NEW HAVEN, Connecticut-‘‘We’ve hit the wall in management of small- cell lung cancer (SCLC). We need a paradigm shift," John R. Murren, MD, stated. He is associate professor of medicine at Yale University School of Medicine in New Haven, Connecticut.
NEW HAVEN, Connecticut‘‘We’ve hit the wall in management of small- cell lung cancer (SCLC). We need a paradigm shift," John R. Murren, MD, stated. He is associate professor of medicine at Yale University School of Medicine in New Haven, Connecticut.
"Escalated-dose trials have shown that intensification to the maximum tolerated dose (MTD) of cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin), and vincristine (Oncovin) (CAV) or etoposide (VePesid) and cisplatin (Platinol)(EP) increases toxicity without impact on survival. Dose intensification by interval compression improves survival, but chemotherapy must be given without excessive toxicity, and both the regimen and patient factors define the risk of toxicity," he continued.
Risk Factors of Early Death with Chemotherapy
Dr. Murren reviewed four studies of risk factors associated with early death with chemotherapy. These were conducted by the Manchester Lung Study Group, the London Lung Study Group, the Medical Research Council (MRC) Lung Cancer Working Party, and the Copenhagen Lung Cancer Group.
The MRC study of deaths in the first 3 weeks of chemotherapy found that risk of death was greatest for patients with performance status (PS) of 2 or greater, white blood cell count of 10,000/µL or higher, or undergoing treatment with four or more drugs. "There was 16.7% excess mortality in the high-risk group during the second week of treatment, and 3-year survival in this group was only 0.6%," Dr. Murren said.
The Copenhagen Lung Cancer Group study found that early death was associated with age of 65 or older, performance status of 3 or 4, or lactate dehydrogenase (LDH) levels higher than two times normal. "In the high risk group, median survival time was 133 days, and 2-year survival was 4%. Mortality during the first chemotherapy cycle was 33% and was as high as 41% with certain chemotherapy combinations," Dr. Murren explained. "More than half of early deaths occurred in elderly patients with high LDH and good performance status."
With these factors in mind, Dr. Murren said that irinotecan (Camptosar) and paclitaxel (Taxol) had been tested in a phase I trial. Irinotecan was infused over 90 minutes and escalated, and paclitaxel at 75 mg/m² was infused over 1 hour immediately following the irinotecan infusion. The planned treatment cycle consisted of 4 weeks on, 2 weeks rest. Once the MTD was reached, the order of the drug administration was reversed during cycle 2 for pharmacokinetic studies.
"There was no cumulative myelosuppression on this regimen. Nadirs usually occurred at week 3 or 4, causing a delay in the administration of chemotherapy. This supports going to a 2 weeks on, 1 week off schedule," Dr. Murren said. "The recommended phase II dose is 75 mg/m² for paclitaxel and 50 mg/m² for irinotecan."
The combination of irinotecan plus docetaxel (Taxotere) has also been evaluated. Docetaxel was infused over 1 hour followed immediately by irinotecan at 50 mg/m² as a 30-minute infusion. The treatment cycle consisted of 4 weeks on, 2 weeks rest. Once the MTD was defined, the schedule was modified to 2 weeks on 1 week off with the dose of irinotecan escalated.
This study enrolled 44 patients, including 12 with pancreatic or biliary cancer, 20 with non-small-cell lung cancer, two with gastric cancers, and 2 with other cancers. The recommended dose for further study was 35 mg/m² of docetaxel and 50 mg/m² of irinotecan on the 4-weeks-on, 2-weeks-off schedule. "Dosing of 35 mg/m² docetaxel and 60 mg/m² of irinotecan is feasible on the 2-weeks-on, 1-week-off schedule, but individualized dosing would be better because there is considerable individual variation," Dr. Murren said.
Moving to Phase II
The irinotecan/paclitaxel combination has moved into phase II studies in SCLC. In one arm, irinotecan will be given at 60 mg/m² over 30 minutes on day 1 and cisplatin at 60 mg/m² on days 1 and 8, with cycles repeating every 3 weeks. The other arm will be paclitaxel 75 mg/m² followed by irinotecan 60 mg/m² over 30 minutes, both given weekly for 2 weeks, followed by 1 week rest.
"We have learned from the risk factor analyses that better outcomes can be achieved with better therapy and better patient selection. Acuity and co-morbidity support use of weekly chemotherapy administration in SCLC. We expect that irinotecan/paclitaxel will be better tolerated than irinotecan/cisplatin, and comparable activity in the randomized phase II trial would support further evaluation of irinotecan/paclitaxel," Dr. Murren concluded