Neoadjuvant chemoradiotherapy with capecitabine and irinotecan guided by UGT1A1 status in patients with locally advanced rectal cancer: 5-year update of the CinClare trial

Abstract

Background: The optimal regimen and chemotherapy intensity are still under investigation for neoadjuvant treatment of locally advanced rectal cancer (LARC). The CinClare trial has demonstrated improved pathologic complete response (pCR) with the addition of irinotecan to neoadjuvant chemoradiotherapy (CRT) guided by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype in LARC. Here, we report the 5-year follow-up outcomes of the CinClare study.

Methods: From November 2015 to December 2017, this randomized, open-label, multicenter, phase III trial enrolled 360 patients with LARC and assigned them in a 1:1 ratio to CapIriRT (radiation with capecitabine combined with irinotecan followed by irinotecan and capecitabine) or CapRT (radiation with concurrent capecitabine followed by oxaliplatin and capecitabine). Irinotecan dosing was guided by UGT1A1 genotype (80 mg/m² for *1/*1 and 65 mg/m² for *1/*28). The endpoints, including local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS), were analyzed using the log-rank test, Cox proportional hazards regression and restricted mean survival time (RMST) test at the data cut-off date of June 2023.

Results: With a median follow-up of 60 months, the CapIriRT group showed numerically higher 5-year LC (95.6% vs. 93.9%), 5-year DMFS (83.9% vs. 77.9%), 5-year DFS (77.7% vs. 70.6%), and 5-year OS rates (82.9% vs. 76.1%) than the CapRT group. Further RMST test also showed a statistically significant difference in DFS (P < 0.05) and a borderline difference in OS (P = 0.050). Among the UGT1A1 *1/*1 population, the CapIriRT group had significantly improved 5-year rates of DMFS, DFS, and OS (all P < 0.05). Patients achieving pCR also had significantly longer DFS and OS compared to non-pCR patients (P < 0.05).

Conclusions: The addition of irinotecan guided by UGT1A1 genotype to a standard capecitabine-based scheme brings clinical benefits with improved LC, DMFS, DFS, and OS. Patients with the UGT1A1 *1/*1 genotype derived notable benefit from irinotecan, with improved survival outcomes. Achievement of pCR is crucial as it is associated with improved long-term survival. These findings support the integration of genomic testing into clinical practice to achieve a personalized irinotecan dosing regimen, which can optimize efficacy and safety.

Trial registration: ClinicalTrials.gov (NCT02605265).

Keywords

antineoplastic combined chemotherapy protocols / capecitabine / capecitabine-irinotecan combination / irinotecan / neoadjuvant therapy / Rectal neoplasms

References

[1] Bhudia J, Glynne-Jones R. The Evolving Neoadjuvant Treatment Paradigm for Patients with Locoregional mismatch Repair Proficient Rectal Cancer. Curr Treat Options Oncol. 2022;23(4):453–473.

[2] Kitz J, Fokas E, Beissbarth T, Ströbel P, Wittekind C, Hartmann A, et al. Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial. JAMA Surgery. 2018;153(8):e181607.

[3] Miller JA, Wang H, Chang DT, Pollom EL. Cost-Effectiveness and Quality-Adjusted Survival of Watch and Wait After Complete Response to Chemoradiotherapy for Rectal Cancer. J Natl Cancer Inst. 2020;112(8):792–801.

[4] Kagawa Y, Smith JJ, Fokas E, Watanabe J, Cercek A, Greten FR, et al. Future direction of total neoadjuvant therapy for locally advanced rectal cancer. Nat Rev Gastroenterol Hepatol. 2024;21(6):444–455.

[5] Scott AJ, Kennedy EB, Berlin J, Brown G, Chalabi M, Cho MT, et al. Management of Locally Advanced Rectal Cancer: ASCO Guideline. J Clin Oncol. 2024;42(28):3355–3375.

[6] Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):29–42.

[7] Conroy T, Bosset JF, Etienne PL, Rio E, Francois E, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(5):702–715.

[8] Conroy T, Castan F, Etienne PL, Rio E, Mesgouez-Nebout N, Evesque L, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial. Ann Oncol. 2024;35(10):873–881.

[9] Gollins S, Sun Myint A, Haylock B, Wise M, Saunders M, Neupane R, et al. Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long-term clinical outcomes. J Clin Oncol. 2011;29(8):1042–1049.

[10] Innocenti F, Schilsky RL, Ramírez J, Janisch L, Undevia S, House LK, et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol. 2014;32(22):2328–2334.

