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ISSN: 3068-014X | DOI: 10.33140/ADCI

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Research Article - (2026) Volume 2, Issue 1

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Efficacy of Short-Term Versus Long-Term Radiotherapy in Rectal Cancer: A Frisbee-Based Meta-Analysis (A Friendly Evidence-Based Review of The Literature)

Gustavo Gomez Barbieri 1,2 *, Giovanni Petracca 2,3 and Antonella Capomolla 2,3
 
1Faculty of Medicine, Sapienza University, Italy
2G. Jazzolino Hospital, Vibo Valentia, Calabria, Italy
3Magna Graecia University, Catanzaro, Italy
 
*Corresponding Author: Gustavo Gomez Barbieri, Faculty of Medicine, Sapienza University, Italy Gustavo Gomez Barbieri, G. Jazzolino Hospital, Vibo Valentia, Calabria, Italy

Received Date: Sep 06, 2025 / Accepted Date: Nov 24, 2025 / Published Date: Jan 23, 2026

Copyright: ©2026 Gustavo Gomez Barbieri, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation: Barbieri, G. G., Petracca, G., Capomolla, A. (2026). Efficacy of Short-Term Versus Long-Term Radiotherapy in Rectal Cancer: A Frisbee-Based Meta-Analysis (A Friendly Evidence-Based Review of The Literature). Arch Cienc Investig, 2(1), 01-06.

Abstract

Introduction Rectal cancer is the second most common cancer in Italy, with nearly 50,000 cases expected by 2024. Given the high cost and quality of life for its families, its mortality rate is low, ranging from 5 to 7% in the early stages too high in the advanced stages, with a mortality rate of 90%.

Methods A search was conducted in Epistemonikos, the largest database of systematic reviews in the healthcare field, maintained by screening multiple sources of information, including MEDLINE, EMBASE, and Cochrane, among others. Data were extracted from the identified reviews, data from the primary studies were analyzed, a meta-analysis was performed, and a summary table of the results was prepared using the GRADE method.

Results and Conclusions Six systematic reviews were identified, which together include thirty-seven primary studies, of which 37 correspond to randomized trials. It was concluded that the use of short-term IMRT plus immediate chemotherapy compared to neoadjuvant chemotherapy, surgery, and radiotherapy increases local control and disease-free survival and reduces complications and the need for surgery compared to long-term radiotherapy, with a high degree of evidence.

Keywords

RAP, TME, LAR, Opthra Protocol, Long-Term Survival Protocol, Rectal Cancer, IMRT Radiotherapy, Hospitalization, Epistemonikos, GRADE

Problem

Rectal cancer is the third most common cancer with the highest incidence and mortality worldwide and the first in terms of years of life lost. (Globocan, 2020) A study in medical history reveals the first wide abdominoperineal resection (RAP), which later became more common, followed by low anterior resection (LAR). More recently, the emphasis on TME (half-rectal transection) has significantly improved locoregional disease control rates thanks to en bloc resection of the mesorectum, which contains the perirectal lymph nodes, the first level of drainage of the rectal lymph nodes. (Khullar, 2022) Beginning in the 1970s, the first clinical trial evaluating local control and recurrence for surgery alone, surgery plus chemotherapy, radiotherapy plus chemotherapy, and radiotherapy plus surgery demonstrated that surgery and radiotherapy provided greater local control and subsequently improved overall patient survival. It was with the advent and improvement in the application of 2D radiotherapy concurrent with surgery that disease-free survival, as well as overall survival, improved. Sauer, in 2004, demonstrated that the combination of chemotherapy, surgery, and 2D radiotherapy in a long-term regimen improved local control but not overall survival. This paradigm has remained entrenched in clinical practice for the past 20 years.

Nowadays, with the advent of next-generation sequencing techniques and the genetic study of colorectal cancers, several drug targets and tumor markers have been discovered, which have made it possible to recognize genetic models of these tumors such as hereditary tumors such as familial adenomatous polyposis (FAP) due to mutations in the gene that regulates the degradation of beta-catenin and overexpression of the wnt-frizzled pathway causing the appearance of hundreds of polyps in the colon and Lynch syndrome explained by the Knudson double-hit theory where there are mutated genes acquired as hereditary, causing the development of multiple breast, ovarian and prostate tumors in multiple relatives.

