A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results.
BACKGROUND
Tetrathiomolybdate (TM) is an oral copper-depleting agent that has been shown to inhibit angiogenesis, and angiogenesis is a predictor of poor prognosis in malignant pleural mesothelioma. We hypothesized that cytoreduction of malignant pleural mesothelioma followed by TM will delay time to progression.


METHODS
Between November 2000 and August 2003, 30 patients with malignant pleural mesothelioma received postoperative TM beginning 4 to 6 weeks after surgery at a dose adjusted to keep ceruloplasmin between 5 and 15 mg/dL). Time to progression was compared with the 55 stage I and II patients and 109 stage III patients previously treated with cytoreduction by one of us (H.P.).


RESULTS
The 30 patients (25 men, 5 women; 13 stage I and II, 17 stage III), median age 67 years (range, 49-81 years), remained on TM a median of 14.9 months (range, 2 to 57 months). All patients reached target ceruloplasmin levels at a mean of 34 +/- 2 days (95% confidence interval, 30 to 39 days), and vascular endothelial growth factor levels at baseline (ceruloplasmin = 45.2 +/- 2 mg/dL) decreased from 2,086 +/- 390 pg/mL to 1,250 +/- 712 pg/mL (p < 0.002) at target ceruloplasmin (13 +/- 2 mg/dL; p < 0.0001 from baseline). The time to progression for all stage I or II TM patients was 20 months whereas that of 55 stage I or II non-TM-treated patients was 10 months (p = 0.046 versus TM). No differences in time to progression for the stage III TM patents from surgery were seen (7 months).


CONCLUSIONS
Tetrathiomolybdate has antiangiogenic effects in malignant pleural mesothelioma patients after resection of gross disease, and exhibits minimal toxicity and comparable efficacy to previous multimodality trials. Tetrathiomolybdate should be evaluated for efficacy in combination with standard malignant pleural mesothelioma regimens, as well as for postsurgical maintenance therapy.
Pass
Harvey I
HI
Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 10016, USA. harvey.pass@med.nyu.edu
Brewer
George J
GJ
Dick
Robert
R
Carbone
Michele
M
Merajver
Sofia
S
D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002570:Ceruloplasmin / Q000032:analysis; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D008875:Middle Aged; D008982:Molybdenum / Q000627:therapeutic use*; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D016879:Salvage Therapy; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin