An expansion study of genotype-driven weekly irinotecan and capecitabine in combination with neoadjuvant radiotherapy for locally advanced rectal cancer with UGT1A1 *1*1 genotype

Author:

Guan Yun1234,Shen Yunzhu5,Xu Ye62,Li Chao12,Wang Jingwen12,Gu Weilie62,Lian Peng62,Huang Dan72,Cai Sanjun62,Zhang Zhen89,Zhu Ji810ORCID

Affiliation:

1. Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Shanghai, China

2. Department of Oncology, Fudan University, Shanghai, China

3. Department of Neurosurgery, Fudan University, Shanghai, China

4. Department of Cyberknife, Fudan University, Shanghai, China

5. Department of Oncology, Nanjing Medical University, Nanjing, China

6. Department of Colorectal Surgery, Fudan University Shanghai Cancer Centre, Shanghai, China

7. Department of Pathology, Fudan University Shanghai Cancer Centre, Shanghai, China

8. Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, No. 270, Dong’An Road, Shanghai 200032, China

9. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

10. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

Abstract

Background: In our previous dose-escalation study, we uncovered the maximum tolerated dose (MTD) of weekly irinotecan was escalated to 80 mg/m2 and 65 mg/m2 for UDP glucuronosyltransferase family 1 member A1 (UGT1A1) *1*1 and *1*28 rectal cancer patients in neoadjuvant chemoradiotherapy (nCRT). This is an expansion study for *1*1 patients. Methods: Patients with clinical stage T3–4, N0–2 rectal cancer eligible for preoperative chemoradiotherapy were screened for the UGT1A1*28 genotype. A total of 52 patients with the *1*1 genotype were enrolled. Whole-pelvic intensity-modulated radiation therapy was given in 50 Gy/25 fractions. Concurrently, irinotecan of 80 mg/m2 and capecitabine of 625 mg/m2 twice daily from Monday to Friday were administered weekly. Primary endpoint was toxicities; secondary endpoints included pathological complete response (pCR), tumour-regression grading, treatment compliance, overall survival, local recurrence and disease-free survival. Results: All patients completed capecitabine-based radiotherapy as scheduled, and 42 (81%) patients completed more than three cycles of weekly irinotecan. Overall, grade 3/4 toxicities were observed in 20 cases, including 11 leucopenia, 10 neutropenia and 12 diarrhoea. Forty-three patients (83%) underwent a radical surgery, and 12 were evaluated as pCR. Another four patients accepted a watch-and-wait strategy because of clinical complete response (CCR). Conclusions: Our data demonstrated manageable toxicities and an encouraging CCR rate for UGT1A1 *1*1 genotype in an enhanced neoadjuvant therapy. A phase III trial is ongoing to evaluate the value of irinotecan in neoadjuvant therapy (CinClare) [ClinicalTrials.gov identifier: NCT02605265].

Funder

Natural Science Foundation of Shanghai

Publisher

SAGE Publications

Subject

Gastroenterology

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