Short-course radiotherapy followed by consolidation chemotherapy may allow selected patients with locally advanced rectal cancer to avoid radical surgery while maintaining acceptable mid-term cancer control, according to a retrospective study published in Clinical and Translational Radiation Oncology.
The study, conducted in a public healthcare setting in Chile, found that 37.3% of evaluable patients achieved a clinical complete response following short-course radiotherapy-based total neoadjuvant therapy (TNT). Among patients subsequently managed with a watch-and-wait strategy, 16.7% experienced local tumor regrowth, with all cases successfully treated through salvage surgery achieving negative resection margins.
The findings provide additional evidence supporting response-adapted organ preservation using short-course radiotherapy, particularly in healthcare systems where access to prolonged radiotherapy schedules may be limited.
Why Organ Preservation Matters in Rectal Cancer
Total neoadjuvant therapy has significantly changed the management of locally advanced rectal cancer by integrating systemic chemotherapy and radiotherapy before definitive treatment.
Traditionally, total mesorectal excision (TME) has been the standard surgical approach for locally advanced rectal cancer. Although effective, surgery can be associated with substantial morbidity, including bowel dysfunction, urinary and sexual complications, and the possibility of a permanent stoma.
For patients who achieve a clinical complete response after neoadjuvant treatment, nonoperative management through a watch-and-wait strategy has become an important alternative.
Watch-and-wait involves avoiding immediate radical surgery while maintaining intensive surveillance to detect local tumor regrowth at an early and potentially salvageable stage.
Much of the evidence supporting this approach comes from studies using long-course chemoradiotherapy.
However, short-course radiotherapy, typically delivered as 25 Gy in five fractions, has become an established component of TNT regimens and may offer advantages in treatment accessibility and resource utilization.
Whether short-course radiotherapy-based TNT can consistently support safe organ preservation remains an important clinical question.
Study Design and Patient Population
Researchers conducted a retrospective, single-center cohort study at a public tertiary hospital in Santiago, Chile.
The study included patients treated between January 2020 and December 2023 with biopsy-confirmed stage II–III locally advanced rectal adenocarcinoma.
Eligible patients had cT3–T4 and/or node-positive disease, clinically palpable tumors located within 8 cm of the anal verge, and ECOG performance status of 0–1.
A total of 62 patients initiated treatment, while 51 completed the treatment and assessment pathway and were included in the final efficacy analysis.
The median age of the initial cohort was 63 years, and the median tumor distance from the anal verge was 6 cm.
The study aimed to evaluate whether a response-adapted treatment strategy could allow patients achieving a clinical complete response to preserve their rectum without compromising mid-term oncologic outcomes.
Treatment Protocol
All patients received short-course radiotherapy consisting of 25 Gy in five consecutive daily fractions of 5 Gy.
Radiotherapy was delivered using three-dimensional conformal radiotherapy (3D-CRT), reflecting the equipment available within the public healthcare setting.
Following radiotherapy, patients received consolidation chemotherapy with either nine cycles of FOLFOX6 or six cycles of CAPOX.
Consolidation chemotherapy was preferably initiated 11–18 days after completion of radiotherapy, and no later than four weeks.
Tumor response was assessed 8–12 weeks after completion of the entire TNT regimen.
The evaluation included digital rectal examination, flexible sigmoidoscopy, high-resolution pelvic MRI, and carcinoembryonic antigen (CEA) measurement.
Patients achieving a clinical complete response were offered watch-and-wait management, while those with incomplete response underwent total mesorectal excision.
Near-complete responders were reassessed after an additional 6–8 weeks to determine whether further tumor regression had occurred.
Clinical Complete Response and Organ Preservation
Among the 51 evaluable patients, 19 patients (37.3%) achieved a clinical complete response after short-course radiotherapy-based TNT.
Of these, 18 patients entered the watch-and-wait protocol, representing 35.3% of the evaluable cohort.
One patient with a clinical complete response underwent surgery because of severe symptomatic post-radiation rectal stenosis that prevented adequate endoscopic surveillance.
The remaining 33 patients underwent total mesorectal excision.
In the surgical cohort, four patients (12.1%) achieved a pathological complete response.
Overall, 22 of the 51 evaluable patients (43.1%) achieved either a clinical or pathological complete response.
These findings suggest that short-course radiotherapy followed by consolidation chemotherapy can produce substantial tumor regression in a proportion of patients with locally advanced rectal cancer.
Local Regrowth and Salvage Surgery
After a median follow-up of 43.2 months in the watch-and-wait group, three of the 18 patients (16.7%) developed local tumor regrowth.
The median time to local regrowth was 14.8 months.
Importantly, all three patients underwent successful salvage total mesorectal excision with R0 resection margins.
Two remained disease-free at the last follow-up. One subsequently developed lung and brain metastases and died from systemic progression.
