During the 1980s, platinum-based regimens were yielding response rates typically less than 25%, median survival durations of about 25 weeks, and 1-year survival rates less than 25% in patients with advanced non-small-cell lung cancer (NSCLC). Currently, results from single institution phase II trials of agents introduced in the 1990s show a doubling of these numbers, and results from multiinstitutional trials are demonstrating response rates ranging from 30% to 40%, median survival durations of 40 weeks, and 1 year survivals of 40%. Single agent irinotecan shows significant activity against NSCLC in preclinical and early phase I/II clinical studies, with activity similar to that for other new agents. Therapeutic synergy is observed in preclinical tumor models when irinotecan and cisplatin are combined, and phase I/II trials of this combination have demonstrated response rates ³ 50% . Herein the author provides an overview of data from phase II trials of irinotecan and focuses on preliminary results of a large US multicenter phase II trial of weekly irinotecan plus monthly cisplatin in 52 patients with advanced NSCLC. A response rate of 28.9% (95% CI, 16.5% - 41.2%) and a median survival of 9.9 months were observed in this trial. US studies to design a more optimal irinotecan/cisplatin regimen in the same patient population are ongoing, and early results are encouraging. [ONCOLOGY 12(Suppl 6):79-83, 1998]
Preclinical and early phase clinical studies have demonstrated that irinotecan (CPT-11 [Camptosar]) is active against non-small cell lung cancer, [1-8] with single-agent activity similar to that reported for other newer agents introduced during the 1990s, including vinorelbine (Navelbine), gemcitabine (Gemzar), paclitaxel (Taxol), and docetaxel (Taxotere).
During the 1980s, platinum-based regimens for advanced non-small cell lung cancer were yielding response rates typically less than 25%, median survival durations of about 25 weeks, and 1-year survival rates less than 25%. Currently, results from single institution phase II trials of agents introduced during the 1990s are showing a doubling of these numbers, with response rates of 50%, median survival durations of 50 weeks, and 1-year survival of 50%. Multiinstitutional trials are showing response rates ranging from 30% to 40%, median survival durations of 40 weeks, and 1 year survivals of 40%.
This review will provide an overview of data from phase II trials of irinotecan both as a single agent and in combination with cisplatin in Japan and in the United States. The focus will be on preliminary data from the first US trial of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer.
Japan Multicenter Trial of Single-Agent Irinotecan
In the first large multicenter phase II trial of irinotecan, described by Fukuoka and colleagues, 73 patients with chemotherapy-naïve, advanced non-small-cell lung cancer received single-agent irinotecan (100 mg/m2/wk). An overall response rate of 32% and median survival time of 9.8 months were observed. Grade 3 or 4 toxicities included leukopenia (25%), diarrhea (21%), nausea/vomiting (22%), anemia (15%), alopecia (4%), and pneumonitis (3%). Patients did not routinely receive antiemetics or antidiarrheal medications.
Preliminary results of a US multicenter trial of single-agent irinotecan were reported at the American Society of Clinical Oncology meeting in 1997. Irinotecan (100 mg/m2) produced a response rate of 15% and median survival of 6.2 months in 48 patients with chemotherapy-naïve, advanced non-small-cell lung cancer
Phase I/II Trial of Irinotecan Plus Cisplatin
Recent biological studies have indicated that topoisomerase I may have a role in the subsequent DNA degradation and cell death that follow DNA damage induced by other sources, including cisplatin (Platinol).[10,11] Furthermore, camptothecin appears to enhance this process by stimulating the DNA-cleaving activity of the enzyme. Preclinical studies in lung cancer models demonstrate therapeutic synergy when topoisomerase I-targeting agents are used in combination with cisplatin.[1,12] Because cisplatin is a staple in the management of non-small-cell lung cancer, it is logical to combine these two agents in clinical trials.
To this end, Masuda and colleagues conducted a phase I-II trial of irinotecan and cisplatin in patients with advanced non-small-cell lung cancer. The recommended phase II doses were 80 mg/m2 of cisplatin and 60 mg/m2 of irinotecan. Cisplatin dose was fixed at 80 mg/m2 and given on day 1 of each 4-week treatment cycle. Irinotecan doses were gradually escalated and given on days 1, 8, and 15. Dose-limiting toxicities included diarrhea and neutropenia. The response rate was 54%. Survival data were not reported.
