightly greater than that observed with cisplatin. The reduced toxicity and equivalent efficacy of carboplatin have resulted in the increased use of carboplatin-based regimens to treat small-cell lung cancer. 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. New combination chemotherapy regimens that include carboplatin may improve survival in patients with small-cell lung cancer and potentially cure those patients with limited disease. Further investigation of carboplatin and other new agents is warranted.[ONCOLOGY 12(Suppl 2):36-43, 1998]

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,[1] approximately 17% to 25% will be small-cell lung cancer (SCLC).[2] 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.[2] 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.[2]

Combination cytotoxic therapies given at frequent intervals have yielded the best response rates in small-cell lung cancer patients.[2] Overall response rates of 85% to 95% and 75% to 85% can be expected in patients with limited and extensive disease, respectively.[2] 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.[3] 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.[4]

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.[5] 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.[7] 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.[7] The dose-limiting toxicity of carboplatin is myelosuppression, particularly thrombocytopenia.[8] 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.[7]

Carboplatin Dosing

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).[8] 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,[8] measured with ⁵¹CrEDTA (ethylenediaminetetraacetic acid) clearance:

Total dose (mg) = target AUC × (GFR + 25)

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.[8] 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.

Carboplatin-Etoposide Regimens

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[9] (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.[10]

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.[10] 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.

Treatment—Patients 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.[10] 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.

Response—Overall 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.[10]

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).

Toxicity—In addition, patients who received etoposide and carboplatin experienced significantly less toxicity, both nonhematologic and hematologic (Table 2).[10] 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.

Conclusion—The 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.[11] 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.[12] 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.[13]

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.[14] 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.[15] As discussed, the use of AUC dosing may help reduce hematologic side effects.

Combination Carboplatin and Etoposide With Other Agents

A comparative, phase III trial randomized patients with small-cell lung cancer to receive either carboplatin, etoposide, and vincristine (Oncovin) or etoposide and vincristine.[16] Patients in the carboplatin arm received carboplatin 300 mg/m² IV day 1, etoposide 140 mg/m² days 1 through 3, and vincristine 1.4 mg/m2 (maximum 2 mg) IV on days 1, 8, and 15. Patients assigned to the two-drug regimen received etoposide 200 mg/m² on days 1 through 3 and vincristine 1.4 mg/m² (maximum, 2 mg) on days 1 and 8. Cycles were repeated every 4 weeks to a maximum of 6 cycles.

Seventy-five patients with previously untreated extensive disease were evaluable. In the carboplatin group, 83% of patients had objective responses compared with 65% of those who received only etoposide and vincristine. Complete response rates were 20% and 15% for patients receiving the three- and two-drug regimens, respectively. Thus, carboplatin-containing regimens appear to be more active at this time.

Leukopenia and nonhematologic toxicities were similar for both treatment arms; however, thrombocytopenia was more frequent in the group that received carboplatin.

The Australian Lung Cancer Study Group compared etoposide 120 mg/m²/day and carboplatin 100 mg/m²/day (both given IV on days 1 through 3) with etoposide and carboplatin (same dose and schedule) plus cyclophosphamide (Cytoxan, Neosar) 750 mg/m² and vincristine 1.4 mg/m² (both given IV on day 1).[17] Patients were assessed after three cycles and thoracic irradiation was administered to responding patients with limited disease. Those limited-disease patients who had a complete response also received prophylactic cranial irradiation.[17]

Of the 90 evaluable patients (40 limited disease, 50 extensive disease), overall response rates of 65% and 81% were observed for etoposide-carboplatin and etoposide-carboplatin plus cyclophosphamide-vincristine, respectively. The median survival time also increased from 10.6 to 11.1 months when cyclophosphamide and vincristine were added.[17]

Neutropenia was dose limiting in both treatment groups; nonhematologic toxicity was more severe in patients who received the four-drug combination, however.

Carboplatin and Etoposide in the Elderly

Patients over 65 years of age frequently are not good candidates for systemic chemotherapy because of coexisting medical conditions, including chronic heart disease and renal impairment.[18] Further, the elderly do not tolerate intensive chemotherapy as well as younger patients do, attaining only modest gains relative to the increased toxicity.[19] The over-70 population continues to increase and one third of lung cancers occur in this age group. Thus, treatment of elderly patients is increasingly important.

Results of studies evaluating the use of combination etoposide and carboplatin in elderly or medically compromised patients are shown in Table 3. Response rates range from 66% to 93% for patients with extensive disease and from 82% to 88% for those with limited disease. Median survival time was approximately 11 months for patients with extensive disease and approximately 14 to 15 months for those with limited disease.

