Complete neoadjuvant therapy shows promising results in the treatment of rectal cancer

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

The modified TNT regimen was found to achieve similar complete response (CR) rates and lower neurotoxicity compared with the RAPIDO study, despite treating older patients with more advanced tumors.

Test: Neoadjuvant complete treatment with short-course radiotherapy and four cycles of CAPOX in locally advanced rectal cancer with high risk of recurrence criteria: the Swedish nationwide cohort study (LARCT-US). Photo source: Modern Africa/Shutterstock.com

Background

Preoperative chemoradiotherapy (CRT) is the standard treatment for LARC, often supplemented with adjuvant chemotherapy. However, while CRT effectively reduces locoregional recurrence, it has restricted impact on distant metastases and overall survival.

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

The Uppsala Recruitment Center, a key participant in RAPIDO, observed positive results with TNT, especially due to reduced radiation burden and better response rates. Therefore, a modified TNT regimen (LARC treatment Uppsala style, LARCT-US) was introduced with fewer chemotherapy cycles, predicting non-inferiority.

This treatment regimen was adopted by many Swedish centers and the results were monitored through the Swedish Colorectal Cancer Registry (SCRCR), which includes patients treated according to the protocol but not formally included in the study.

In this study, the researchers reported the treatment outcomes of Swedish LARC patients with an abbreviated RAPIDO TNT regimen, comparing them with the outcomes of the experimental group of the RAPIDO study.

About the study

The study involved 16 hospitals and 273 patients, with some patients treated outside the study at two hospitals. measure (AdmL, n=189) due to logistical challenges or during the coronavirus disease 2019 (COVID-19) pandemic.

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

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

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

The primary endpoint was CR rate, a composite of pathological 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 Common Terminology for Adverse Events (CTCAE) criteria, and quality of life was assessed three years after treatment, although assessments were delayed due to the pandemic.

Statistical methods used included Kaplan-Meier analysis, Clopper-Pearson confidence intervals, odds ratios, and cumulative incidence for comorbid risks.

Results and discussion

Patients in this study were older and had more advanced tumors than those in the RAPIDO study. CR was achieved in 24% of LARCT-US patients 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%. During a follow-up period of 3.6 to 7.6 years, disease-related treatment failure occurred in 29% of patients in LARCT-US and 27% of patients in AdmL.

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

Long-term results showed that the risk of recurrence correlated with treatment response, NAR (brief for neoadjuvant rectal cancer) scores, and pathological stage. Fewer sensory problems were reported compared with previous studies.

This study is based on the inclusion of real-world patients with advanced cancers, a high complete response rate, and thorough recording of outcomes.

However, study limitations include incomplete toxicity reporting, missing quality of life assessments, incomplete patient data, and uncertainties regarding follow-up and eligibility criteria, which impact the validity of comparisons with the RAPIDO study.

Application

In conclusion, in patients with LARC at high risk of relapse, a shortened TNT regimen consisting of scRT followed by four cycles of chemotherapy (instead of six) appears to be equally effective in combating LARC in real-world settings that often present with tumors that are more advanced than those studied in clinical trials.

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

Although a shorter treatment regimen may not reduce the rate of systemic relapses as effectively as six cycles, it may lend a hand reduce LRR in destitute responders.