Irinotecan and Carboplatin in Metastatic or Recurrent NSCLC: An Update

Lung cancer is the most common cancer in the United States, and the most common cause of cancer death for both men and women. Non-small-cell lung cancer (NSCLC) accounts for 84% of all lung cancer diagnoses, with nearly 60% of patients presenting with unresectable or metastatic disease.[1] The incorporation of newer chemotherapeutic agents into treatment regimens has improved survival as compared to those used in earlier decades, but survival has reached a plateau with currently available drugs. Further improvements in survival for these patients will require continuing investigations of novel treatment regimens. Irinotecan(Drug information on irinotecan) (Camptosar) is a camptothecin- derived chemotherapeutic which is being used to treat an increasing variety of cancers. In metastatic colon cancers, the addition of irinotecan to fluorouracil(Drug information on fluorouracil) (5-FU) resulted in a survival advantage compared to 5-FU alone, resulting in US Food and Drug Administration approval of irinotecan for this indication.[ 2] A study of small-cell lung cancer comparing standard treatment with cisplatin(Drug information on cisplatin) and etoposide(Drug information on etoposide) to cisplatin and irinotecan also found irinotecan to confer a survival advantage for the irinotecan-treated group.[3] There have been several small phase II studies combining cisplatin with irinotecan for stage IIIB and IV NSCLC. These studies report response rates of approximately 45% with an average 1-year survival rate of 46%- results that compare favorably with other modern two-drug combinations.[ 4] Two phase III studies have been reported from Japan in which cisplatin and irinotecan were compared to a standard NSCLC regimen of cisplatin with vindesine(Drug information on vindesine) (Eldisine).[5,6] Both studies used a combination of cisplatin at 80 mg/m² every 3 weeks together with irinotecan at 60 mg/m² on days 1, 8, and 15. These two studies reported encouraging response rates for cisplatin and irinotecan (29% for Niho et al vs 43% for Negoro et al). Median survival was comparable (45.4 vs 50 weeks) and did not differ significantly from the survival of patients treated with cisplatin plus vindesine, although subgroup analysis performed by Negoro et al suggested a superior survival for stage IV patients treated with irinotecan. Carboplatin(Drug information on carboplatin) (Paraplatin) is frequently substituted for cisplatin for the treatment of lung cancer patients in the United States because of its convenience and ease of tolerability. This prompted studies combining carboplatin and irinotecan for patients with NSCLC. Takeda et al reported a phase II study in which 36 patients with stage IIIB or IV NSCLC received carboplatin at an area under the concentration- time curve (AUC) of 5 combined with irinotecan at 50 mg/m² on days 1, 8, and 15.[7] The reported response rate was 25%, with a median survival of 10.2 months. The authors noted that the increased myelosuppression attributable to carboplatin made it difficult to give the day 15 irinotecan dose, which was omitted more than half of the time. While weekly administration of irinotecan has been studied extensively, irinotecan can also be administered every 3 weeks. Cardenal et al reported a phase II study in which 74 NSCLC patients received cisplatin at 80 mg/m² and irinotecan at 200 mg/m² every 3 weeks.[8] The reported response rate was 34.2% with a 1-year survival of 31%, similar to results reported for other regimens used in this disease. We are conducting a phase II study of irinotecan and carboplatin administered once every 3 weeks in patients with advanced NSCLC, and have reported the preliminary results of this study previously. This report summarizes the toxicity and efficacy data on 37 patients. Materials and Methods The primary objective of this study was to determine the response rate in patients with stage IIIB or IV NSCLC treated with the combination of carboplatin and irinotecan administered every 3 weeks. Secondary objectives included characterization of toxicities and determination of 1-year survival. In addition, pharmacogenomic data were obtained to study correlate gene polymorphisms that are associated with altered irinotecan metabolism with toxicity and response. Eligible patients had metastatic (stage IV) or stage IIIB (those with pleural effusion) NSCLC who had not received prior chemotherapy for NSCLC. Patients were to have had a Zubrod performance status of 0 or 1, and adequate bone marrow, liver, and renal func- tions. Patients requiring anticonvulsant treatment with phenytoin(Drug information on phenytoin) or carbamazepine(Drug information on carbamazepine) (Tegretol) were excluded because of the known interaction between anticonvulsants and irinotecan. All patients received carboplatin at an AUC of 5. The first five patients received irinotecan at a dose of 250 mg/m², but in light of frequent dose delays for neutropenia, the dose of irinotecan was changed to 200 mg/m². Chemotherapy was administered every 3 weeks. Patients underwent a complete blood count (CBC) every week while on treatment, and CBC with metabolic tests every 3 weeks before treatment. Patients underwent assessment of measurable disease sites with computed tomography scan every two cycles or as clinically warranted. Patients with response or stable disease could receive up to six cycles of treatment on study. Results To date, 129 cycles of chemotherapy have been administered to 37 patients. Twenty-five patients received at least two cycles, 20 received at least four cycles, and 12 received all six planned cycles. Three deaths occurred on study (within 30 days of receiving chemotherapy). One death, due to neutropenic sepsis and diarrhea, was treatment-related, and the other two were considered to be unrelated (one patient had disease progression and one had transfusion-related acute lung injury). All deaths on study occurred after the first cycle. Grade 4 neutropenia (absolute neutrophil count < 500) occurred in 10 patients and 19 treatment cycles. Two of these patients also reported grade 4 diarrhea (see Table 1). Thirty-six cycles (30%) were delayed for neutropenia, six of which occurred among the first five patients who received irinotecan at 250 mg/m². The rate of severe neutropenia was 27%, including data from the patient who died.