In a recent prospective observational cohort study published in eClinicalMedicine, researchers evaluated a modified regimen of total neoadjuvant treatment (TNT) in high-risk locally advanced rectal cancer (LARC) patients in Sweden.

They found that the modified TNT regime achieved similar complete response (CR) rates and lower neurotoxicity compared to the RAPIDO trial, despite treating older patients with more advanced tumors.

Study: Total neoadjuvant treatment using short-course radiotherapy and four CAPOX cycles in locally advanced rectal cancer with high-risk criteria for recurrence: a Swedish nationwide cohort study (LARCT-US). Image Credit: New Africa/Shutterstock.com

Background

Preoperative chemoradiotherapy (CRT) is the standard treatment for LARC, often followed by adjuvant chemotherapy. However, while CRT effectively reduces locoregional recurrences, it has limited impact on distant metastases and overall survival.

This led to interest in TNT, which involves delivering systemic treatment before surgery. The RAPIDO (short for Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation)  trial compared CRT with a TNT regimen of short-course radiotherapy (scRT) followed by preoperative chemotherapy (CAPOX or FOLFOX), showing improved outcomes.

The Uppsala recruiting center, a key participant in RAPIDO, observed positive results with TNT, particularly due to the reduced radiation burden and better response rates. Consequently, they introduced a modified TNT regimen (LARC treatment–Uppsala style, LARCT-US) with fewer chemotherapy cycles, anticipating non-inferior outcomes.

This regimen was adopted by multiple Swedish centers, and outcomes were tracked through the Swedish Colorectal Cancer Registry (SCRCR), including patients treated according to the protocol but not formally enrolled in the study.

In the present study, researchers reported the outcomes of Swedish LARC patients treated with a shorter RAPIDO TNT schedule, comparing the results with the experimental arm of the RAPIDO trial.

About the study

The present study involved 16 hospitals with 273 patients, with some patients in two hospitals treated off-study ad modum (AdmL, n=189) due to logistical challenges or during the coronavirus disease 2019 (COVID-19) pandemic.

Together, these 18 hospitals represented nearly all centers treating (LARC in Sweden. Patients were staged using magnetic resonance imaging (MRI) and computed tomography (CT). The inclusion criteria were identical to the RAPIDO trial— rectal adenocarcinoma less than 16 cm from the anal verge, high-risk MRI features, age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status ≤1, and adequate follow-up potential.

Patients with nonresectable tumor growth, distant metastases, recurrent rectal cancer, significant comorbidities, specific genetic conditions, contraindications to MRI, recent malignancies or investigational treatments, pregnancy, breastfeeding, or significant cardiac or neurological conditions were excluded.

The included patients were treated with short-course radiotherapy (5×5 Gy) followed by 12 weeks of CAPOX or FOLFOX-6 chemotherapy. Surgery followed unless a clinical CR (cCR) allowed for a watch-and-wait (W&W) approach.

The primary endpoint was the CR rate, combining pathologic complete response (pCR) and sustained cCR. Secondary endpoints included toxicity, disease-free survival (DFS), overall survival (OS), distant metastases (DM), locoregional recurrence (LRR), and quality of life (QoL).

Toxicity was assessed using the common terminology criteria for adverse events (CTCAE) criteria, and QoL was evaluated at three years post-treatment, although assessments were delayed due to the pandemic.

The statistical methods used included Kaplan–Meier analysis, Clopper-Pearson confidence intervals, odds ratios, and cumulative incidence with competing risks.

Results and discussion

The patients in the present study were older and with more advanced tumors than the RAPIDO trial. CR was achieved in 24% of LARCT-US and 23% of AdmL patients.

Surgery was performed in 84% (LARCT-US) and 85% (AdmL) of patients, with an R0/R1 resection rate of 98%. Over a follow-up period of 3.6 to 7.6 years, disease-related treatment failure occurred in 29% of LARCT-US and 27% of AdmL patients.

Toxicity was observed during radiotherapy and chemotherapy, mostly as grade-3 diarrhea, but overall survival at three years was similar in both groups (88% LARCT-US, 89% AdmL).

Long-term outcomes showed that recurrence risks correlated with response to treatment, NAR (short for neoadjuvant rectal cancer) scores, and pathological staging. Fewer sensory problems were reported compared to previous studies.

The inclusion of a real-life patient mix with advanced tumors, a high complete response rate, and the meticulous registration of outcomes strengthens the study.

However, the study’s limitations include incomplete toxicity reporting, missing QoL evaluations, partial patient data, and uncertainties in follow-up and eligibility criteria, impacting the validity of comparisons with the RAPIDO trial.

Conclusion

In conclusion, in LARC patients with a high risk of recurrence, a shortened TNT regimen that includes scRT followed by four chemotherapy cycles (instead of six) appears to be equally effective in combating LARC in real-life scenarios, which often involve more advanced tumors than those studied in clinical trials.

The low risk of locoregional failure or locoregional recurrence (LRR) observed with this regimen is encouraging, suggesting that this resource-saving approach can be effectively implemented in routine care.

Although the shorter regimen may not reduce systemic recurrences as effectively as six cycles, it may help to reduce LRR in patients who respond poorly to treatment.