The estimated local regrowth-free survival was:
- 88.5% at 12 months
- 82.2% at 24 months
- 82.2% at 36 months
No additional local regrowth events were observed after 24 months during the available follow-up.
Thirteen of the 18 watch-and-wait patients (72.2%) maintained a sustained clinical complete response without any oncologic event.
At the last follow-up, 15 patients, corresponding to 29.4% of the evaluable cohort, had avoided total mesorectal excision. This included 13 patients without an oncologic event and two patients who developed distant metastases without local regrowth.
Disease-Free and Overall Survival
The researchers also reported disease-free survival and overall survival outcomes for the watch-and-wait and surgical cohorts. At 24 months, estimated disease-free survival was 77.0% in the watch-and-wait group and 49.4% in the surgical group.
Estimated overall survival at 24 months was 100% and 74.6%, respectively. However, these outcomes should not be interpreted as demonstrating superiority of watch-and-wait over surgery.
Patients were assigned to treatment according to their response to TNT rather than randomization.
Those undergoing surgery generally had less favorable tumor characteristics, including more advanced disease and residual tumor after neoadjuvant treatment. The authors therefore presented survival outcomes descriptively without formal comparative testing.
Safety and Treatment Feasibility
The study also highlights important safety considerations.
Of the 62 patients who initially started treatment, 11 were excluded from the efficacy analysis because of treatment-related or intercurrent mortality, major vascular events, severe toxicity or treatment discontinuation, or early disease progression.
Three treatment-related deaths were reported in the initial cohort, including two pulmonary embolisms and one case of neutropenic enterocolitis.
Other serious events included ischemic stroke, status epilepticus, severe febrile neutropenia, and gastrointestinal toxicity.
In the surgical cohort, one patient died in the perioperative period due to hemoperitoneum and anastomotic leakage.
The study did not systematically evaluate acute and late toxicity using standardized CTCAE grading or collect patient-reported functional outcomes.
These limitations are important when assessing the overall risk-benefit balance of short-course radiotherapy-based TNT and nonoperative management.
Watch-and-Wait Surveillance
Structured follow-up was a central component of the organ-preservation strategy.
During the first two years, patients underwent digital rectal examination, CEA testing, and flexible sigmoidoscopy every four months, pelvic MRI every six months, and annual CT imaging.
Surveillance frequency was subsequently reduced between years three and five.
This intensive approach was designed to identify local regrowth early, when salvage surgery may remain feasible.
The successful R0 salvage resections observed in all three patients with local regrowth underline the importance of maintaining a reliable surveillance pathway.
Implications for Resource-Limited Healthcare Systems
An important aspect of the study is its real-world setting.
The protocol was implemented within a public healthcare system where radiotherapy capacity and access to advanced treatment techniques were limited.
Short-course radiotherapy allows pelvic irradiation to be completed in five treatment sessions, rather than over several weeks.
This shorter schedule may reduce the burden on radiotherapy services, improve treatment accessibility, and allow systemic chemotherapy to begin earlier.
The investigators demonstrated that response-adapted organ preservation could be integrated into this treatment pathway without relying on routinely available IMRT or advanced adaptive radiotherapy.
However, the authors emphasize that careful patient selection, multidisciplinary decision-making, and structured follow-up remain essential.
Clinical Interpretation
The findings add to growing interest in short-course radiotherapy-based TNT as a potential platform for organ preservation.
While established watch-and-wait data largely come from long-course chemoradiotherapy protocols, this study suggests that meaningful clinical complete response rates can also be achieved with five-fraction radiotherapy followed by consolidation chemotherapy.
The 16.7% local regrowth rate and successful salvage surgery in all affected patients are encouraging.
Nevertheless, the small sample size, retrospective design, selection bias, and differences in follow-up between treatment groups limit the conclusions that can be drawn.
The absence of systematic late toxicity and quality-of-life assessment also leaves important questions unanswered.
Prospective studies with larger populations and longer follow-up will be needed to better define optimal patient selection, treatment sequencing, local regrowth risk, and long-term functional outcomes.
Clinical Takeaway
Short-course radiotherapy-based total neoadjuvant therapy may support organ preservation in carefully selected patients with locally advanced rectal cancer who achieve a clinical complete response.
In this retrospective study, 37.3% of evaluable patients achieved a clinical complete response, and 35.3% entered a watch-and-wait protocol. Local regrowth occurred in 16.7% of watch-and-wait patients, with all cases successfully salvaged through R0 surgery.
The findings support the feasibility of response-adapted organ preservation using short-course radiotherapy, including in resource-limited public healthcare settings.
However, the serious adverse events observed in the initial cohort, the absence of comprehensive functional outcomes, and the study’s nonrandomized design reinforce the need for careful patient selection, intensive surveillance, and further prospective evaluation.
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