These same investigators attempted to increase irinotecan doses in this regimen by adding granulocyte colony-stimulating factor (G-CSF [Neupogen]). Irinotecan doses could be safely escalated to 80 mg/m2 with growth factor support, but further dose escalation was precluded by dose-limiting diarrhea. The response rate was an encouraging 50%.
The first US trial of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer described herein employed the phase II regimen recommended by Masuda and colleagues without growth factor. End points included response, survival, quality of life, irinotecan pharmacokinetics/pharmacodynamics, and pharmacoeconomics. A preliminary analysis of toxicity and primary efficacy end points is described.
Patients and Methods
Entry criteria included cytologically or histologically confirmed stage IIIB or IV non-small-cell lung cancer with bidimensionally measurable disease; Southwest Oncology Group (SWOG) performance status of 0 to 2; predicted life expectancy of at least 12 weeks; no prior chemotherapy; pretreatment granulocyte count > 1,500/mL; hemoglobin > 9.0 g/dL; and platelet count > 100,000/mL. Patients had to have adequate liver function (bilirubin £ 2.0 mg/dL and serum glutamic oxaloacetic transaminase [SGOT] £ 3 times the upper limit of normal) and adequate renal function (serum creatinine £ 1.5 mg/dL). Patients with controlled brain metastases were eligible.
Irinotecan (60 mg/m2) was administered as a 90-minute infusion in 500 mL of 5% dextrose in water (D5W) on days 1, 8, and 15 of each 28-day treatment cycle. Two hours following the completion of the irinotecan infusion on day 1 only, cisplatin (80 mg/m2) was given as a 30-minute infusion. Patients received aggressive intravenous hydration and conventional antiemetics prior to cisplatin administration. All patients received 10 mg of dexamethasone prior to chemotherapy unless they had a relative or absolute contraindication to corticosteroids.
Irinotecan dose adjustments are outlined in Table 1. Doses were adjusted differently depending on whether adjustments were made during a given cycle of therapy or on day 1 of a subsequent treatment cycle. Dose adjustments were based on the worst grade of toxicity occurring since the last treatment if adjusted during a treatment cycle, or on the worst toxicities occurring during the entire previous cycle of therapy if adjusted on day 1 of a subsequent cycle.
Cisplatin doses were fixed, and dose adjustment was not allowed. Patients who developed prohibitive cisplatin toxicities or a serum creatinine ³ 1.5 g/dL were removed from the study.
Loperamide was used for diarrhea in the following manner: All patients were instructed to begin taking loperamide at the earliest sign of diarrhea and/or abdominal cramping that occurred more than 8 hours after receiving irinotecan. They were told to take 4 mg of loperamide orally at the first onset of diarrhea and then 2 mg every 2 hours (except at night during sleep) until they were free of diarrhea for at least 12 hours. During sleeping hours, patients were instructed to take 4 mg of loperamide every 4 hours.
Treatment was continued until the development of regimen intolerance or progressive disease.
Measurable disease was evaluated prior to each treatment cycle. Conventional definitions of partial and complete response and of stable and progressive disease were used. Classification of a partial or complete response required confirmation after at least 4 weeks.
Toxicity was graded weekly using the National Cancer Institute (NCI) Common Toxicity Scale. Quality of life was evaluated prior to each treatment cycle using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire.
Plasma for irinotecan pharmacokinetics was sampled prior to treatment and 1, 2, 4, and 24 hours following the completion of the irinotecan infusion during weeks 1 and 3 of the first treatment cycle. Data relating to medical resource utilization were collected weekly and were categorized as related to chemotherapy, hospitalization, outpatient visits, or home care.
Preliminary results of toxicity, response, and survival analyses are reported here. A more detailed report is planned once the final analysis is complete.
Patient characteristics are summarized in Table 2. A total of 52 patients were enrolled, all of whom were evaluable for response, survival, and toxicity. A majority (79%) of patients had stage IV disease, and 85% of patients had a SWOG performance status of 0 or 1. Median age was 61 years.
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