Clinical Practice Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2018; 10(1): 40-47
Published online Jan 15, 2018. doi: 10.4251/wjgo.v10.i1.40
Neoadjuvant hyperfractionated accelerated radiotherapy plus concomitant 5-fluorouracil infusion in locally advanced rectal cancer: A phase II study
Zeynep Gural, Sezer Saglam, Serap Yucel, Esra Kaytan-Saglam, Oktar Asoglu, Cetin Ordu, Hediye Acun, Rasul Sharifov, Semen Onder, Ahmet Kizir, Ethem N Oral
Zeynep Gural, Serap Yucel, Department of Radiation Oncology, Acibadem University Medical Faculty, Istanbul 34303, Turkey
Sezer Saglam, Cetin Ordu, Department of Medical Oncology, Istanbul Bilim University, Istanbul 34349, Turkey
Esra Kaytan-Saglam, Ahmet Kizir, Ethem N Oral, Department of Radiation Oncology, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey
Oktar Asoglu, Department of General Surgery, Academia of Clinical Science of Bogazici, Istanbul 34357, Turkey
Hediye Acun, Department of Medical Biophysics, Harran University Medical Faculty, Şanlıurfa 60300, Turkey
Rasul Sharifov, Department of Radiology, Bezm-i Alem University, Istanbul 34093, Turkey
Semen Onder, Department of Pathology, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey
Author contributions: All the authors contributed to this study; Gural Z and Saglam S contributed equally to the study.
Institutional review board statement: The study was reviewed and approved by the Istanbul Medical Faculty Institutional Review Board.
Informed consent statement: All information was obtained with the appropriate institutional review board waivers, and the data were collected without revealing any personal information.
Conflict-of-interest statement: The authors have no conflicts of interest, financial or otherwise.
Data sharing statement: Dataset is available from the corresponding author by e-mail at:
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Dr. Zeynep Gural, MD, Attending Doctor, Department of Radiation Oncology, Acibadem University Medical Faculty, Halkalı Merkez Mahallesi, Turgut Özal Blv No:16, Istanbul 34303, Turkey.
Telephone: +90-533-2696742 Fax: +90-212-4044445
Received: September 4, 2017
Peer-review started: September 7, 2017
First decision: October 9, 2017
Revised: November 26, 2017
Accepted: December 4, 2017
Article in press: December 4, 2017
Published online: January 15, 2018
Research background

Currently, preoperative chemoradiation (CRT) is the preferred treatment regimen in locally advanced rectal cancer patients, owing to low local recurrence rates and higher chance of sphincter-sparing surgery. Besides conventional radiotherapy consisting of 45-50 Gy/1.8-2 Gy/5-6 wk, other radiotherapy schemes are also used. The hyperfractionated accelerated radiotherapy (HART) scheme reduces the risk of repopulation in tumor cells by shortening the treatment time and increases the repair capacity of normal tissues. In this background, a HART scheme and the combination of infusional 5-fluorouracil (5-FU) was examined in this study to augment the pathological complete response.

Research motivation

Local recurrence is still a substantial problem for locally advanced rectal cancers. Investigating tolerability and the effect of different radiotherapy schemes on local control other than conventional and hypofractionated radiotherapy can be a solution.

Research objectives

This study was mainly designed to observe the early and late effects of HART regimen in combination with neoadjuvant chemotherapy in patients diagnosed with locally advanced rectal cancer. The primary aim of this study was to search for possible therapeutic strategies that may help increase the rate of pathological tumor response and to decrease late side effects.

Research methods

Previously untreated locally advanced rectal cancer patients with histological confirmation were included in the study. The patients were clinically staged according to positron emission-computed tomography and pelvic-diffusion magnetic resonance imaging. All patients received preoperative HART (42 Gy/1.5 Gy/18 d/bid) and concurrent continuous infusion of 5-FU (325 mg/m2) and were hospitalized during treatments to observe the possible acute side effects. Total mesorectal excision was performed 4-8 wk after the completion of chemoradiotherapy. Four cycles of 5-FU (400 mg/m2, D1-5, q 28 d) plus folinic acid (20 mg/m2, D1-5, q 28 d) were administered postoperatively. The primary endpoint was pathological response rate after CRT, and secondary endpoints included the local control rate, surgical margin positivity, survival and toxicity.

Research results

Thirty patients were included between October 2007 and March 2009. The median age was 53 years. Most of the patients clinically staged as T3N+ disease (90%). Surgery was performed at week 4 in half of the patients. Twelve patients (41%) underwent sphincter-sparing surgery. The Dworak total regression scoring system was used to evaluate pathological response, and grade IV (total) regression was found in 6 of 29 (21%) patients; nine patients (31%) had grade III (near total) regression. Positive margins were found in 2 patients (6.6%). One (3.3%) patient had local recurrence during a median follow-up of 60 mo. The 5-year disease-free survival rate was 53%, while the 5-year overall survival rate was 53.1%. There were no interruptions in RT due to toxicity, while in 4 patients chemotherapy was interrupted for 1 wk. Sixteen (53%) patients underwent adjuvant chemotherapy.

Research conclusions

Improved local control rates and tumor regression may be achieved with HART but with higher acute toxicity. Toxicity could be reduced by giving chronomodulated concomitant chemotherapy or reducing the dose of 5-FU. Surgery timing has no effect on survival but still should be considered because of increased acute side effects due to HART fractionation. Besides an increased pathological response rate, this study showed no survival benefit.

Research perspectives

Different HART schemes can be examined with concomitant chemotherapy in the future studies. Because of the high incidence of acute toxicity, fraction dose and chemotherapy doses should be designed properly for new studies.