This is the first retrospective population-based study to evaluate the effect of radiation-based neoadjuvant treatments on the long-term prognosis of LARC patients in the TME era. Patients who received preoperative radiotherapy had a significantly prolonged OS and a slightly higher 5-year survival rate compared to those without. The nomogram, constructed based on the multivariate Cox regression analysis, predicted the prognosis better than the 8th AJCC staging system and showed that high-risk patients are more likely to benefit from preoperative radiotherapy, as indicated by their OS.
Radiotherapy was initially introduced as an adjuvant treatment to prevent local rectal cancer recurrence [18, 19]. Later on, radiotherapy was tested as a preoperative treatment, resulting in stronger anti-recurrence efficacies, higher R0 resection rate, increased sphincter-preserving, and less radiation toxicity [7, 13, 20, 21]. Generally, radiation based neoadjuvant therapies, including long-course radiotherapy (LCRT) combined with concurrent chemotherapy and short-course radiotherapy (SCRT), followed by instant or delayed surgery, have been the standard treatment for patients with LARC [13, 22, 23]. Numerous single-center and multi-center trials have laid the foundation for radiation-based neoadjuvant treatment for LARC management, which is now used in clinics worldwide. In this study, 80.0% of LARC patients received radiation-based neoadjuvant treatment.
However, there has always been controversy regarding preoperative radiotherapy. First, the pathological complete response (pCR) rate following radiation-based neoadjuvant treatments varies different from different modalities (LCRT: 2.2 to 33.8%; SCRT: 0.3 to 28.0%) [15, 22, 24–27]. Second, acute radiation-induced injury, such as radiation colitis, decreases treatment compliance and quality of life [28–30]. Third, late radiation-induced injury, such as fibrosis, increases the surgical dissection difficulty and the risk for postoperative complications [31, 32]. Ultimately, the long-term survival benefit (e.g., disease-free survival [DFS] and OS) of radiation-based neoadjuvant treatments (regardless of the modality) is not clear. Since the start of TME, the primary treatment failure indicator is distant metastasis rather than local recurrence, suggesting that the clinical value of preoperative radiotherapy for LARC management needs re-evaluation.
The key to correctly evaluate the clinical efficacy of a treatment modality is endpoint selection. pCR is the most widely used endpoint to evaluate neoadjuvant treatments, but using pCR as an optimal surrogate endpoint remains controversial [33]. This may be because the correlation between pCR and long-term survival is not definite [34–37], and pCR is influenced by other non-treatment factors (e.g., the interval between radiotherapy completion and surgery) [38, 39]. DFS is the time from randomization to recurrence or death from any cause [40], which was found to be a stronger predictor of OS than pCR among 2795 patients receiving neoadjuvant treatment [41]. However, DFS is also not an ideal surrogate endpoint because the DFS starting time varies, especially regarding surgery. OS is a hard endpoint for any treatment, although it has been confounded by salvage treatments (in recurrence cases) and potential causes of non-cancer-related mortality. OS also often requires a larger sample size, longer follow-up, and higher costs. Radiation-based neoadjuvant treatment advantages on the OS were rarely observed among phase III RCTs (Table 4) [8, 10, 42–49], but advantages were identified in a meta-analysis including 6426 trial patients in 2000 and a population-based analysis including 49 439 patients in 2019 [17, 50]. The most likely reason for this divergence was the sample size.
In the TME era, local recurrence is no more than a primary cause of treatment failure. Intensified neoadjuvant chemotherapy was also found to be comparable to radiation-based neoadjuvant treatments in terms of OS, and even had a weak DFS advantage [51, 52]. Both of above have caused the necessity of preoperative radiotherapy to be questioned. In this study, 7582 patients between 2011 and 2015 from the SEER database were eligible for survival analysis, and the pooled HR for the median OS favored the preoperative radiotherapy group compared to the group without preoperative radiotherapy. In addition, a nomogram was developed to predict the long-term prognosis of LARC patients with better calibration than the 8th AJCC staging system and a significantly higher C-index. The nomogram also indicated that high-risk patients would benefit from preoperative radiotherapy more than low-risk patients regarding long-term survival. Therefore, we concluded that radiation-based neoadjuvant treatments should been conducted in the management of LARC patients in the era of TME and intensified chemotherapy.
From the other hand, watch and wait strategy has been pouring new vigor into the application of preoperative radiotherapy. Although radical surgery followed by neoadjuvant treatment is the standard treatment for LARC patients, there are two kinds of particular cases. Some patients are reluctant to undergo surgery, and some are not tolerant to surgery. A retrospective study analyzed 71 patients with a complete clinical response using the “watch and wait” strategy and 21 patients with an incomplete clinical response but a complete pathologic response post-TME [53]. The 5-year OS and DFS rates were 100% and 92% in the “watch and wait” group, and 88% and 83% in the surgery group, respectively. The “watch and wait” advantage was also confirmed in a study by three neighboring UK regional cancer centers that used a propensity score-matched cohort to analyze the 3-year rates of non-regrowth DFS (wait: 88%, surgery: 78%), OS (wait: 96%, surgery: 87%), and colostomy-free survival (wait: 74%, surgery: 47%) [54]. In a retrospective study of 3298 patients receiving neoadjuvant chemoradiotherapy, pCR was found to be significantly associated with the radiotherapy dose [55]. A prospective single-arm study including 55 patients reported that the clinical complete response rate was up to 73% using high-dose chemoradiotherapy (60 Gy/30 fractions) [56]. Hence, multidisciplinary management combined with patient willingness is strongly recommended to make decision for LARC patients, and intensified curative chemoradiotherapy may be an alternative for select patients.
This study has several limitations. First, this was a retrospective study. Second, preoperative radiotherapy data, including modality, gross tumor volume, clinical target volume, dose, and combination with chemotherapy, were not available. Third, chemotherapy administration before or after surgery is unknown. Although, LCRT is preferred in the USA, and chemotherapy is increasingly suggested. Finally, the TME technique has been popular worldwide since 2002 [57–60] and we only enrolled patients after 2010, but data on surgery in the SEER database were unavailable.