Phase II study of a combination of cisplatin, all-trans-retinoic acid and interferon-alpha in squamous cell carcinoma: Clinical results and pharmacokinetics

Preclinical and clinical data suggest a certain anti-tumor efficacy for com bination of retinoids, cytokines and cytotoxic compounds. Patients and Meth ods: Between November 1994 and October 1996 38 patients with advanced squam ous cell carcinoma were enrolled in a phase II study to investigate an asso ciation of low-dose all-trans-retinoic acid (tRA) (40 mg/m(2)/day, 84 days) , interferon-alpha (IFN-alpha) (6.10(6) UI/day 84 days s.c.) and cisplatin (40 mg/m(2)/day, day 1, 28 and 56 iv.). A Pharmacokinetic evaluation was pe rformed an 12 patients. Results: The incidence of grade 3/4 hematologic tox icities was moderate (< 20%). Extra hematological toxicities were frequent but easily manageable and not life threatening. However, treatment delivery was poor since only 6 patients (16%) received full therapy. Seven objectiv e responses were observed (21%), suggesting some degree of synergism betwee n tRA, IFN-alpha and cisplatin. Interestingly, continuous tRA treatment in combination with IFN-alpha and cisplatin did not induce a significant decre ase in plasma levels, as had been previously described. Conclusions: Regard ing the short median response duration and the frequency of toxic events, t his regimen should no longer be recommended in pretreated patients with adv anced disease. However; the consistent response rate reported hen may warra nt further investigation in an early setting.