Long T, Gao H, He WQ, Xiao WW, Wang XC. High-dose vs standard radiotherapy in rectal cancer: Effects on tumour response, toxicity, and organ preservation. World J Gastrointest Oncol 2026; 18(8): 120904 [DOI: 10.4251/wjgo.120904]
Corresponding Author of This Article
Xi-Cheng Wang, Professor, Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, No. 19 Nonglinxia Road, Yuexiu District, Guangzhou 510080, Guangdong Province, China. 13902400598@126.com
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Long T, Gao H, He WQ, Xiao WW, Wang XC. High-dose vs standard radiotherapy in rectal cancer: Effects on tumour response, toxicity, and organ preservation. World J Gastrointest Oncol 2026; 18(8): 120904 [DOI: 10.4251/wjgo.120904]
Ting Long, Han Gao, Xi-Cheng Wang, Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
Wan-Qi He, Department of Ultrasound, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, Guangdong Province, China
Wei-Wei Xiao, The State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510060, Guangdong Province, China
Co-corresponding authors: Wei-Wei Xiao and Xi-Cheng Wang.
Author contributions: Long T performed the research, analyzed the data, wrote the manuscript; Long T, Gao H and He WQ collected the data; Long T, Xiao WW and Wang XC designed the research study; Xiao WW and Wang XC supervised the study, revised the manuscript as co-corresponding authors; all authors have read and approved the final manuscript.
AI contribution statement: AI-assisted tools (e.g., ChatGPT) were used during the preparation of the answering-reviewers to improve language clarity and readability. All responses to the reviewers were independently developed by the authors, and the scientific content and interpretations were fully verified and approved by the authors. No AI tool was used in the writing of the main manuscript. No AI tool was involved in the design of the study, data analysis, or interpretation of results. No images or figures in the manuscript were generated by AI.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Xi-Cheng Wang, Professor, Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, No. 19 Nonglinxia Road, Yuexiu District, Guangzhou 510080, Guangdong Province, China. 13902400598@126.com
Received: March 11, 2026 Revised: April 8, 2026 Accepted: June 2, 2026 Published online: August 15, 2026 Processing time: 149 Days and 21.2 Hours
Abstract
BACKGROUND
The impact of high-dose radiotherapy (HDRT) on improving clinical complete response (cCR) and organ preservation in rectal cancer remains uncertain.
AIM
To evaluate the efficacy and safety of HDRT (> 54 Gy) compared with standard-dose radiotherapy (45-54 Gy) in patients with clinically staged I-III rectal cancer.
METHODS
We systematically searched PubMed, EMBASE, MEDLINE (via Web of Science), and the Cochrane Library for randomized controlled trials published between January 1, 2014, and November 11, 2024. The primary outcome was cCR; secondary outcomes included pathological complete response, tumour regression grade (TRG) 1-2, organ preservation, grade ≥ 3 toxicity, overall survival, disease-free survival, local recurrence, and distant metastasis.
RESULTS
Seven randomised controlled trials involving 1056 patients were analysed. An improvement in cCR was observed with HDRT (> 54 Gy) compared with standard-dose radiotherapy (45-54 Gy) [risk ratios (RR) = 1.34, 95%CI: 1.00-1.80; P = 0.05]. HDRT showed no significant advantage in pathological complete response (RR = 1.07, 95%CI: 0.77-1.50) but enhanced TRG 1-2 responses (RR = 1.52, 95%CI: 1.16-1.99; P = 0.002). There were no significant differences in rates of organ preservation, grade ≥ 3 toxicity, local recurrence, and distant metastasis between treatment groups. Overall survival and disease-free survival were inconsistently reported and remain inconclusive.
CONCLUSION
HDRT improves cCR and increases the proportion of TRG 1-2 in patients with stage I-III rectal cancer, without significant increase in severe toxicity. These findings suggest that HDRT may enhance the feasibility of organ-preserving strategies in selected patients and highlight the potential of individualized, image-guided dose escalation.
Core Tip: Radiotherapy dose escalation has been investigated as a potential approach to improve tumour response in rectal cancer. In this meta-analysis of randomized controlled trials, high-dose radiotherapy (> 54 Gy) increased clinical complete response and the proportion of patients achieving tumour regression grade 1-2 compared with standard-dose radiotherapy. Importantly, dose escalation did not significantly increase severe toxicity. These findings suggest that radiotherapy dose intensification may enhance tumour response and provide supportive evidence for organ preservation strategies in selected patients with stage I-III rectal cancer.
