Determining the survival benefit of postoperative radiotherapy in patients with pT1-3N1M0 rectal cancer undergoing total mesorectal excision: a retrospective analysis

Traditionally, postoperative adjuvant chemoradiotherapy has been administered to patients with locally advanced rectal cancer (LARC) who do not receive preoperative neoadjuvant therapy. Currently, however, the National Comprehensive Cancer Network (NCCN) recommends postoperative adjuvant radiotherapy and chemotherapy for almost all patients whose perioperative pathology results have confirmed their cancer to be pT3-4 or N1-2, except for some patients with pT3N0M0 cancers who have positive pathological prognostic features [1]. The aforementioned NCCN recommendations are primarily based on data from previous studies on postoperative adjuvant radiotherapy and chemotherapy for the treatment of rectal cancer, including NSABPR-01 [2], GTSG71-75 [3], and NCCTG79-47-51 [4]. However, these studies were completed in the 1990s. Currently, when using mesorectal integrity as the standard of evaluation, high-quality total mesorectal excision (TME) surgery results in a local recurrence rate of rectal cancer as low as 5% [5, 6]. However, it is unknown whether postoperative radiotherapy should be routinely implemented. In the present study, we evaluated the benefits of postoperative radiotherapy in addition to adjuvant chemotherapy after primary surgery in patients with pT1-3N1M0 rectal cancer who did not receive preoperative neoadjuvant therapy.

In 1982, Heald et al. [7] proposed that TME reduces the local recurrence rate of rectal cancer to approximately 10%. However, this idea was not accepted by most surgical experts around the world until the end of the twentieth century, when it became the gold standard for treatment of middle and lower rectal cancers. Subsequent studies, such as CAO/ARO/AIO-94 [8, 9], CKVO9504 [10], and MRCCR07 [11], showed that preoperative neoadjuvant radiotherapy and chemotherapy further reduced the local recurrence rate of LARC after radical resection to approximately 5%. Since then, preoperative neoadjuvant radiotherapy in conjunction with TME has become the standard treatment plan for middle- and lower-grade LARC. Although it reduces the local recurrence rate by approximately 5%, preoperative radiotherapy does not improve the overall survival (OS). In view of the fact that long-term adverse reactions caused by radiotherapy seriously affect patient quality of life by impairing anal, voiding, and sexual functions, injuries that can still increase with the passage of time, potentially increasing the risk of developing a second tumor [12, 13], some scholars have attempted to remove radiotherapy from the perioperative treatment of LARC.

The Chinese FOWARC study [14] was the first phase III clinical randomized controlled trial to introduce preoperative neoadjuvant chemotherapy into a neoadjuvant therapy plan for the treatment of rectal cancer. The results showed no significant differences in disease-free survival (DFS) and local recurrence rates between the perioperative mFOLFOX6 chemotherapy regimen without radiotherapy and standard fluorouracil-based neoadjuvant radiotherapy and chemotherapy. The 3-year local recurrence rates in the two groups were 8.3% and 8.0%, respectively. The aforementioned study speculated that mFOLFOX6 chemotherapy may be used as the initial regimen of neoadjuvant therapy for LARC, and radiotherapy can be used as a selective supplement based on the efficacy of chemotherapy. The American PROSPECT study [15] was the most anticipated study on neoadjuvant chemotherapy for rectal cancer, as it was a head-to-head control study that aimed to compare neoadjuvant therapy using a simple mFOLFOX6 regimen with standard neoadjuvant radiotherapy and chemotherapy. The results of the aforementioned study will have a decisive impact on the status of radiotherapy in the perioperative treatment of LARC and whether the comprehensive treatment of LARC will enter the era of neoadjuvant chemotherapy. The results of the FOWARC study posed a strong challenge to the perioperative use of radiotherapy for LARC.

One retrospective study found that the 10-year local control rate and recurrence-free survival rate of pT3N0M0 rectal cancer with good prognostic pathological features were 95% and 87%, respectively, whereas those of patients without good prognostic pathological features were 71% and 55%, respectively. This study suggests that postoperative adjuvant therapy has little benefit for pT3N0M0 rectal cancer with good prognosis [16]. Based on the aforementioned study, the NCCN guidelines recommend follow-up observation for patients with pT3N0M0 rectal cancer with good prognostic characteristics, whereas routine postoperative adjuvant radiotherapy and chemotherapy are recommended for patients with postoperative pathology confirmed as pT3-4 or N1-2 tumors.

The results of the present study show that in the era of relatively established TME procedures (2004–2016), radiotherapy based on the efficacy of adjuvant chemotherapy does not improve tumor-specific survival in rectal cancer patients with low-risk disease (pT1-3N1M0). To eliminate bias, we matched the baseline clinical data through propensity score balancing, after which we obtained the same results. In a real-world study, these results suggest that postoperative adjuvant radiotherapy does not significantly improve the prognosis of pT1-3N1M0 rectal cancer in conjunction with TME, which is an effective treatment for patients with pT1/pT2, pT3, and pN1 rectal cancer. If there is good quality smooth intact mesorectum post-TME, postoperative chemoradiotherapy is ineffective and unnecessary, as recommended by the European Society for Medical Oncology (ESMO) [17].

