Annals of Oncology Advance Access originally published online on July 15, 2008
Annals of Oncology 2008 19(11):1903-1909; doi:10.1093/annonc/mdn412
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lung cancer |
Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study
1 Departments of Medicine, Pharmacology and College of Pharmacy, The Ohio State University, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, The National Cancer Institute, Bethesda, MD
2 Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA
* Correspondence to: Dr M. A. Villalona-Calero, The Ohio State University, B406 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210-1240, USA. Tel: +1-614-293-7511; Fax: +1-614-293-4372; E-mail: miguel.villalona{at}osumc.edu
Background: The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients.
Patients and methods: Patients received paclitaxel (Taxol) (200 mg/m2) and carboplatin (area under the concentration–time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10–50 µM.
Results: Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 µM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for 
4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for 4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M).
Conclusions: Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.
Key words: chemosensitization, drug resistance, FGF, lung cancer, suramin
Received for publication February 19, 2008. Revision received May 28, 2008. Accepted for publication June 5, 2008.