A Phase II Trial of Preoperative Chemoradiotherapy with Oral DPD-Inhibitory Fluoropyrimidines in Patients with Advanced Rectal Cancer — Oak Academic Publishing
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A Phase II Trial of Preoperative Chemoradiotherapy with Oral DPD-Inhibitory Fluoropyrimidines in Patients with Advanced Rectal Cancer
Department of Surgery, Tokushima University Hospital, Tokushima, Japan
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Department of Surgery, Tokushima Red Cross Hospital, Tokushima, Japan
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Department of Surgery, Shikoku Central Hospital, Ehime, Japan
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Department of Surgery, Kochi Health Sciences Center, Kochi, Japan
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Department of Surgery, Tokushima Municipal Hospital, Tokushima, Japan
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Department of Surgery, Takamatsu City Hospital, Takamatsu, Japan
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Department of Surgery, National Hospital Organization Kochi National Hospital, Kochi, Japan
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Department of Surgery, Tokushima Prefectural Central Hospital, Tokushima, Japan
1 Department of Surgery, Tokushima University Hospital, Tokushima, Japan
2 Department of Surgery, Tokushima Red Cross Hospital, Tokushima, Japan
3 Department of Surgery, Shikoku Central Hospital, Ehime, Japan
4 Department of Surgery, Kochi Health Sciences Center, Kochi, Japan
5 Department of Surgery, Tokushima Municipal Hospital, Tokushima, Japan
6 Department of Surgery, Takamatsu City Hospital, Takamatsu, Japan
7 Department of Surgery, National Hospital Organization Kochi National Hospital, Kochi, Japan
8 Department of Surgery, Tokushima Prefectural Central Hospital, Tokushima, Japan
Background: Preoperative chemoradiotherapy (CRT) with 5-FU has been widely used to improve local control of disease and to preserve anal sphincter in the treatment of rectal cancer. UFT and S-1 as oral dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidines enhance the therapeutic effect of 5-FU by modulating its metabolic pathways. The purpose of this study was to evaluate the efficacy and toxicity of CRT using UFT versus S-1 in patients with locally advanced rectal cancer. Methods: Fifty-nine patients who received preoperative CRT (40 Gy radiotherapy) were randomly assigned to either UFT or S-1 groups. UFT and S-1 were administered during the radiotherapy course. Response to CRT was determined using a histopathologic examination and RECIST of surgically resected specimens and classified as responders (CR, PR and grade 2, 3) or nonresponders (SD, PD and grade 0, 1). Results: All patients were randomly allocated to S-1 group (n = 30) or UFT group (n = 29). Pathological response rate (Grade2 and Grade3) was 57% in the S-1 group and 45% in the UFT group (p = 0.36). Pathological complete response (CR) rate (Grade3) was 7% in the S-1 group and 4% in the UFT group (p = 0.98). There was no statistically significant difference between the two groups in regard to the response rate of RECIST (p = 0.52). There was no statistically significant difference between the groups based on the downstaging rate, resection of tumor, sphincter preservation and marginal invasion. The incidence of Grade 3 diarrhea was significantly more frequent in the S-1 group (7%) compared with the UFT group (0%) (p = 0.02). Conclusion: The results supported the conclusion that CRT using UFT or S-1 is effective and feasible for patients with locally advanced rectal cancer.
KeywordsS-1UFTChemoradiationRectal Cancer
C. Camma, M. Giunta, F. Fiorica, L. Pagliaro, A. Craxi and M. Cottone, “Preoperative Radiotherapy for Resectable Rectal Cancer: A Meta-Analysis,” Journal of the American Medical Association, Vol. 284, No. 8, 2000, pp. 1008-1015. doi:10.1001/jama.284.8.1008
Colorectal Cancer Collaborative Group, “Adjuvant Radiotherapy for Rectal Cancer: A Systematic Overview of 8,507 Patients from 22 Randomised Trials,” Lancet, Vol. 358, No. 9290, 2001, pp. 1291-1304. doi:10.1016/S0140-6736(01)06409-1
J. F. Bosset, L. Collette, G. Calais, L. Mineur, P. Maingon, L. Radosevic-Jelic, A. Daban, E. Bardet, A. Beny and J. C. Ollier, EORTC Radiotherapy Group Trial 22921, “Chemotherapy with Preoperative Radiotherapy in Rectal Cancer,” The New England Journal of Medicine, Vol. 355, 2006, pp. 1114-1123. doi:10.1056/NEJMoa060829
S. Fujii, S. Kitano, K. Ikenaka and T. Shirasaka, “Effect of coadministration of Uracil Or Cytosine on the Anti-Tumor Activity of Clinical Doses of 1-(2-Tetrahy-drofuryl)-5-Fluorouraciland Level of 5-Fluorouracil in Rodents,” Japanese Journal of Cancer Research: Gann, Vol. 70, No. 2, 1979, pp. 209-214.