Even in this 10% of cases, therefore, the new therapy will focus on gene therapy and immunotherapy, as well as the development of molecular scissors, gene editing, and genetic tweezers that modulate the expression and silence the activity of gene families through histone methylation and demethylation, which epigenetically regulate rectal cancer. Hereditary factors have been identified in these 20% of rectal cancers, and in the remaining 70%, risk factors such as alcohol, tobacco, a lack of plant-based diets, high salt and dried meat consumption, and lack of physical activity explain the development of these diseases, as well as ulcerative colitis and Crohn’s disease. Therefore, now more than ever, it is necessary to develop new therapies that involve not only the resection and treatment of a highly preventable disease with a high disease burden, but also the development of genetic vaccines that prevent the spread and persistence of this disease. Radiotherapy, chemotherapy, and surgery must evolve into a personalized, comprehensive precision medicine therapy that covers all variants of this set of diseases, which include cancer. Colorectal cancer, and in this case, rectal cancer.

In recent years, this clinical protocol, the cornerstone of treatment, has been questioned, with claims that it does not improve patient outcomes. On the contrary, IMRT radiotherapy technology contributes to improved dose fractionation and image resolution, optimizing planning, improving quality, and reducing complications and patient mortality.

Methods

We conducted a search in Epistemonikos, the largest database of systematic reviews in healthcare, which is maintained by searching multiple sources of information, including MEDLINE, EMBASE, Cochrane, and others. We extracted data from the identified reviews and analyzed data from the primary studies. With this information, we generated a structured summary called FRISBEE (Friendly Summaries of Body of Evidence using Epistemonikos), following a predefined format. This summary includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analyses of the total studies where possible, a GRADE summary table of results, and a section on other considerations for decision-making.


                      Regarding the body of evidence for this question

 

 

What is the evidence? See evidence matrix in Epistemonikos below.

We                           found                           six                            systematic reviews [4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] that collectively included 37 primary studies addressing the clinical question, 37 of which were randomized controlled trials. This table and the summary in general are based on these latter studies, since observational studies did not increase the certainty of the existing evidence or provide any additional relevant information.

 

 

 

 

What type of patients did the studies include?*

All trials included patients with T2 to T4 rectal cancer, diagnosed clinically, by colonoscopy, and by magnetic resonance imaging (MRI) with  computed  tomography  (CT)  and/or positron emission tomography (PET). All patients included were over 18 years of age [15][16]. The age range in one trial was 48–79 years [15], while in the other, the mean age was 60.56 years [16].

 

Patients with a diagnosis or suspicion of other diseases on CT, such as colon cancer and inflammatory bowel disease, were excluded. One trial included patients with a history of previous acute diverticulitis [15].

 

 

 

 

What types of interventions did the studies include?*

One trial used the intervention of administering 25 Gy IMRT in 5 short-course sessions without delay to chemotherapy or the need for surgery. The Stockholm III trial included an intervention with and without a 5- to 6-week delay to chemotherapy [15].

 

The other trial used the intervention of administering 60 Gy IMRT in 15 fractions followed by surgery and chemotherapy with a 6-week delay [16].

 

For comparison, both trials used one treatment, chemotherapy alone, surgery alone, and IMRT regimens with and without delay [15]. Trials using brachytherapy or comparing surgery with radiotherapy or chemotherapy alone were excluded from this study [16].

 

What kind of outcomes did they me

The outcomes measured were as follows: Overall survival Local recurrence

Local control Quality of life

 

Follow-up in both trials was 5.5 years[15][16].

Effectiveness of short versus long radiotherapy regimen in patients with locally advanced rectal cancer

Patients                      Pacientes en tratamiento por cáncer de recto localmente avanzado T2-T3 Y T4

Intervention                Radioterapia

Comparison                Radioterapia de esquema corto versus largo

 

Desenlaces

Absolut effect *

Efecto relativo (IC 95%)

Certeza de la evidencia (GRADE)

RT SC

RT LC

Difference: patie 1000

Overall Survival (5 years)

362 per 1000

333 per 1000

RR 0.97

(0.88 a

1.07)

⊕⊕⊕⊕

Alta

Difference: 29 más

(26 less to 31 plus)

Local recurrence (5 years)**

79 per 1000

121 per 1000

RR 0.65

(0.47 a

0.88)

⊕⊕⊕⊕

Alta

42 less per 1000

(from 64 less to 15 less)

 

Toxicity

147 per 1000

150 per 1000

RR 0.94

(0.79 a

1.12)

 

⊕⊕⊕1,2

MODERADA

9 less per 1000

(de 31 menos a 18 más )

 

R0 resection rate

886 per 1000

953 per 1000

RR 0,93

(0,81 a

1,07)

 

⊕⊕ 1,2

MODERADA

Diferencia: 67 less per 1000

( 54 less to 72 plus)

 

Overall Quality of life

240 per 400

242 per 400

RR 0,99

(0,99 a

1,09)

 

⊕ ⊕ oo¯ 1,2

Baja

7 menos por 1000

(de 63 menos a 63 más)

Margin of error: 95% confidence interval (95% CI).

