Real-World Data Show Total Neoadjuvant Therapy Boosts Tumor Response in Rectal Cancer

For patients diagnosed with locally advanced rectal cancer, the weeks and months before surgery can determine the entire trajectory of their disease. A new real-world study from Thailand’s Siriraj Hospital, published in BMC Cancer, offers one of the clearest pictures yet of how three different preoperative treatment strategies perform outside the controlled environment of clinical trials. The findings confirm that total neoadjuvant therapy, an approach that front-loads all chemotherapy before radiation and surgery, delivers substantially higher rates of complete tumor disappearance than conventional chemoradiotherapy, even though that advantage did not translate into measurable gains in survival within the study period.

The research team, led by Jitlada Khonglim and Krittiya Korphaisarn of the Division of Medical Oncology at Mahidol University’s Faculty of Medicine, analyzed 339 patients with stage II or III locally advanced rectal cancer who completed preoperative treatment between January 2018 and October 2023. Rather than enrolling patients in a randomized trial, the investigators combined retrospective and prospective data from routine clinical practice, capturing the messier realities of patient adherence, comorbidities, and treatment delays that trials often exclude. Patients were divided into three groups according to the strategy their multidisciplinary team selected: conventional neoadjuvant chemoradiotherapy followed by surgery, total neoadjuvant therapy in which chemotherapy precedes and follows radiation before surgery, and neoadjuvant chemoradiotherapy combined with perioperative chemotherapy.

The distribution of patients across these arms reflected real-world decision-making rather than protocol-driven assignment. Conventional neoadjuvant chemoradiotherapy was used in 156 patients, or 46 percent of the cohort, while 152 patients, 45 percent, received total neoadjuvant therapy. The remaining 31 patients, just 9 percent, were treated with the combined chemoradiotherapy and perioperative chemotherapy approach. This imbalance matters for interpretation, because the smallest group carries the widest statistical uncertainty, a caveat the authors themselves emphasize when discussing their results.

The study’s central endpoint was pathological complete response, the moment when a pathologist examines the surgically removed tumor under the microscope and finds no surviving cancer cells. This outcome is more than a laboratory curiosity. Patients whose tumors vanish completely before surgery tend to live longer without recurrence, and in selected cases a complete clinical response can open the door to a watch-and-wait strategy that spares patients the operation entirely. In this cohort, 27 patients achieved a clinical complete response and were managed without immediate surgery, while 24 patients experienced disease progression during preoperative treatment, underscoring that intensifying therapy is not universally beneficial.

Among the 274 patients for whom pathological data were available, the differences between strategies were striking. Pathological complete response was achieved by only 11 percent of patients treated with conventional chemoradiotherapy, 15 of 131 patients. Total neoadjuvant therapy more than doubled that figure, reaching 24 percent, or 27 of 114 patients. The combined chemoradiotherapy and perioperative chemotherapy group performed best of all at 31 percent, with 9 of 29 patients achieving a complete pathological response, though the authors caution that this small subgroup makes the estimate fragile. When the researchers ran multivariable analysis to separate true treatment effects from confounding factors, two variables emerged as independently associated with complete response: poorly differentiated tumor histology, which carried an odds ratio of 7.1 with a P value of 0.018, and treatment with either total neoadjuvant therapy or the combined approach, with an odds ratio of 2.37 and a P value of 0.03.

The survival analysis added an important layer of nuance. Patients who achieved a pathological complete response had dramatically better outcomes than those who did not, with a hazard ratio of 0.19 for three-year event-free survival and 0.12 for overall survival, both statistically significant at P less than 0.001. In practical terms, eradicating every visible cancer cell before surgery was among the strongest predictors of staying alive and recurrence-free. Yet when the researchers compared the three treatment strategies against one another directly, they found no significant differences in event-free survival or overall survival between the groups. The higher response rates of the intensified regimens did not, within the follow-up window of this study, convert into longer lives.

One of the most revealing findings concerns chemotherapy completion, a metric that clinical trials frequently report but real-world practice often undermines. Patients in the conventional chemoradiotherapy group completed their planned chemotherapy only 57 percent of the time. In the total neoadjuvant therapy group, completion climbed to 87 percent, and in the combined perioperative group to 68 percent, a difference that was highly significant at P less than 0.001. The explanation lies in treatment sequencing. When chemotherapy comes first, patients are typically healthier, less fatigued, and free of the side effects of pelvic radiation, making them far more likely to tolerate and finish the full course. Radiation followed by surgery often leaves patients too depleted to complete adjuvant chemotherapy, which historically was the standard sequencing.

These results arrive at a moment when the standard of care for locally advanced rectal cancer is actively shifting. Total neoadjuvant therapy gained prominence after large randomized trials demonstrated that delivering all systemic therapy upfront improves response rates and allows earlier assessment of treatment effect. Guidelines in many countries now recommend the approach, but guideline recommendations rest heavily on trial populations that tend to be younger, fitter, and more adherent than the average clinic patient. The Siriraj data provide reassurance that the pathological response advantage of total neoadjuvant therapy persists in routine practice, and that the regimen is actually delivered more completely in the real world, not less.

At the same time, the study tempers expectations about what those response gains mean for survival. The absence of a survival difference among the three strategies could reflect insufficient follow-up time, the modest sample size, or the possibility that salvage treatments after recurrence narrow the gap between groups. It could also mean that pathological complete response, while a powerful prognostic marker within any treatment arm, is an imperfect surrogate for survival benefit across different sequencing strategies. This distinction matters for ongoing trials that use response rates as primary endpoints, and it reinforces the need for longer follow-up of real-world cohorts before declaring any strategy definitively superior.

For clinicians and patients weighing options today, the study offers practical guidance. Total neoadjuvant therapy appears to be the more reliable way to deliver the full drug regimen and to maximize the chance of complete tumor eradication, which itself predicts excellent three-year outcomes. The combined chemoradiotherapy and perioperative approach showed the highest response rate of all, but with only 31 patients it remains an open question rather than an established alternative. The authors, whose work was conducted without dedicated funding and approved by the Siriraj Institutional Review Board under protocol Si 106/2022, followed STROBE reporting guidelines and published their findings open access. As watch-and-wait strategies and organ preservation move closer to the mainstream, knowing which preoperative pathway most often empties the rectum of cancer, and which patients are most likely to reach that goal, becomes one of the most consequential decisions in modern rectal cancer care.

Subject of Research: Preoperative treatment strategies and pathological complete response in locally advanced rectal cancer

Article Title: Clinical outcomes of different preoperative treatment approaches in locally advanced rectal cancer: real-world experience

Article References: Khonglim, J., Angkathunyakul, N., Pongpaibul, A., Petsuksiri, J., Veerasarn, V., Riansuwan, W., Chinswangwatanakul, V., Akewanlop, C., & Korphaisarn, K. (2026). Clinical outcomes of different preoperative treatment approaches in locally advanced rectal cancer: real-world experience. BMC Cancer. https://doi.org/10.1186/s12885-026-17078-9

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17078-9

Keywords: rectal cancer, total neoadjuvant therapy, chemoradiotherapy, pathological complete response, event-free survival, overall survival, neoadjuvant chemotherapy, watch-and-wait, real-world evidence, oncology, radiotherapy, surgical oncology