Results of a Dose-Intense Phase 1 Study of a Combination Chemotherapy Regimen With Cisplatin and Epidoxorubicin Including Medroxyprogesterone Acetate and Recombinant Interleukin-2 in Patients With Inoperable Primary Lung Cancer

Based on the role of cytokines in the pathogenesis of cancer-related anorexia–cachexia and the ability of progestins, such as medroxyprogesterone acetate, to reduce cytokine production and relieve cancer-related anorexia–cachexia symptoms, the authors designed an open, dose-finding phase I study of a combined chemotherapy regimen (cisplatin [CDDP], epidoxorubicin [EPI]), including recombinant interleukin-2 (IL-2) and medroxyprogesterone acetate for patients with stage IIIB to IV inoperable primary lung cancer. The end points were clinical response and toxicity with definition of dose-limiting toxicity and maximal tolerable dose; relief of cancer-related anorexia–cachexia symptoms; the assessment of patient serum levels of IL-1&bgr;, IL-6, tumor-necrosing factor-&agr; (TNF-&agr;), and soluble IL-2 receptor (sIL-2R). From March to October 1997, 16 patients (M:F ratio, 14:2; mean age, 60.5 years; age range, 41 to 74 years) were enrolled. All patients were evaluable for toxicity and 14 of them for response. The patients were assigned to increasing dose levels of drugs according to a dose-escalation schedule. The weekly schedule consisted of a combination of CDDP given intravenously on day 1, EPI given intravenously on day 1, 1 g/day medroxyprogesterone acetate given orally on days 1 to 7, and recombinant IL-2 1.8 MIU administered subcutaneously on days 2 to 7 plus 300 &mgr;g granulocyte-colony stimulating factor support given subcutaneously on days 2 to 5. Administration of medroxyprogesterone acetate began 1 week before the first cycle. Dose escalation of the drugs was as follows: 30 mg·m2·week−1 CDDP and 25 mg·m2·week−1 EPI (first level, two patients); 30 mg·m2·week−1 CDDP and 33 mg·m2·week−1 EPI (second level, 2 patients); 40 mg·m2·week−1 CDDP and 33 mg·m2·week−1 EPI (third level, 6 patients); and 40 mg·m2·week−1 CDDP and 40 mg·m2·week−1 EPI (fourth level, 6 patients). Six cycles were planned for each patient. The actual dose intensity delivered was more than 80% of the projected dose intensity of all drugs. After six cycles, clinical response (according to World Health Organization criteria), toxicity (according to World Health Organization criteria), Eastern Cooperative Oncology Group (ECOG) performance status, body weight, appetite, and serum levels of cytokines were evaluated. After six cycles, 9 of 14 patients (64.3%) had partial response, 3 of 14 (21.4%) had stable disease, and 2 of 14 (14.3%) had progressive disease, and the objective response rate was 64.3%. ECOG performance status and body weight did not change significantly after treatment, whereas appetite showed an increase that was of borderline statistical significance. Toxicity was acceptable and only hematologic. Dose-limiting toxicity was established at the fourth dose level; consequently, maximal tolerable dose was assessed at the third dose level. Before treatment, the serum levels of IL-1&bgr;, IL-6, and TNF-&agr; were significantly greater in the patients than in healthy persons. The comparison between pretreatment and posttreatment serum values of IL-1&bgr;, IL-6, TNF-&agr;, and sIL-2R did not reveal significant differences in the patients. Similar results were obtained when the patients were considered as responders (partial response) or nonresponders (stable or progressive disease) to therapy. Only IL-6 serum levels were increased (p = 0.014) after treatment.