However, not all patients with pT1-3N1M0 rectal cancer can not benefit from postoperative radiotherapy. The subgroup analysis in the present study showed that having three positive lymph nodes and a tumor size > 50 mm, in combination with postoperative adjuvant chemotherapy, could result in improved tumor-specific survival rates, whereas other patients may not benefit from postoperative radiotherapy. Therefore, postoperative chemoradiotherapy (CRT) is only suitable for some LARC patients with poor selective prognoses, and the key lies in screening these patients. As an international pioneer in the individualized treatment of rectal cancer, the 2017 edition of the ESMO guidelines for rectal cancer points out that routine use of CRT is not necessary for LARC that has not been treated preoperatively if high-quality TME can be guaranteed. Postoperative CRT may be selectively used in patients with adverse histopathological features after primary surgery.

The ESMO guidelines specify four recommendations for postoperative adjuvant radiotherapy and chemotherapy: ① sufficient and necessary—circumferential resection margin (CRM) ≤ 1 mm, pT4b or pN2, extracapsular spread close to the mesorectal fascia (MRF), extranodal deposits (N1c), or pN2 if poor mesorectal quality/defects; ② sufficient—lower pN2 tumors within 4 cm of the anal verge (risk of involved lateral pelvic lymph node) or extensive extramural vascular or perineural invasion close to the MRF; ③ borderline sufficient—pN2 in the middle or upper rectum if good mesorectal tissue quality, CRM 1–2 mm, or circumferential obstructing tumors; and ④ insufficient and unnecessary—pT1/pT2, pT3, CRM > 2 mm, pT4a above reflection, or pN1 if good quality, smooth, intact mesorectum.

The ESMO guideline-based recommendations are largely based on the MERCURY study, in which patients with a good prognosis based on high-resolution magnetic resonance imaging (MRI) were treated solely with TME, with no adjuvant radiotherapy performed before or after the operation. A total of 374 patients were enrolled in the study, of which 122 (33%) had a 5-year local recurrence rate of 3%. Subgroup analysis showed that the local recurrence rate of stage T3 rectal cancer with good prognosis, as assessed by MRI (invasion of the mesorectum < 5 mm, regardless of N stage), was only 1.7% [5]. The results of the MERCURY study suggest that radiotherapy is likely to have no value in T3a or T3bN rectal cancers. Taylor et al. [6] reported the 5-year follow-up results of all cases included in the MERCURY study as follows: based on high-resolution MRI, all cases were divided into the MRI-clear CRM and MRI-involved CRM groups; predicted clear mrCRM was defined as the distance from the tumor to the MRF > 1 mm, while for lower-third rectal tumors, mrCRM involvement was defined as tumor ≤ 1 mm from the levator muscle. If the tumor was present at or below the level of the puborectalis sling, the mrCRM was predicted to be involved if there was invasion into the intersphincteric plane or beyond. A total of 205 patients in the MRI-clear CRM group underwent TME without postoperative adjuvant radiotherapy, and 58% of the patients were treated with adjuvant chemotherapy. Of these patients, the pathological circumferential resection margin (pCRM) was negative in 190 cases, and local recurrence occurred in 11 cases during the follow-up period. pCRM was positive in 15 cases, and local recurrence occurred in 3 of these cases during the follow-up period. The overall local recurrence rate was 6.8%, whereas the local recurrence rate for 190 cases with negative CRMs was only 5.8%. In the MERCURY study, the quality of TME was strictly controlled, and the aforementioned ESMO guideline-based recommendations strongly depend on the quality of the surgery, as a smooth and intact mesorectum is necessary to negate the need for radiotherapy. Therefore, the quality of the operation is an important factor when deciding whether to use radiotherapy. For patients with LARC who do not receive preoperative neoadjuvant therapy, if high-quality TME can be guaranteed, routine postoperative CRT should only be selectively utilized in patients with poor histopathological features after primary surgery. The ESMO guidelines indicate that adverse histopathological features include CRM ≤ 1 mm, pT4b, pN2, extracapsular spread close to the MRF, extranodal deposits (N1c), pN2 if poor mesorectal quality/defects, and extensive extramural vascular or perineural invasion close to the MRF. Based on the results of the present study, the presence of 3 positive lymph nodes and a tumor size > 50 mm should be regarded as poor histopathological features, indicative of sufficient conditions for the utilization of postoperative radiotherapy. The results of the present study are applicable to patients whose preoperative staging was underestimated and those who did not receive preoperative neoadjuvant radiotherapy or chemotherapy. Preoperative neoadjuvant radiotherapy and chemotherapy are the first choices for the treatment of newly diagnosed LARC, including total neoadjuvant treatment (TNT).

There are several limitations in this study. Some patients might not have undergone neoadjuvant treatment or postoperative adjuvant radiotherapy because of comorbidity, so this study has a selection bias. Since the present study was retrospective in nature, operation details and the quality of the postoperative rectal specimens are unknown. This study reflects real-world data, but is a study spanning 12 years, during which time surgical techniques and adjuvant chemotherapy regimens may have changed. Therefore, there may be a potential offset. In the post-TME era, multicenter phase III clinical studies on postoperative adjuvant radiotherapy for rectal cancer are still needed to confirm our findings.

In conclusion, the results of the present study show that for the overall cohort of patients with pT1-3N1M0 rectal cancer, radiotherapy in addition to postoperative adjuvant chemotherapy did not significantly improve survival. The poor histopathological features proposed in the ESMO guidelines are important indicators for postoperative adjuvant radiotherapy screening; the number of positive nodes (3) and tumor size (> 50 mm) may also be screening indicators.