[11] Toffoli G, Sharma MR, Marangon E, Posocco B, Gray E, Mai Q, et al. Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. Clin Cancer Res. 2017;23(4):918–924.

[12] Diasio RB, Innocenti F, Offer SM. Pharmacogenomic-Guided Therapy in Colorectal Cancer. Clin Pharmacol Ther. 2021;110(3):616–625.

[13] Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, et al. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020;38(36):4231–4239.

[14] Weng S, Yuan Y, Wang X, Chen G, Wang Y, Sheng W, et al. Updates in version 2020 of CSCO guidelines for colorectal cancer from version 2019. Chin J Cancer Res. 2020;32(3):403–407.

[15] Chinese Society of Clinical Oncology Guidance Working Committee. CSCO Guidelines for colorectal cancer version 2020. Beijing: People's Medical Publishing House; 2020.

[16] Wong SJ, Moughan J, Meropol NJ, Anne PR, Kachnic LA, Rashid A, et al. Efficacy endpoints of radiation therapy group protocol 0247: a randomized, phase 2 study of neoadjuvant radiation therapy plus concurrent capecitabine and irinotecan or capecitabine and oxaliplatin for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2015;91(1):116–123.

[17] Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, et al. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 2022;40(23):2546–2556.

[18] Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019;37(34):3212–3222.

[19] Fokas E, Schlenska-Lange A, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol. 2022;8(1):e215445.

[20] Zhu J, Gu W, Lian P, Sheng W, Cai G, Shi D, et al. A phase II trial of neoadjuvant IMRT-based chemoradiotherapy followed by one cycle of capecitabine for stage II/III rectal adenocarcinoma. Radiat Oncol. 2013;8:130.

[21] Saltz LB, Niedzwiecki D, Hollis D, Goldberg RM, Hantel A, Thomas JP, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007;25(23):3456–3461.

[22] Van Cutsem E, Labianca R, Bodoky G, Barone C, Aranda E, Nordlinger B, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009;27(19):3117–3125.

[23] Papadimitriou CA, Papakostas P, Karina M, Malettou L, Dimopoulos MA, Pentheroudakis G, et al. A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study. BMC Med. 2011;9:10.

[24] Dijkstra EA, Nilsson PJ, Hospers GAP, Bahadoer RR, Meershoek-Klein Kranenbarg E, Roodvoets AGH, et al. Locoregional Failure During and After Short-course Radiotherapy Followed by Chemotherapy and Surgery Compared With Long-course Chemoradiotherapy and Surgery: A 5-Year Follow-up of the RAPIDO Trial. Ann Surg. 2023;278(4):e766–e772.

[25] Simões AR, Fernández-Rozadilla C, Maroñas O, Carracedo Á. The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment? J Pers Med. 2020;10(4).

[26] Shulman K, Cohen I, Barnett-Griness O, Kuten A, Gruber SB, Lejbkowicz F, et al. Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients. Cancer. 2011;117(14):3156–3162.

[27] Miarons M, Riera P, Garcia-Gil S, Gutierrez-Nicolas F. Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review. Farm Hosp. 2022;46(4):224–233.

[28] Biason P, Masier S, Toffoli G. UGT1A1*28 and other UGT1A polymorphisms as determinants of irinotecan toxicity. J Chemother. 2008;20(2):158–165.

[29] Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22(8):1382–1388.

[30] Fernandez-Martos C, Garcia-Albeniz X, Pericay C, Maurel J, Aparicio J, Montagut C, et al. Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial†. Ann Oncol. 2015;26(8):1722–1728.

[31] Li JY, Huang XZ, Gao P, Song YX, Chen XW, Lv XE, et al. Survival landscape of different tumor regression grades and pathologic complete response in rectal cancer after neoadjuvant therapy based on reconstructed individual patient data. BMC Cancer. 2021;21(1):1214.

[32] Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, Barni S. Pathologic complete response and disease-free survival are not surrogate endpoints for 5-year survival in rectal cancer: an analysis of 22 randomized trials. J Gastrointest Oncol. 2017;8(1):39–48.

[33] Karas S, Innocenti F. All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide. JCO Oncol Pract. 2022;18(4):270–277.

[34] Zhu X, Ma R, Ma X, Yang G. Association of UGT1A1*6 polymorphism with irinotecan-based chemotherapy reaction in colorectal cancer patients: a systematic review and a meta-analysis. Biosci Rep. 2020;40(10):BSR20200576.

[35] Jiang PC, Wang SW, Li C, Fan J, Zhu J. UGT1A1 genotype-guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN-38 concentration. Int J Cancer. 2024;154(8):1484–1491.

RIGHTS & PERMISSIONS

2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.