Combination interleukin-2 and doxorubicin in advanced adult solid tumors: Circumvention of doxorubicin resistance in soft-tissue sarcoma?

Based on the likelihood of antitumor interactions between cytokines and cyt otoxic drugs, we designed a pilot study to evaluate feasibility, clinical, pharmacologic, and immunologic effects of concomitantly administered subcut aneous (SQ) recombinant interleukin-2 (r-IL-2) and doxorubicin (ADR) in pat ients with advanced solid tumors (AST). Patients received one injection of ADR alone (70 mg/m(2)) and 3 weeks later a combination of r-IL-2 (18 MIU/m( 2) days 1-5 so) and ADR at the same dose either 3-4 h after the first r-IL- 2 injection (arm 1) or 2 days after the last r-IL-2 injection (arm 2). The same combination was repeated every 4 weeks according to the evolution of t he disease. Pharmacokinetics were assessed over 48 h after injection of ADR alone and after the first ADR-IL-2 cycle and immunologic monitoring at day s 1 and 8 of the first ADR-IL-2 cycle. Tumors were measured at baseline, af ter ADR alone, and after each ADR-IL-2 cycle until progression. Twenty-one adult patients with various AST including 14 soft-tissue sarcomas (STS) ent ered the study, ii in arm 1 and 10 in arm 2. All patients were heavily pret reated; IG had received an anthracycline-containing chemotherapy regimen. E leven patients were ADR refractory and I ADR resistant. Grade 3 neutropenia occurred in 18, 82, and 40% of patients after ADR alone, ADR-IL-2 in arm 1 and ADR-IL-2 in arm 2, respectively. Mucitis was higher in arm 1 (7 of 11 patients) compared with arm 2 (0 of 10) and ADR alone (0 of 21). so injecti ons of r-IL-2 did not affect ADR pharmacokinetics. ADR injection in arm 1 p revented IL-2-induced lymphocyte rebounds in all patients but did not alter qualitatively non-major histocompatibility complex-restricted cytotoxicity . There was no response after ADR alone. Two patients, one in each arm, exp erienced a prolonged (8 and 5 months) objective response after ADR-IL-2. Bo th had ADR-refractory STS with a local relapse and metastatic metastases. I nterestingly, both patients had unusually elevated TNF-alpha levels before and after the first ADR cycle. Combination ADR-IL-2, although toxic, is fea sible and manageable with routine clinical support. r-IL-2 enhanced ADR hem atologic and extrahematologic toxicities. The two objective responses obser ved in these heavily pretreated patients refractory to ADR supports the hyp othesis of a modulation of ADR resistance, possibly mediated by means of a mechanism involving TNF-a. Elevated baseline TNF-cr levels could be predict ive of response to ADR-IL-2 and deserves further investigation.