Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings.
Vol 23, No 16S (June 1 Supplement), 2005: 3024
© 2005 American Society of Clinical Oncology

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Abstract

Genotype-guided neoadjuvant therapy for rectal cancer

Washington Univ, St Louis, MO

3024

Background: Neoadjuvant therapy with 5-fluorouracil (5FU) and radiation has become standard therapy for bulky rectal cancer and achieves a downstaging (DS) rate of 45%. The presence of two 28 bp repeats (*2) in thymidylate synthase was recently associated with superior DS (60%) compared with homozygous triple repeat (*3/*3; 22% DS) (J Clin Oncol 2001;19:1779–86). Multiple studies have linked TYMS *3/*3 with risk of 5FU failure. Pharmacogenomics has provided the promise of better therapy, based on retrospective evaluation of patient treatment. Therefore a study was conducted to provide initial experience with the conduct of genotype-guided therapy and to generate data for the design of future randomized pharmacogenomics trials. Methods: A two-stage design was used to construct 2 distinct phase II studies, directed by TYMS genotype. After informed consent, patients with stage T3/T4 rectal cancer were genotyped for the TYMS repeat sequence. ’Good risk’ patients (TYMS *2/*2 or *2/*3) received 5 weeks of 5FU 225 mg/m²/day and 45 Gy radiation. ’Bad risk’ patients (TYMS *3/*3) received 5FU/radiation plus irinotecan 50 mg/m² weekly x 5 doses. Surgical resection was performed 6–10 weeks post therapy. The primary endpoint of both phase II studies was DS. Toxicity was measured by CTC criteria. Results: Successful accrual occured for 60/61 patients treated during the study period for T3/T4 rectal cancer. The 32 evaluable ’good risk’ patients achieved 56% DS, with 28% pCR. Grade 3 leukopenia (85%) and diarrhea (15%) was observed, with 9% hospitalization. The 13 evaluable ’bad risk’ patients recieved triple therapy and achieved 85% DS, with 62% pCR. Grade 3 leukopenia (93%) and diarrhea (29%) was observed, with 33% hospitalization. One patient died of cardiac arrest. Conclusions: Genotype-guided neoadjuvant therapy was successfully conducted for treatment of rectal cancer. The use of 5FU/radiation in patients with a TYMS ’good risk’ genotype enriched for a higher rate of DS and pCR than previously observed. Intervention with additional chemotherapy in patients anticipated to have lower DS (TYMS *3/*3) led to high DS and pCR, but a higher incidence of toxicity-associated hospitalization. Accrual continues to enroll 77 TYMS *2/*2 or *2/*3 and 31 TYMS *3/*3 patients.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Neopharm, Orion Genomics, Sanofi- Synthelabo, Veridex Merck

Abstract presentation from the 2005 ASCO Annual Meeting