What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long‐term outcomes over the past decades? A systematic review and meta‐analysis based on 41,121 patients

Abstract

We asked what preoperative radiotherapy/chemoradiotherapy (PRT/PCRT) has brought to patients in terms of perioperative and long-term outcomes over the past decades. A systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to PRT/PCRT and surgical resection and which analyzed survival, postoperative and quality of life outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. Data from 106 comparative studies based on 80 different trials enrolling 41,121 patients were included in our study. Based on our overall analyses, PRT/PCRT significantly improved patients' local recurrence-free survival (LRFS), but neither overall survival (OS) nor metastasis-free survival (MFS) showed improvement. In addition, PRT significantly increased the postoperative morbidity and mortality but PCRT did not have a significant effect. Furthermore, PRT/PCRT significantly increased the risk of postoperative wound complications but not anastomotic leakage and bowel obstruction. Our comprehensive subgroup analyses further supported the aforementioned results. Meanwhile, long-term anorectal symptoms (impaired squeeze pressures, use of pads, incontinence and urgency) and erectile dysfunction were also significantly increased in patients after PRT/PCRT. The benefits of PRT/PCRT as applied over the last several decades have not been sufficient to improve OS. Metastases of primary tumor and postoperative adverse effects were the two primary obstacles for an improved OS. In fact, the greatest advantage of PRT/PCRT is still local tumor control and a significantly improved LRFS.

Radiosensitization by irinotecan is attributed to G2/M phase arrest, followed by enhanced apoptosis, probably through the ATM/Chk/Cdc25C/Cdc2 pathway in p53-mutant colorectal cancer cells

“…Pre-operative chemoradiotherapy (CRT), followed by total mesorectal excision, is the standard of care for patients with locally advanced rectal cancer (LARC) (2)(3)(4). The combination of radiation with capecitabine has been shown to significantly improve local control and local recurrence-free survival, but does not improve metastasis-free survival or overall survival (5). To acquire better outcomes, researchers have attempted to identify novel radiosensitizers, such as oxaliplatin, irinotecan and some molecular targeting agents (6).…”

The potential predictive value of tumor budding for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer

“…The multidisciplinary approach including radiotherapy, chemotherapy, and surgery is regarded as the standard of care for locally advanced (T3/4 and/or node positive) mid-to-low rectal cancer patients [ 1 , 2 ]. Neoadjuvant regimens consisting of preoperative long-course 5‑FU (5‑fluorouracil) based chemoradiotherapy (CRT; 45–50.4 Gy, 25–28 fractions) and preoperative short-course radiotherapy (25 Gy, five fractions) are considered the primary treatments of choice [ 3 – 5 ]. The CAO/ARO/AIO-94 trial demonstrated the superiority of preoperative CRT with respect to local control, treatment compliance, and overall toxicity profile, but not in overall survival benefit, when compared to postoperative CRT [ 2 , 5 ].…”

Comparative survival analysis of preoperative and postoperative radiotherapy in stage II-III rectal cancer on the basis of long-term population data

“…Irradiation before surgical resection sterilizes gross and microscopic tumor cells under the better condition of tumor oxygenation, suggesting potential benefits in preventing further tumor spread within the locoregional RT field 5 , 9 . In clinics, main reasons for the recommendation have been derived from some favorable oncologic outcomes: down-staging effect, increased likelihood of sphincter preservation, and relatively better treatment compliance expected 6 , 7 , 9 – 11 . In this study, the unadjusted results indicating better survival with preoperative RT might be attributable to favorable factors related to the use of RT prior to surgery.…”

“…Recently, preoperative use of RT has become the preferred option for locally advanced rectal adenocarcinomas 6 . Given that the Dutch trials demonstrated improved local control with neoadjuvant RT 7 , 8 , three phase III randomized controlled trials, including the German CAO/ARO/AIO-94, National Surgical Adjuvant Breast and Bowel Project (NSABP) R-03, and a Korean study, compared pre- and postoperative use of RT 9 – 11 .…”