Citation: Long T, Gao H, He WQ, Xiao WW, Wang XC. High-dose vs standard radiotherapy in rectal cancer: Effects on tumour response, toxicity, and organ preservation. World J Gastrointest Oncol 2026; 18(8): 120904
Rectal cancer, a globally prevalent malignancy, accounts for nearly one-third of all colorectal cancers[1]. The incidence of rectal cancer among individuals under 50 years of age has been increasing over recent decades[2]. For localized rectal cancer (clinical stages I-III), the current standard of care is centred on radical surgery, supplemented by neoadjuvant or adjuvant chemoradiotherapy depending on recurrence risk and the intent of organ preservation[1]. According to current National Comprehensive Cancer Network guidelines, the recommended dose range for long-course radiotherapy is 45-54 Gy. However, the pathological complete response (pCR) rate with standard-dose regimens remains modest at approximately 10%-20%[3], suggesting that conventional dosing may be insufficient to maximise tumour regression. For patients considered for organ-preserving strategies, a total radiotherapy dose of at least 54 Gy is generally required to achieve an adequate tumour response[4]. Biologically, high-dose radiotherapy (HDRT) may promote tumour downstaging through multiple mechanisms, including enhanced induction of DNA double-strand breaks, vascular endothelial damage, immune activation, and modulation of the tumour microenvironment[5,6]. Appelt et al[7] reported a clear dose-response relationship in preoperative chemoradiotherapy for rectal cancer, showing that dose escalation within the range of 50.4-70 Gy significantly improved tumour regression [Mandard tumour regression grade (TRG) 1-2]. This suggests HDRT may promote a deeper tumour response beyond merely enhancing pCR rates. Subsequent studies have confirmed that HDRT combined with chemotherapy can further improve local tumour control and increase the opportunities for organ preservation, potentially providing a non-invasive alternative to abdominoperineal resection, particularly for patients with low rectal cancer[8-10]. Previous meta-analyses of radiotherapy doses have predominantly focused on pathological outcomes, while neglecting comprehensive assessments of clinical complete response (cCR), organ preservation rates, and toxicity[11,12]. Importantly, cCR represents the cornerstone of organ-preserving strategies. Among patients who achieve cCR following neoadjuvant therapy, a watch-and-wait approach substantially increases the likelihood of preserving anorectal function, thereby avoiding permanent colostomy and maintaining favourable quality of life (QoL)[13,14]. To our knowledge, this meta-analysis represents the first systematic synthesis of high-quality randomized controlled trials (RCTs), aiming to comprehensively evaluate the efficacy and safety of HDRT (> 54 Gy) vs standard-dose radiotherapy (SDRT) (45-54 Gy) in patients with clinically staged I-III rectal cancer.
MATERIALS AND METHODS
Study registration and reporting guidelines
This systematic review and meta-analysis was performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline (Figure 1)[15]. The study protocol was registered with PROSPERO (CRD420251017477).
Figure 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of study selection.
Literature search
A comprehensive literature search was conducted by combining the following terms and their related synonyms: (1) Rectal cancer; (2) Radiotherapy; (3) Chemoradiotherapy; (4) High-dose; (5) Boost; and (6) Curative. Searches were performed in MEDLINE (via Web of Science), Cochrane Library, EMBASE, and PubMed to identify studies published between January 1, 2014, and November 11, 2024. Additionally, the reference lists of included studies were manually screened, and potentially eligible studies were further identified through searches of clinical trial registries such as ClinicalTrials.gov and abstracts from major international oncology conferences. Two reviewers independently screened the titles and abstracts and extracted the data in duplicate using a standardised form.
Study selection and inclusion criteria
Two reviewers independently screened the titles, abstracts, and subsequently, the full texts of potentially eligible studies using a standardised form. The inclusion criteria were as follows: (1) RCTs in which neoadjuvant treatment was categorized into a SDRT group (45-54 Gy) and a HDRT group (> 54 Gy); and (2) Patients diagnosed with stage I-III rectal cancer via colonoscopy or magnetic resonance imaging, with staging consistent with indications for neoadjuvant therapy: Clinical T stage 2 or higher (cT2+), regardless of lymph node status on preoperative imaging, and no evidence of distant metastasis.
