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A phase II trial of Tetrathiomolybdate [TM] after cytoreductive surgery for malignant pleural mesothelioma (MPM).

SOURCE: ASCO, 2004 Annual Meeting

H. I. Pass, G. Brewer, T. Stevens, S. Sharma, D. Smith, A. Wali, S. Merajver; Karmanos Cancer Institute/Wayne State University, Detroit, MI; University of Michigan, Ann Arbor, MI.

Background: Resection and adjuvant therapy for MPM results in a 2-year survival of 60% for Stages I/II, and 25% for Stage III (Rusch et al; Proc ASCO 2000). Median time to progression is 7-12 months after resection. Angiogenesis is a predictor of poor prognosis in MPM; TM is an oral copper (Cu)-depleting agent that inhibits angiogenesis and decreases levels of VEGF when ceruloplasmin (Cp) is reduced to 5-15 mg/dl. We hypothesize that cytoreduction of MPM followed by continuous TM can increase survival and delay progression by keeping residual disease in a dormant state.

Methods: 34 cytoreduced MPM patients were registered for postoperative TM beginning 4-6 weeks after surgery at 180 mg/day with the dose adjusted to maintain Cp between 5-15 mg/dl. TM was continued until progression; chest/abdominal CTs were performed every 4 months.

Results: 4 patients progressed prior to reaching target Cp. The remaining 25 men and 5 women, median age 67 (range 49-81yrs.) remained on TM a median of 10 months (range 4 to>36 mos.). The most common Grade (Gr) 3 toxicity was anemia: 27 episodes (15 patients), requiring transfusion in 7, or TM dose reduction alone (8). One patient had asymptomatic Gr 3 SGPT/SGOT rise which reversed with TM dose modification. All patients reached target Cp levels within 34+2 days (95% CI 30-39 days), and VEGF levels at baseline Cp (Cp=45.2+2 mg/dl) decreased from 2086+390 pg/ml to 1250+712 pg/ml (p<0.002) at target Cp [13+2 mg/dl (p<0.0001 from baseline)]. Survival /progression data are seen shown below.

24 month Overall Survival
24 month Progression Free Survival
Stage I/II (n=13)
Stage III (n=17)

Conclusions: TM has antiangiogenic effects in postoperative MPM patients and the VEGF serum level is a robust biomarker in this therapy. TM has minimal toxicity and is at least comparable in efficacy to previous multimodality trials of cytotoxic agents for MPM. TM should be evaluated for use with standard MPM regimens, as well as for postsurgical maintenance monotherapy.