Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma.

Abstract

BACKGROUND:

This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS).

METHODS:

Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected.

RESULTS:

Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m(2). At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively.

CONCLUSIONS:

The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.

• Authors: William W Tseng, Shouhao Zhou, Christina A To, Peter F Thall, Alexander J Lazar, Raphael E Pollock, Patrick P Lin, Janice N Cormier, Valerae O Lewis, Barry W Feig, Kelly K Hunt, Matthew T Ballo, Shreyaskumar Patel, Peter W T Pisters
• Journal: Cancer (Cancer) Vol. 121 Issue 20 Pg. 3659-67 (Oct 15 2015) ISSN: 1097-0142 [Electronic] United States
• PMID: 26177983 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Cancer Society.

Chemical References

• Radiation-Sensitizing Agents
• Deoxycytidine
• Gemcitabine

Topics

• Adult
• Bayes Theorem
• Chemoradiotherapy, Adjuvant
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives)
• Dose Fractionation, Radiation
• Drug Administration Schedule
• Extremities (pathology)
• Humans
• Maximum Tolerated Dose
• Middle Aged
• Neoadjuvant Therapy (methods)
• Radiation-Sensitizing Agents (administration & dosage, adverse effects)
• Sarcoma (pathology, therapy)
• Survival Analysis
• Torso (pathology)
• Treatment Outcome
• Gemcitabine