For multiple publications originating from the same study (e.g., initial results and extended follow-up), they were identified by comparing research institutions, enrollment periods, sample sizes, and baseline characteristics. If overlap was confirmed, only the version with the longest follow-up or the most complete data was included to avoid duplicate patient inclusion. Where different reports provided complementary outcome measures, relevant data were extracted separately for different endpoints.
Data extraction
After full-text review, seven randomised controlled trials met the inclusion criteria and were included in the final meta-analysis[16-22]. Data were extracted independently by two reviewers using a predefined data extraction form. The following information was collected: (1) Study characteristics (first author, year, country, sample size, age, and clinical stage); (2) Treatment details (radiotherapy technique, neoadjuvant regimen, and radiation dose); and (3) Outcomes [cCR, pCR, Mandard TRG 1-2, overall survival (OS), disease-free survival (DFS), grade ≥ 3 toxicity (CTCAE v4.0), organ preservation rate, and local recurrence rate]. The full details of the extracted study characteristics are presented in Table 1. Denominators were defined as follows: (1) PCR was analyzed in the surgical population; (2) The cCR and organ preservation rates were assessed in clinically evaluable population, as defined in each study; and (3) Toxicity was evaluated in the safety population. Additionally, some outcomes were defined as follows: Multiple studies indicate that patients achieving either cCR or near-cCR following total neoadjuvant therapy are typically recommended for a watch-and-wait or organ preservation strategy. Therefore, in this study, cCR and near-cCR were combined into a composite endpoint termed cCR[14,23]. Organ preservation was defined according to the criteria reported in each individual trial and generally referred to retention of the rectum in situ, including non-operative management (Watch-and-Wait) or organ-sparing surgical approaches such as local excision. OS and DFS were extracted and analysed descriptively due to heterogeneity in follow-up duration and reporting formats across studies.
Table 1 Summary of efficacy and safety outcomes for high-dose vs standard-dose radiotherapy in rectal cancer.
The risk of bias for randomised controlled trials was assessed using the Cochrane Risk of Bias Tool (RoB 1.0) implemented in RevMan 5.4, evaluating random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. The results of the risk of bias assessment are summarised in Supplementary Figure 1[16-22].
Statistical analysis
All statistical analyses were performed using RevMan version 5.4. Risk ratios (RR) were calculated for all dichotomous variables. Heterogeneity was assessed using the I² statistic, with I² > 50% indicating substantial heterogeneity and warranting the use of a random-effects model; otherwise, a fixed-effects model was applied. Effect estimates are presented in forest plots and summary tables. All estimates are reported with 95%CI, and a P value < 0.05 was considered statistically significant.
RESULTS
Study selection
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (Figure 1) illustrates the screening process. From initially identified records, seven randomised controlled trials involving 1056 patients met inclusion criteria (high-dose: n = 587; standard-dose: n = 469). The baseline characteristics of the included studies are summarized in Table 2[16-22].
Table 2 Baseline characteristics of included studies, n (%)/median (range).
Among the studies included in the analysis, four studies reported cCR outcomes. The pooled cCR rate was 57.0% (200/351; range, 51.6%-62.2%) in the HDRT group and 50.6% (119/235; range, 44.2%-57.1%) in the standard-dose group. Using a random-effects model, it was observed that HDRT was associated with higher cCR rates (RR = 1.34; 95%CI: 1.00-1.80; P = 0.05; I² = 75%; Figure 2A), although substantial heterogeneity was observed[16,17,19,21]. To further evaluate the robustness of this finding, a leave-one-out sensitivity analysis was performed (Supplementary Table 1)[16,17,19,21]. The pooled effect size ranged from 1.25 to 1.53 across different analyses, with all estimates consistently favoring HDRT. Notably, exclusion of the study by Yariv et al[17] resulted in a marked reduction in heterogeneity (I² from 75% to 0%) and an increased effect estimate (RR = 1.51; 95%CI: 1.28-1.78; P < 0.01; Figure 2B), suggesting that this study was a major contributor to heterogeneity[16,17,19,21]. The imbalance in sample size between the high-dose and standard-dose groups in the study by Yariv et al[17] (210 vs 93) may have contributed to the observed heterogeneity. An additional sensitivity analysis excluding the study by Gerard et al[16], which used contact X-ray brachytherapy (CXB), showed consistent directional results (RR = 1.32; 95%CI: 0.84-2.06). When both this study and the study by Yariv et al[17] were excluded, the pooled estimate increased, reaching 1.62 (95%CI: 1.23-2.15).
