In a recent prospective observational cohort study published in eClinical Medicineinvestigators evaluated a modified total neoadjuvant therapy (TNT) regimen in high-risk locally advanced rectal cancer (LARC) patients in Sweden.
They found that the modified TNT regimen 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 therapy using short-course radiotherapy and four cycles of CAPOX in locally advanced rectal cancer with high-risk criteria for recurrence: a Swedish nationwide cohort study (LARCT-USA). 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 local recurrences, it has limited impact on distant metastases and overall survival.
This has led to interest in TNT, which involves the delivery of systemic therapy prior to surgery. The RAPIDO trial (abbreviation for rectal cancer and preoperative induction therapy followed by exclusive surgery) compared CRT with a short-course TNT radiotherapy (scRT) regimen followed by preoperative chemotherapy (CAPOX or FOLFOX), showing improved outcomes.
The Uppsala recruitment center, a key participant in RAPIDO, has seen positive results with TNT, particularly due to reduced radiation load and better response rates. Consequently, they introduced a modified TNT regimen (LARC therapy – Uppsala style, LARCT-US) with fewer chemotherapy cycles, predicting non-inferior outcomes.
This regimen was adopted by several Swedish centers and outcomes were monitored through the Swedish Colon Cancer Registry (SCRCR), including patients treated according to the protocol but not formally enrolled in the study.
In the present study, the researchers reported the results 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, while some patients in two hospitals were treated outside the study ad modum (AdmL, n=189) due to logistical challenges or during the coronavirus disease 2019 (COVID-19) pandemic.
Together, these 18 hospitals represented almost all treatment centers (LARCs in Sweden. Patients were staged by magnetic resonance imaging (MRI) and computed tomography (CT). Inclusion criteria were identical to the RAPIDO trial – rectal adenocarcinoma less than 16 cm from the rectal margin, high-risk MRI features, age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status ≤1, and adequate follow-up.
Patients with unresectable 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 disease were excluded.
Enrolled 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) permitted a watch-and-wait (W&W) approach.
The primary endpoint was CR rate, combining pathologic complete response (pCR) and sustained cCR. Secondary endpoints included toxicity, disease-free survival (DFS), overall survival (OS), distant metastases (DM), local recurrence (LRR), and quality of life (QoL).
Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 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 with competing risks.
Results and discussion
Patients in the present study were older and with more advanced tumors than in the RAPIDO trial. 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%. Over a follow-up period of 3.6 to 7.6 years, disease-related treatment failure occurred in 29% of LARCT-US patients and 27% of AdmL patients.
Toxicity was seen during radiotherapy and chemotherapy, mainly as grade 3 diarrhea, but overall survival at three years was similar in both groups (88% LARCT-US, 89% AdmL).
Long-term results showed that recurrence risks correlated with treatment response, NAR (short for neoadjuvant rectal cancer) scores, and pathologic staging. Fewer sensory problems were reported compared to previous studies.
The inclusion of a mix of real-life patients with advanced tumors, the high complete response rate, and the meticulous recording of results strengthen the study.
However, study limitations include incomplete reporting of toxicity, incomplete quality of life assessments, partial patient data, and uncertainties in follow-up and eligibility criteria, affecting the validity of comparisons with the RAPIDO trial.
Conclusion
In conclusion, in LARC patients at high risk of relapse, an abbreviated TNT regimen including scRT followed by four cycles of chemotherapy (rather than six) appears to be equally effective in combating LARC in real-life scenarios, which often include more advanced tumors than those studied in clinical trials.
The low risk of local failure or local recurrence (LRR) observed with this regimen is encouraging, suggesting that this resource-sparing approach can be effectively implemented in routine care.
Although the shorter regimen may not reduce systemic relapses as effectively as six cycles, it may help reduce LRR in poor responders.