T. Shirasaka, Y. Shimamato, H. Ohshimo, M. Yamaguchi, T. Kato, K. Yonekura and M. Fukushima, “Development of A Novel Form of an Oral 5-Fluorouracil Derivative (S-1) Directed to the Potentiation of the Tumor Selective Cytotoxicity of 5-Fluorouracil by Two Biochemical Modulators,” Anti-Cancer Drugs, Vol. 7, No. 5, 1996, pp. 548-557. doi:10.1097/00001813-199607000-00010
T. Shirasaka, K. Nakano, T. Takechi, H. Satake, J. Uchida, A. Fujioka, H. Saito, H. Okabe, K. Oyama, S. Takeda, N. Unemi and M. Fukushima, “Antitumor Activity of 1 M Tegafur-0.4 M 5-Chloro-2,4-Dihydroxypyridine-1 M Potassium Oxonate (S-1) Against Human Colon Carcinoma Orthotopically Implanted into Nude Rats,” Cancer Research, Vol. 56, No. 11, 1996, pp. 2602-2606.
P. M. Hoff, N. Janjan, E. D. Saad, J. Skibber, C. Crane, Y. Lassere, K. R. Cleary, S. Benner, J. Randolph, J. L. Abbruzzese and R. Pazdur, “Phase I Study of Preoperative Oral Uracil and Tegafur plus Leucovorin and Radiation Therapy in Rectal Cancer,” Journal of Clinical Oncology, Vol. 18, No. 20, 2000, pp. 3529-3534.
J. Feliu, J. Calvilio, A. Escribano, J. de Castro, M. E. Sanchez, A. Mata, E. Espinosa, A. G. Grande, A. Mateo, M. G. Baron, “Neoadjuvant Therapy of Rectal Carcinoma with Uft-Leucovorin plus Radiotherapy,” Annals of Oncology, Vol. 13, No. 5, 2002, pp. 730-736. doi:10.1093/annonc/mdf116
L. W. Vestermark, A. Jacobsen, C. Qvortrup, F. Hansen C. Bisgaard, G. Baatrup, P. Rasmussen and P. Pfeiffer, “Long-Term Results of a Phase II Trial of High Dose Radiotherapy (60 Gy) and UFT/l-Leucovorin in Patients with Non-Resectable Locally Advanced Rectal Cancer (LARC),” Acta Oncologica, Vol. 47, No. 3, 2008, pp. 428-433. doi:10.1080/02841860701798866
C. Fernández-Martos, J. Aparicio, C. Bosch, M. Torregrosa, J. M. Campos, S. Garcera, J. M. Vicent, I. Maestu, M. A. Climent, J. L. Mengual, A. Tormo, A. Hernandez, R. Estevan J. M. Richart, V. Viciano, N. Uribe, J. Campos, R. Puchades F. Arlandis and D. Almenar, “Preoperative Uracil, Tegafur, and Concomitant Radiotherapy in Operable Rectal Cancer: A Phase II Multicenter Study with 3 Years’ Follow-Up,” Journal of Clinical Oncology, Vol. 22, 15, 2004, pp. 3016-3022. doi:10.1200/JCO.2004.11.124
A. de la Torre, M. I. García-Berrocal, F. Arias, I. Zapata, C. de la Fuente, E. Fernandez-Lizarbe, G. Vergara, B. Belinchon, M. Veiras, R. Moleron and I. Millan, “Preoperative Chemoradiotherapy for Rectal Cancer: Randomized Trial Comparing Oral Uracil and Tegafur and Oral Leucovorin vs. Intravenous 5-Fluorouracil and Leucovorin,” International Journal of Radiation Oncology, Biology, Physics, Vol. 70, No. 1, 2008, pp. 102-110. doi:10.1016/j.ijrobp.2007.05.068
M. Fukushima, K. Sakamoto, M. Sakata, F. Nakagawa, H. Saito and Y. Sakata, “Gimeracil, a Component of S-1, May Enhance the Antitumor Activity of X-Ray Irradiation in Human Cancer Xenograft Models in Vivo,” Oncology Reports, Vol. 24, No. 5, 2010, pp. 1307-1313. doi:10.3892/or_00000987
S. Morimoto, M. Shimada, N. Kurita, H. Sato, T. Iwata, M. Nishioka, K. Yoshikawa, T. Miyatani, H. Kashihara, C. Takasu and H. Ikushima, “Preoperative Radiotherapy Combined with S-1 for Advanced Lower Rectal Cancer: Phase I Trial,” Hepatogastroenterology, Vol. 59, No. 117, 2012, pp. 1428-1432. doi:10.5754/hge11699
“Response Assessment of Nonsurgical Treatment for Colorectal Carcinoma. Japanese Classification of Colorectal Carcinoma. Japanese Society for Cancer of the Colon and Rectum, “1st English Edition, Kanehara & Co. Ltd., Tokyo, 1997, pp. 77-82.