Figure 2 Forest plots of tumour response outcomes and safety and disease control outcomes.
A: Forest plot of clinical complete response; B: Forest plot of clinical complete response after exclusion of Yariv et al[17]; C: Forest plot of pathological complete response; D: Forest plot of tumour regression grade 1-2.
Secondary outcomes
Pathological outcome: A total of four studies provided data on pCR. The pCR rate was slightly higher in the high-dose group compared with the standard-dose group (21.1% vs 19.6%), but the difference was not statistically significant (RR = 1.07; 95%CI: 0.77-1.50; P = 0.67; I² = 2%) (Figure 2C)[18-20,22]. Two studies reported TRG 1-2 outcomes, demonstrating a significant increase in the high-dose group (RR = 1.52; 95%CI: 1.16-1.99; P = 0.002; I² = 0%) (Figure 2D)[19,20].
Survival: Survival outcomes were inconsistently reported across studies. OS data were available from four randomised trials, with survival assessed at 3 years in two studies and at 5 years in the remaining two. For DFS, three trials contributed data, including two with 3-year follow-up and one with 5-year follow-up. Owing to heterogeneity in follow-up duration and the lack of consistently reported hazard ratios, quantitative pooling of OS and DFS was not feasible. Across individual studies, Kaplan-Meier analyses showed no apparent separation between the high-dose and SDRT groups, and no trial demonstrated a statistically significant improvement in OS or DFS with dose escalation.
Toxicity and organ preservation: The forest plot for grade ≥ 3 toxicity is presented in Figure 3A[18,19,21,22]. The incidence of grade ≥ 3 toxicity was 20.0% (39/195) in the high-dose group and 14.3% (28/196) in the standard-dose group, representing an absolute increase of 5.7%, which did not reach statistical significance (RR = 1.40; 95%CI: 0.90-2.18; P = 0.13; I² = 0%). Notably, the study by Garant et al[21] reported a markedly higher toxicity risk in the high-dose group RR = 6.00. However, the sample size was small (n = 20 per group) and the confidence interval was wide (0.79-45.42), indicating high uncertainty. After excluding the 2022 study by Garant et al[21], the incidence of grade ≥ 3 toxicity in the high-dose group was 18.9% vs 15.3% in the standard-dose group, with the difference still failing to reach statistical significance (RR = 1.23, 95%CI: 0.78-1.94; P = 0.37; I² = 0%). This figure is presented in Supplementary Figure 2[16-19,21,22].
Figure 3 Forest plots of safety and disease control outcomes.
A: Forest plot of grade ≥ 3 toxicity; B: Forest plot of organ preservation rates; C: Forest plot of local recurrence; D: Forest plot of distant metastasis.
Four studies reported organ preservation outcomes, which in this meta-analysis included both rectal and sphincter preservation. As shown in Figure 3B, the pooled analysis using a random-effects model revealed a higher organ preservation rate in the high-dose group than in the standard-dose group (60.8% vs 55.9%), although this difference was not statistically significant (RR = 1.17, 95%CI: 0.95-1.43; P = 0.15; I² = 71%)[16,17,19,22]. After excluding the study by Yariv et al[17], the effect remained non-significant (RR = 1.29, 95%CI: 0.93-1.78; P = 0.12; I² = 83%), with the corresponding forest plot presented in Supplementary Figure 2[16-19,21,22].
Local recurrence and distant metastasis: Among the four studies reporting local recurrence, the high-dose group exhibited a marginally higher recurrence rate, though without statistical significance (RR = 1.35; 95%CI: 0.81-2.24; P = 0.25; I² = 0%), as shown in Figure 3C[16,18,20,22]. Distant metastasis, reported in three studies, showed similar pooled rates between the high-dose and standard-dose groups (19.3% vs 21.6%), with no significant difference observed (RR = 0.90; 95%CI: 0.64-1.28; P = 0.57; I² = 0%). The corresponding forest plot is shown in Figure 3D[16,20,22].
