Treatment of poor-prognosis extensive disease small-cell lung cancer with an all-oral regimen of etoposide and cyclophosphamide - a Southwest Oncology Group clinical and pharmacokinetic study

Purpose: An all-oral regimen of etoposide and cyclophosphamide was develope d for use in poor-prognosis extensive disease small-cell lung cancer. Limit ed pharmacokinetic sampling was used to derive a pharmacodynamic model pred ictive of myelosuppression early in the course of therapy. Patients and Met hods: Eligible patients were chemotherapy-naive and had extensive disease s mall-cell lung cancer with either SWOG performance status 2 or serum albumi n <3.5 g/dl. The first cohort(n = 18) received etoposide orally at 50 mg da ily and cyclophosphamide orally at 50 mg daily days 1-14 every 28 days. Due to good hematologic tolerance, the second cohort (n = 39) received both ag ents orally at 50 mg twice daily days 1-14 every 28 days. Plasma etoposide levels were determined in samples drawn at baseline, and at I h, 2 h, and 2 3.5 h (trough) after the first dose. Linear regression analysis was used to determine pharmacokinetic and demographic parameters predictive of myelosu ppression. Results: A total of 173 treatment cycles were delivered. Patient s on the daily regimen had a 22% response rate(complete and partial) a 22% unconfirmed response rate, and a 5-month median survival, while patients on the twice-daily regimen had a 28% response rate (complete and partial), a 13% unconfirmed response rate, and a 7-month median survival. Granulocytope nia and alopecia were the most common toxicities seen. Significant granuloc ytopenia could be predicted for the twice-daily regimen according to the fo rmula In(AGC nadir)=7.80 - 1.88(trough), with an increased incidence of gra nulocytopenia if the etoposide trough value was greater than or equal to 1. 49 mu g/ml. Conclusion: Oral etoposide and oral cyclophosphamide given days 1-14 every 28 days is well tolerated and results in an acceptable response rate and median survival in poor-prognosis (poor performance status or low serum albumin) extensive disease small-cell lung cancer. A trough etoposid e level obtained within 24 h of starting therapy can predict severe granulo cytopenia.