 

RR: Relative risk.

MD: Mean difference.

GRADE: GRADE Working Group levels of evidence (see below).

 

*Risks/averages are based on the risks/averages of the control group in the studies. The risk/average (and its margin of error) is calculated from the relative effect/mean difference (and its margin of error).

  1. The certainty of evidence was lowered by one level due to risk of bias, as the evaluated studies exhibit selection bias, detection bias, and reporting bias.
  2. The certainty of evidence was lowered by one level due to imprecision, since evaluating each end of the relative effect result promotes different clinical approaches.
  3. The certainty of evidence was lowered by one level due to inconsistency, because there is heterogeneity among the evaluated studies, which is expressed by an index I² > 70%.
           


 

Regarding the certainty of the evidence(GRADE)*

High: The investigation has a very good indication of the probable effect. The probability that the effect will be substantially different is low.

 

Moderate: The investigation enters into a good indication of the probable effect. The probability that the effect will be substantially different is moderate.

 

Low: The investigation has some indication of the probable effect. Sin embargo, the probability that the effect will be substantially different is the same.

 

Well, the investigation does not involve a reliable estimate of the probable effect. The probability that the effect is substantially different is very high.

*This is also referred to as ‘quality of evidence’ or ‘confidence in effect estimates’.

 

†Substantially different = a difference large enough to affect the decision.

Otras consideraciones para la toma de decisión

To whom does this evidence apply and to whom does it not apply?

The results of this study apply to patients with T2 and T4 stage rectal cancer without metastasis, managed in an inpatient setting.

  • These results could be extrapolated to adult patients without recurrence, without metastatic involvement, with diverticular or polyposis disease, who are immunocompetent, without decompensated comorbidities, and without signs of sepsis.
  • This evidence does not apply to pregnant patients or those in the lactation period.

Regarding the outcomes included in this summary
  • The outcomes selected in the summary of results table are those considered critical for clinical decision-making, according to the opinions of the authors of this summary, the clinicians who perform these treatments, and the patients treated at our center. These outcomes are consistent with those reported in the systematic reviews.
  • The outcome of local recurrence was considered relevant for decision-making by the authors; however, quality

of life and toxicity were not reported in all the systematic reviews evaluated.

Balance of risk/Benefits and certainly of evidence.
  • The body of evidence shows a benefit of short-course versus long-course treatment for recurrence, overall survival, and PFS outcomes; however, the certainty of the evidence was assessed as low for quality of life.
  • For readmission and length of hospital stay, it is not possible to draw a conclusion regarding the harm or benefit of the intervention, given the very low certainty of the evidence.
  • Although the evidence presented does not show a benefit of short-course over long-course treatment, it is possible to make an appropriate assessment of risks and benefits due to the existing uncertainty about its effects, associated with the limitations of the available evidence.

Consideration of the recommendation

Some systematic reviews analyzed in this summary mention that long-course versus short-course treatment may be equivalent.

  • It is also noted that in patients where the clinician chooses a short-course over a long-course regimen, quality of life improves, and there is a lower risk of radiation colitis and perforation, as well as a greater chance of rectal resection [5].
  • However, considering the heterogeneity of the studies, we can also state with moderate evidence, and in one randomized controlled trial (RCT) with high evidence due to the longer follow-up period and larger sample size, that the short-course regimen is more cost-effective

than the long-course regimen.

What do you think about patients and clinicians

While there is considerable national debate about whether the short-course versus the long- course regimen should be used, evidence suggests that two clinical trials, including RAPIDO, achieve the same disease-free survival (DFS) as OPRA in patients with a much worse prognosis. Which, then, is the best treatment? In T4 tumors, OPRA has 11% versus RAPIDO 32% disease survival, OPRA 28%, RAPIDO 9%, OPRA 76%, and RAPIDO 76%. It's worth noting that RAPIDO has a 4.6-year follow-up period compared to OPRA's 3 years. Furthermore, RAPIDO randomized 912 patients, while OPRA randomized 324. There is no reason to choose the OPRA protocol over the RAPIDO protocol.