DISCUSSION
This meta-analysis synthesized RCTs to evaluate the impact of HDRT (> 54 Gy) vs SDRT (45-54 Gy) on survival, toxicity, and organ preservation in patients with stage I-III rectal cancer under contemporary neoadjuvant treatment paradigms. The primary finding was that HDRT was associated with an improvement in cCR rates (RR = 1.34). However, this finding should be interpreted with caution, as the observed effect was borderline statistically significant (P = 0.05) and substantial heterogeneity was present. Sensitivity analyses indicated that, although the magnitude of the effect varied across analyses, the direction of effect consistently favored HDRT. These findings suggest that dose escalation may enable more patients to achieve cCR and become candidates for “watch-and-wait” strategies, thereby increasing the likelihood of organ preservation and avoiding total mesorectal excision, which is associated with substantially improved QoL[2,24]. This observation aligns closely with the principles underlying current organ-preservation trials such as STAR-TREC[25]. Given the heterogeneity in dose ranges and delivery techniques, including EBRT-based dose escalation and endoluminal approaches such as CXB, the present findings should be interpreted as reflecting the overall effect of dose intensification strategies rather than a single, biologically uniform modality.
Our findings are consistent with prior prospective studies. Appelt et al[26] investigated patients with distal rectal adenocarcinoma (≤ 6 cm from the anal verge, T2-3, N0-1) using a regimen of external beam radiotherapy (60 Gy/30 fractions to the tumour, 50 Gy/30 fractions to elective lymph nodes) plus a 5 Gy endorectal brachytherapy boost, achieving a cCR rate of 78% (40/51). Similarly, Jensen et al[27] investigated patients with low rectal cancer (T1-3, N0-1) who received 62 Gy to the primary tumour delivered in 28 fractions, concurrently with capecitabine. A cCR was observed in 86.0% of patients (92/107), with 61% (63/103) maintaining locoregional tumour control at two years of follow-up. Additional smaller studies have corroborated that radiotherapy dose escalation may improve cCR rates while concurrently reducing the risk of local recurrence[10,28,29]. A randomised trial comparing dose-escalated regimens in the APHRODITE trial (ISRCTN16158514) is ongoing, with the high-dose group receiving 62 Gy in 28 fractions to the tumour region and cCR at 6 months as the primary endpoint, aiming to evaluate the efficacy of non-surgical management for early rectal cancer. It is noteworthy that HDRT is commonly delivered via sequential boosts rather than in a single course[30]. For instance, Wang et al[31] applied standard pelvic irradiation of 45-50 Gy, followed by an additional 20-30 Gy boost to the primary tumour and involved lymph nodes.
Several previous studies have consistently demonstrated that radiotherapy dose escalation can improve pCR[32-35]. The survey by Burbach indicated that elevating preoperative radiotherapy doses to an equivalent dose in 2 Gy ≥ 60 Gy achieved a pCR rate of 20.4% in patients with locally advanced rectal cancer, significantly surpassing the 15% observed in the standard-dose group[11]. However, our study did not observe a significant improvement in pCR within the high-dose group. There are several possible explanations. First, the present analysis was restricted to randomised controlled trials directly comparing different radiation doses, which provides a more conservative estimate than single-arm or observational studies. Second, the included dose range primarily concentrated between 54-56 Gy, whereas prior studies demonstrating pCR benefit frequently employed ≥ 60 Gy, suggesting a potential dose-threshold effect. This indicates that dose escalation promotes tumour downstaging, although such improvements do not necessarily translate into higher pCR rates. Mandard TRG 1-2 is widely regarded as a “good responder” category and has been associated with favourable long-term outcomes following neoadjuvant chemoradiotherapy for rectal cancer[36]. Lupattelli reported that radiation doses ≥ 50 Gy were associated with a favorable trend toward major response (TRG 1-2), which aligns with our findings[37]. Recent studies have increasingly focused on enhancing tumour sensitivity through immunomodulation. Trials such as VOLTAGE[38] and PANDORA[39] have reported encouraging pCR rates with the addition of programmed death 1 inhibitors to long-course chemoradiotherapy. This implies that, rather than relying solely on dose escalation, integrating immunotherapy with chemoradiotherapy may represent a feasible therapeutic option.