R. Glynne-Jones, J. Dunst and D. Sebag-Montefiore, “The Integration of Oral Capecitabine into Chemoradiation Regimens for Locally Advanced Rectal Cancer: How Successful Have We Been?” Annals of Oncology, Vol. 17, 3, 2006, pp. 361-371. doi:10.1093/annonc/mdj052
N. A. Janjan, J. Abbruzzese, R. Pazdur, V. S. Khoo, K. Cleary, R. Dubrow, J. Ajani, T. A. Rich, M. S. Goswitz, P. A. Evetts, P. K. Allen, P. M. Lynch and J. M. Skibber, “Prognostic Implications of Response to Preoperative Infusional Chemoradiation in Locally Advanced Rectal Cancer,” Radiotherapy & Oncology, Vol. 51, No. 2, 1999, pp. 153-160. doi:10.1016/S0167-8140(99)00054-7
J. Dunst, T. Reese, T. Sutter, H. Zu¨hlke, A. Hinke, K. Ko¨lling-Schlebusch and S. Frings, “Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal Cancer,” Journal of Clinical Oncology, Vol. 20, No. 19, 2002,3983-3991. doi:10.1200/JCO.2002.02.049
J. Souglakos, N. Androulakis, D. Mavroudis, C. Kourousis, S. Kakolyris, N. Vardakis, K. Kalbakis, A. Pallis, A. Ardavanis, C. Varveris and V. Georgoulias, “Multicenter Dose-Finding Study of Concurrent Capecitabine and Radiotherapy as Adjuvant Treatment for Operable Rectal Cancer,” International Journal of Radiation Oncology, Biology, Physics, Vol. 56, No. 5, 2003, pp. 1284-1287. doi:10.1016/S0360-3016(03)00275-X
I. Craven, A. Crellin, R. Cooper, A. Melcher, P. Byrne and D. Sebag-Montefiore, “Preoperative Radiotherapy Combined with 5 Days Per Week Capecitabine Chemotherapy in Locally Advanced Rectal Cancer,” British Journal of Cancer, Vol. 97, No. 10, 2007, pp. 1333-1337. doi:10.1038/sj.bjc.6604042
C. Aschele, C. Pinto, S. Cordio, G. Rosati, A. Tagliagambe, S. Artale, P. Rosetti, S. Lonardi, L. Boni and L. Cionini, “Preoperative Fluorouracil (FU)-Based Chemoradiation with and Without Weekly Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Response Analysis of the Studio Terapia Adiuvante Reto (STAR)-01 Randomized Phase III Trial (Abstract #4008),” Journal of Clinical Oncology, Vol. 27, 2009, p. 804s.
J. Gerard, D. Azria, S. Gourgou-Bourgade, I. Martel-Laffay, C. Hennequin, P. L. Etienne, V. Vendrely, E. Francois, G. de La Roche, O. Bouche, X. Mirabel, B. Denis, L. Mineur, J. F. Berdah, M. A. Mahe, Y. Becouarn, O. Dupuis, G. Lledo, C. Montoto-Grillot and T. Conroy, “Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2,” Journal of Clinical Oncology, Vol. 28, No. 10, 2010, pp. 1638-1644. doi:10.1200/JCO.2009.25
T. Sato, H. Ozawa, K. Hatate, W. Onosato, M. Naito, T. Nakamura, A. Ihara, W. Koizumi, K. Hayakawa, I. Okayasu, K. Yamashita and M. Watanabe, “A Phase II Trial of Neoadjuvant Preoperative Chemoradiotherapy with S-1 plus Irinotecan and Radiation in Patients with Locally Advanced Rectal Cancer: Clinical Feasibility and Response Rate,” International Journal of Radiation Oncology, Biology, Physics, Vol. 79, No. 3, 2011, pp. 677-683. doi:10.1016/j.ijrobp.2009.11.007
B. Glimelius, U. Isacsson, B. Jung and L. Pahlman, “Radiotherapy in Addition to Radical Surgery in Rectal Cancer: Evidence for a Dose-Response Effect Favoring Preoperative Treatment,” International Journal of Radiation Oncology, Biology, Physics, Vol. 37, No. 2, 1997, pp. 281-287. doi:10.1016/S0360-3016(96)00510-X
K. L. Wiltshire, I. G. Ward, C. Swallow, C. S. Wong, R. Wong, L. L. Siu, M. Moore and J. Brierley, “Preoperative Radiation with Concurrent Chemotherapy for Resectable Rectal Cancer: Effect of Dose Escalation on Pathologic Complete Response, Local Recurrence-Free Survival, Disease-Free Survival, and Overall Survival,” International Journal of Radiation Oncology, Biology, Physics, Vol. 64, No. 3, 2006, pp. 709-716. doi:10.1016/j.ijrobp.2005.08.012
M. Mohiuddin, W. F. Regine, W. J. John, P. F. Hagihara, P. C. McGrath, D. E. Kenady and G. Marks, “Preoperative Chemoradiation in Fixed Distal Rectal Cancer: Dose Time Factors for Pathological Complete Response,” International Journal of Radiation Oncology, Biology, Physics, Vol. 46, No. 4, 2000, pp. 883-888. doi:10.1016/S0360-3016(99)00486-1