The etoposide-carboplatin reg-imen was well tolerated in these patients of these studies.[18,19] As might be expected, myelosuppression was dose limiting.[19] Nonhematologic toxicity was similar to that observed in younger patients, however.[17]

Carboplatin-Ifosfamide Regimens

Ifosfamide (Ifex), an analogue of cyclophosphamide, has a broad range of activity in various tumor types, including lung cancers, sarcomas, lymphomas, breast cancers and gynecologic malignancies, and germ-cell tumors.[20] It is also one of the most active agents in SCLC, with approximately 50% of previously untreated patients achieving objective response to single-agent therapy.[4]

In addition, ifosfamide is relatively nonmyelosuppressive compared with cyclophosphamide, which allows it to be combined with myelosuppressive agents.[21] Side effects include renal and neurologic toxicities and hemorrhagic cystitis, which may be reduced or prevented by administering mesna.[6,20] A number of studies have evaluated ifosfamide in combination with carboplatin and etoposide (ICE), with or without other agents, in previously untreated patients with small-cell lung cancer (Table 4).

ICE-Containing Regimens

The ICE-containing regimens produced overall response rates of 79% to 94% in patients with limited disease.[21-25] The median duration of survival in this group ranged from 15 to 19 months, and 2-year survival rates ranged from 24% to 32%. In patients with extensive disease, overall response rates ranged from 71% to 100%. The median duration of survival ranged from 8.3 to 13.4 months, and 2-year survival rates ranged from 14% to 22%.

 Vincristine was given on day 14 of each carboplatin course in an attempt to prevent between-course relapse.[22] Based on the premise that cisplatin and carboplatin may lack cross-resistance, Prendiville et al alternated the two analogues in combination with ifosfamide and etoposide during successive cycles, combined with mid-cycle vincristine.[24]

Major toxicities of the ICE-containing regimens were neutropenia and thrombocytopenia. The incidence and severity of these toxicities tended to increase with subsequent cycles of treatment, and a 6% to 10% rate of death from infection was observed.[21-24] The severe myelosuppression observed in most patients requires close monitoring and supportive care.[21] Nausea and vomiting, which can be severe, were also common.[21-24]

Carboplatin-Paclitaxel-Etoposide Regimens

Paclitaxel (Taxol), isolated from the western yew tree Taxus brevifolia, exerts its cytotoxic effect by interfering with microtubule structure and function. Dose-limiting toxicities include myelosuppression (neutropenia) and peripheral neuropathy.[26] In two clinical trials, single-agent paclitaxel 250 mg/m² given over 24 hours every 3 weeks resulted in overall response rates of 34% to 68% in previously untreated patients with extensive small-cell lung cancer.[26,27]

The combination of carboplatin, paclitaxel, and etoposide has been evaluated in several trials of patients with small-cell lung cancer (Table 5[28,29]). The results of these clinical trials are encouraging, with total response rates ranging from 65% to 93% in patients with small-cell lung cancer. Most trials are ongoing; therefore, median survival times and 2-year survival rates are not yet available. Grade 3 and 4 leukopenia occurred in 24% to 81% of patients and was more frequent with higher doses of chemotherapy and concurrent radiotherapy. Nonhematologic toxicity was mild.[30] Additional trials are needed to evaluate the activity of paclitaxel-containing combination regimens in small-cell lung cancer and establish its role in treating this disease.

Conclusions

Carboplatin has produced response rates of approximately 60% as a single agent in previously untreated patients with small-cell lung cancer.[7] The combination of carboplatin and etoposide is comparably effective, produces less nonhematologic toxicity, and is easier to administer than cisplatin and etoposide.[10] In addition, carboplatin-based regimens are particularly useful in treating elderly patients and those who are medically compromised. Response rates with carboplatin and etoposide in patients with limited disease and those with extensive disease range from 73% to 93% and 50% to 85%, respectively.[10-15] Median survival has been as long as 15 months in limited-disease patients and 12 months in those with extensive disease.[10-15]

Several investigators evaluated the ICE combination. In patients with limited disease, 2-year survival rates with ICE-containing regimens ranged from 24% to 32%.[21-25] The principal toxicity of ICE regimens is myelosuppression, particularly neutropenia and thrombocytopenia. Nausea and vomiting can be severe, but other nonhematologic toxicities are generally manageable.[21-24]

Further research has combined paclitaxel with carboplatin to treat small-cell lung cancer. Preliminary results are encouraging and they warrant additional, larger trials of this combination.

These multiple approaches and new combination chemotherapy regimens may further determine the ability of systemic therapy that includes carboplatin to improve survival in patients with small-cell lung cancer and, potentially, to cure those with limited disease.

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