This study did not demonstrate a significant increase in grade ≥ 3 toxicity with HDRT, providing supportive evidence for its feasibility and safety. However, specific toxicity profiles warrant careful consideration. In the study by Dizdarevic et al[8], rectal bleeding was the only significantly worsened toxicity, occurring in 81% (21/26) of patients, with 27% (7/26) experiencing moderate or severe bleeding at 24 months. This was likely related to the high mucosal dose from endorectal brachytherapy, necessitating stricter dose constraints for normal mucosal tissues during radiotherapy[40]. Previous studies have shown that the predominant acute toxicity of dose-escalated radiotherapy is diarrhea, whereas rectal bleeding is the main late toxicity[31,34]. Radiation injury may lead to obliterative endarteritis and capillary dilatation within the rectal wall, subsequently triggering delayed bleeding[41]. Clinically, treatments such as formalin enemas[42], sucralfate retention enema, argon plasma coagulation[41,43], radiofrequency ablation[44], and hyperbaric oxygen therapy[45] are used to manage rectal haemorrhage. The tolerance of organs at risk is a key constraint on dose escalation, requiring strict dose limits for structures such as the bladder and small bowel[46]. Excessive dosing may further exacerbate rectal bleeding and other toxicities. Therefore, any strategy involving dose intensification should balance potential improvements in tumour response against the risk of increased toxicity. Crucially, beyond traditional clinician-reported toxicities, the impact of dose escalation on functional sequelae and long-term QoL warrants careful consideration. While dose intensification may transiently worsen patient-reported symptoms in the early post-treatment period, these differences appear to diminish over time[47]. Moreover, recent data suggest that CXB combined with (chemo)radiotherapy does not adversely affect QoL at one year, supporting its role in shared decision-making for selected patients[48].
Although statistical significance was not reached (60.8% vs 55.9%, RR = 1.17, P = 0.15), the 4.9% absolute increase in organ preservation was observed, suggesting a potential trend. Evidence from prior studies supports a beneficial effect of dose escalation on organ preservation. In a retrospective cohort of cT2N0 rectal cancer, extended chemoradiotherapy (54 Gy with consolidation chemotherapy) was associated with a higher 5-year organ preservation rate than standard treatment (67% vs 30%, P = 0.001), without compromising surgery-free survival after cCR[49].
Similarly, Wang et al[31] reported an 85.3% sphincter preservation rate in patients with non-metastatic rectal tumours within 3 cm of the anal verge, treated with dose-escalated EBRT to a median of 80 Gy. Danish studies (WW2) indicate that definitive chemoradiotherapy can achieve disease control in many patients with early low rectal cancer, showing that 62 Gy can be safely delivered to a confined target volume in 2.2-Gy fractions[27]. The ongoing WW3 randomized trial, with 2-year rectal preservation as its primary endpoint, is designed to compare high-dose vs SDRT in terms of rectal preservation outcomes in patients with early rectal cancer[50].
In carefully selected patients, particularly those with small-volume or distal tumours, additional dose intensification using endoluminal techniques such as CXB may further enhance organ preservation. In the Lyon R96-02 trial, the addition of CXB to EBRT significantly improved sphincter preservation compared with EBRT alone (76% vs 44%, P = 0.04)[51]. The OPERA trial further demonstrated that a CXB boost markedly increased 3-year organ preservation in cT2-T3 rectal adenocarcinoma, achieving rates up to 97% in tumours < 3 cm[16]. CXB delivers an extremely high ablative single-fraction dose (25-35 Gy), resulting in rapid tumour regression, with early cCR observed within two weeks in tumours measuring approximately 2.5 cm[46]. Furthermore, for elderly or frail patients who are unfit for surgery, for those with a poor initial treatment response, or for patients with distal rectal cancer in whom rectal preservation is particularly desirable, high-dose chemoradiotherapy offers an important non-operative treatment option[16,26,52].