 

  •   The use of one therapy over another is justified by a shorter treatment time, optimized resource use, and improved patient adherence to treatment, which in turn leads to an improved quality of life.
  •   The toxicity observed in the longer regimen is avoided in the shorter regimen because it is administered simultaneously and without delay (Hospers, 2020). [28,29]
  • Patients' quality of life is not compromised at 3 years according to the study by

Hospers, 2020. [28,30]

Difference between this summary and another research.
  • The 2020 NICE Guideline considers 4 RCTs with a follow-up period of 2.9 to 5.9 years, conferring a moderate level of evidence. Two RCTs (N = 635; median follow-up of 4 to 5.9 years) showed no clinically important differences in overall survival between receiving short-course preoperative radiotherapy with immediate surgery and receiving long-course preoperative radiotherapy (chemotherapy) in patients with non-metastatic rectal cancer. Moderate-quality evidence from one RCT (N = 150; median follow-up of 5 years) showed that receiving short-course preoperative radiotherapy with delayed surgery demonstrated a clinically important decrease in overall survival compared with receiving long-course preoperative radiotherapy (chemotherapy) in patients with non- metastatic rectal cancer. Moderate-quality evidence from one RCT (N = 515; median follow-up of 2.9 years) showed no clinically important differences in overall survival. between receiving 19 short-course preoperative radiotherapy with consolidation chemotherapy and 20 who received long-course preoperative chemoradiotherapy in patients with non-metastatic rectal cancer. • Moderate-quality evidence from 1 RCT (N = 357; median follow-up of 5.2 years) showed that receiving short-course preoperative radiotherapy did not show clinically important differences in overall survival compared with long-course radiotherapy in 25 patients with non-metastatic rectal cancer.

¿Can that change this information in the future?
  • The information presented in this evidence summary is likely to change over time regarding recurrence, complications, and emergency surgery outcomes, as the certainty of the evidence is low. For readmission and length of hospital stay, the information is very likely to remain unchanged, given the very high and moderate certainty of the evidence.
  • Two ongoing systematic reviews were identified through a search of PROSPERO [21][22].
  • No ongoing trials were identified in the World Health Organization's international clinical trial registry platform.
  • It is worth noting that the authors of this summary believe it would be very interesting to

study this same clinical question within an outpatient setting.

                                                                 Table 1: Information on the Evidence Set for this Question

Summary of Evidence

Information Both studies measured local control, local recurrence, overall survival, quality of life (1,151 patients), and recurrence (1,110 patients) [15,16].

The summary of the results is as follows:

It is possible to clearly establish whether the use of short-course RT compared to long-course RT results in better local control (high certainty of evidence). The use of short-course RT may result in a slight improvement in quality of life or no difference in quality of life (low certainty of evidence); however, given the large heterogeneity between studies and measures, further evidence is needed to confirm this (low certainty of evidence). The use of short-course RT will result in better local control, disease-free survival, and less recurrence (high certainty of evidence). The use of the short-term Rt regimen presents lower toxicity than the long- term regimen, an essential pillar of the birth of this regimen (high certainty of the evidence).

How We do this Meta-Analysis

Using automated and collaborative methods, we collect all the evidence relevant to the question of interest and present it in an evidence matrix.

Follow the link to access the interactive version: Link to the relationship matrix from

http:/ /www.epistemonikos.org/matrixes/630fa7ab7d- b23a429db05042

If new systematic reviews on this topic are published after this summary is published, a “new evidence” alert will appear at the top of the matrix. While the project plans to update these summaries periodically, users are encouraged to comment on the Medwave website or contact the authors by email if they believe there is evidence justifying an earlier update.

After creating an Epistemonikos account, saving your matrices will automatically notify you whenever new evidence potentially answers this question.

This article is part of the Epistemonikos evidence synthesis project. It is prepared using a predefined methodology, following rigorous methodological standards and an internal peer review process. Each of these articles corresponds to a summary, called FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos)whose primary objective is to synthesize the body of evidence for a specific question in a format that is friendly to clinical professionals. Its main resources are based on the Epistemonikos evidence matrix and the analysis of results using the GRADE methodology.

The Epistemonikos Foundation is an organization that seeks to bring information closer to healthcare decision makers through the use of technology. Its main development is the Epistemonikos database ( www.epistemonikos.org ).

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