Adjuvant Bestatin Provides Survival Benefit for Stage I Squamous Cell Lung Cancer

Abstract & Commentary

Synopsis: In a multicenter trial from Japan, Bestatin, an aminopeptidase inhibitor, was shown to enhance survival in patients with stage I sqaumous cell carcinoma of the lung. This well-constructed trial will most certainly foster enthusiasm for exploring Bestatin in this role (adjuvant, postresection for low-stage squamous cell carcinoma) as well as in others, such as in combination with various chemotherapeutic or biologic agents.

Source: Ichinose Y, et al. J Natl Cancer Inst. 2003; 95:605-610.

Bestatin is a potent aminopeptidase inhibitor with immunostimulatory and antitumor activity. Ichinose and collaborators throughout Japan performed a prospective, randomized, double-blind, placebo-controlled trial to determine whether postoperative adjuvant treatment with Bestatin could prolong the survival of patients with completely resected stage I squamous cell carcinoma. For this, patients with resected stage I lung cancer were randomly assigned to either Bestatin (30 mg) or placebo daily by mouth for 2 years. Between the years 1992 and 1995, 400 patients were entered in the study—202 were treated with Bestatin and 198 with placebo. The median follow-up for surviving patients was 76 months (range, 58-92 months). The 5-year overall survival was 81% in the Bestatin group and 74% in the placebo group for a difference of 7% (95% confidence interval [CI]; -1.4% to 15%). The 5-year cancer-free survival was 71% in the Bestatin group and 62% in the placebo group for a difference of 9% (95% CI, -.7% to 17.8%). Overall survival (P = .033, log-ranked test) and cancer-free survival (P = .017, log-ranked test) were significantly different by Kaplan-Meier analysis. Few adverse events were observed in either group. Ichinose and colleagues conclude that survival was significantly enhanced for patients with completely resected stage I squamous cell carcinoma who received Bestatin as a postoperative adjuvant therapy when compared to those who received placebo. Ichinose et al conclude that these findings need to be confirmed in additional, large-scale clinical trials.

Comment by William B. Ershler, MD

Despite having localized disease at the time of presentation, patients with stage I lung cancer have a high relapse rate, and many will die of recurrent disease. Bestatin is a potent inhibitor of some, but not all, aminopeptidases.1 In preclinical studies, Bestatin has been shown to inhibit the invasion of metastatic tumor cells2 and induce apoptosis in non-small-cell lung cancer cell lines.3 Furthermore, in tumor-bearing mice, Bestatin inhibits metastases and tumor growth, as well as prolonging survival.4 In the clinical setting, Bestatin has been shown to prolong survival of patients with adult, nonlymphocytic leukemia when used with chemotherapy.5 In a single-institution study examining the role of Bestatin as an adjuvant for non-small-cell lung cancer, a subset (those with completely resected stage I squamous cell lung cancer) showed survival benefit.6 This survival benefit was not demonstrable when examined across other histologic types or stages. The current study, which represents a rather homogenous group of patients, all with squamous cell carcinoma and stage I (T1-2N0) who were treated with a single, daily oral dose of Bestatin, had significantly better survival than placebo controls. The finding is remarkable because it indicates another oral biological therapy with promise for the treatment of at least 1 subset of lung cancer patients, those with squamous cell carcinoma.

The precise role for Bestatin needs to be further defined. Its role as an adjunct to chemotherapy for patients with squamous cell or other forms of non-small-cell lung cancer needs to be evaluated, and certainly the current finding of enhanced survival in stage I squamous cell cancer should be confirmed. If this transpires, Bestatin will be a welcome addition to our arsenal of anticancer agents.

Dr. Ershler is of INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.

References

1. Scornik OA, Botbol U. Curr Drug Metab. 2001;2:67-85.

2. Saiki I, et al. Int J Cancer. 1993;54:137-143.

3. Hashida H, et al. Gastroneterology. 2002;122:376-386.

4. Abe F, et al. Gann. 1984;75:89-94.

5. Ohta K, et al. Cancer Immunol Immunother. 1989;23:5-10.

6. Yasumistsu T, et al. Acta Oncologica. 1990;29:827-831.