Advances in radiotherapy technology may further enhance the therapeutic index of dose escalation. A recent study demonstrated that intraluminal brachytherapy used to intensify total neoadjuvant therapy improved pCR and sphincter preservation in distal rectal cancer, facilitated by image-guided volume-adaptive delivery[53]. An ongoing magnetic resonance-guided adaptive dose-escalation trial has shown that real-time adaptive magnetic resonance imaging-based radiation therapy enables safe escalation to a total dose of 72 Gy, offering the prospect of improved local control[54]. In parallel, Nathan Hear is conducting a prospective study evaluating diffusion-weighted magnetic resonance imaging-guided dose escalation for locally advanced rectal cancer (ACTRN12620000757910). Collectively, these advances underscore the growing role of imaging in individualising radiotherapy, enabling more precise tumour targeting and adaptive dose modulation[55]. Overall, the future development of HDRT will likely center on image-guided treatment and personalized dose escalation, with the aim of expanding the population eligible for organ-preserving approaches.
Controversy persists regarding whether specific T stages derive differential benefit from HDRT. Domingo-Boluda et al[34] identified T stage as an independent predictor of pathologic complete response after neoadjuvant therapy (ypCR), with T2 tumours showing the most favourable likelihood of achieving complete pathological remission (P = 0.01). In contrast, Nicosia et al[32] observed that dose escalation produced more pronounced pCR benefit in patients with cT3-T4 tumours, with cT3 tumours exhibiting a significantly higher downstaging rate under intensified treatment (62.1% vs 49.4%, P = 0.002). Conversely, cT2 tumours appeared less likely to derive further benefit from additional dose escalation. Similarly, a prospective study by Bertocchi et al[56] demonstrated a significant downstaging benefit of HDRT in T3 tumours (P = 0.049), with 67.9% downstaged to pT0-pT2. Current evidence suggests that the benefit of HDRT may be stage-dependent, with the greatest advantage observed in T3 tumours. However, these findings largely stem from single-centre studies with limited sample sizes, underscoring the need for adequately powered trials to validate this hypothesis.
We observed no significant differences between the high-dose and standard-dose groups in terms of local recurrence or distant metastasis, indicating that dose escalation does not appear to compromise curative oncologic outcomes. Specifically, the trend toward a higher local recurrence rate in the HDRT group (RR = 1.35), though not statistically significant (P = 0.25), may be related to the increased utilization of organ-preservation pathways in these patients. Meanwhile, patients in the standard-dose group may have undergone immediate tumor microenvironment, which removes the primary tumour and may reduce the likelihood of local regrowth. In contrast, analysis of National Cancer Database data by Wegner et al[57] showed that, among patients managed non-operatively, dose escalation (> 54 Gy) did not confer a survival benefit compared with SDRT (≤ 54 Gy) and was instead associated with poorer long-term survival. Importantly, patients receiving dose-escalated radiotherapy in that cohort were generally older, carried a greater burden of comorbidities, and were more often medically unfit for surgery, which may have contributed to the observed survival disadvantage. Taken together, these observations highlight the need for adequately powered prospective trials to determine the true influence of HDRT on long-term survival.
Limitations
This study has several limitations. First, the number of eligible RCTs was limited, which may have reduced the statistical power for certain secondary outcomes and subgroup analyses. Second, substantial heterogeneity was observed in cCR and organ preservation outcomes, likely reflecting variations in radiotherapy techniques, concurrent treatments, and outcome definitions across studies. Third, cCR and near-cCR were analysed as a composite endpoint in some included studies, which may introduce variability in outcome assessment, although this approach reflects real-world clinical decision-making. Therefore, these findings should be interpreted with caution.
CONCLUSION
In the neoadjuvant treatment of stage I-III rectal cancer, this study indicated that HDRT (> 54 Gy) improved cCR rates and increased the proportion of patients achieving TRG 1-2 compared with SDRT, without significantly increasing severe toxicity. These findings support organ preservation strategies and underscore the potential of integrating dose escalation with advanced image-guided and endoluminal brachytherapy techniques to enable individualised, precision radiotherapy.
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P-Reviewer: Meng QY, PhD, China; Ren S, MD, PhD, Assistant Professor, Chief Physician, Postdoctoral Fellow, China; Wang HL, Professor, China S-Editor: Luo ML L-Editor: A P-Editor: Lei YY
