Randomised double blind placebo control study of adjuvant treatment with the metalloproteinase inhibitor, Marimastat in patients with inoperable colorectal hepatic metastases: significant survival advantage in patients with musculoskeletal side-effects.

Background: A double blind placebo RCT of adjuvant treatment of the matrix metalloproteinase inhibitor, Marimastat, in patients with unresectable colorectal liver metastases showed no significant effect on survival. There was a statistically significant survival advantage for the marimastat-treated patients with musculoskeletal-side effects, (p = 0. <000). Aim: To assess the effect of adjuvant Marimastat in patients with inoperable colorectal liver metastases (CRCLM). Patients and Methods: Patients (n = 121) with CRCLM, stratified by treatments for their liver disease status prior to randomization, received adjuvant oral Marimastat treatment 10 mg b.d. or placebo for up to two years. Results: Prognostic indicators such as number and size of hepatic lesions and percentage of liver replacement were well distributed between the treatment (57) and placebo (64) groups. There was no significant overall survival advantage for Marimastat treatment: 388 days, 95% Cl, 277-499 and placebo 410 days, 95% CI 306-514, (p = 0.5) log rank. Musculoskeletal symptoms in hands, wrists and/or shoulders developed in 35 out of 57 Marimastat-treated patients. Median survival for 35 patients with musculoskeletal symptoms was 619 days, 95% CI, 360-878 days vs 184 days, 95% Cl, 77-291, (p = 0.000 log rank) for 22 patients without symptoms. Musculoskeletal symptoms developed within three months of study treatment in 28 out of 35 (80%) patients. Conclusion: Increased survival in Marimastat-treated patients with musculoskeletal symptoms suggests that these may be biological evidence of tissue effect with resulting importance for dose optimisation of Marimastat. This should now be studied in the other randomized control trials of Marimastat.