Results of a dose-intense phase 1 study of a combination chemotherapy regimen with cisplatin and epidoxorubicin including medroxyprogesterone acetateand recombinant interleukin-2 in patients with inoperable primary lung cancer

Based on the role of cytokines in the pathogenesis of cancer-related anorex ia-cachexia and the ability of progestins, such as medroxyprogesterone acet ate, to reduce cytokine production and relieve cancer-related anorexia-cach exia symptoms, the authors designed an open, dose-finding phase I study of a combined chemotherapy regimen (cisplatin [CDDP], epidoxorubicin [EPI]), i ncluding recombinant interleukin-2 (IL-2) and medroxyprogesterone acetate f or patients with stage IIIB to IV inoperable primary lung cancer. The end p oints were clinical response and toxicity with definition of dose-limiting toxicity and maximal tolerable dose; relief of cancer-related anorexia-cach exia symptoms; the assessment of patient serum levels of IL-1 beta, IL-6, t umor-necrosing factor-alpha (TNF-alpha), 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 evaluabl e for toxicity and 14 of them for response. The patients were assigned to i ncreasing 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 acetat e given orally on days 1 to 7, and recombinant IL-2 1.8 MIU administered su bcutaneously on days 2 to 7 plus 300 mu g granulocyte-colony stimulating fa ctor support given subcutaneously on days 2 to 5. Administration of medroxy progesterone acetate began 1 week before the first cycle. Dose escalation o f the drugs was as follows: 30 mg.m(2).week(-1) CDDP and 25 mg.m(2).week(-1 ) EPI (first level, two patients); 30 mg.m(2).week(-1) CDDP and 33 mg.m(2). week(-1) (third level, 6 patients): m(2).week(-1) EPI (second level, 2 pati ents); 40 mg.m(2).week(-1) CDDP and 33 mg and 40 mg m(2) week(-1) CDDP and 40 mg.m(2).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 resp onse (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 cyto kines were evaluated. After six cycles, 9 of 14 patients (64.3%) had partia l response, 3 of 14 (21.4%) had stable disease, and 2 of 14 (14.3%) had pro gressive disease, and the objective response rate was 64.3%. ECOG performan ce status and body weight did not change significantly after treatment, whe reas appetite showed an increase that was of borderline statistical signifi cance. 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 leve ls of IL-I beta, IL-6, and TNF-alpha were significantly greater in the pati ents than in healthy persons. The com-parison between pretreatment and post treatment serum values of IL-1 beta, IL-6. TNF-alpha, and sIL-2R did not re veal significant differences in the patients. Similar results were obtained when the patients were considered as responders (partial response) or nonr esponders (stable or progressive disease) to therapy. Only IL-6 serum level s were increased (p = 0.014) after treatment.