Adjuvant radiotherapy improves cause specific survival in stage II, not stage III mucinous carcinoma of the rectum

Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in men and women combined in the US [ 1]. Mucinous adenocarcinoma (MC) is a histological subtype of colorectal cancer, representing approximately 5-15% of primary colorectal cancers [ 2]. In the World Health Organization (WHO) classification, MC is defined as a large amount of extracellular mucin which is produced by secretion from acini and a mucinous layer covering more than 50% of the tumor [ 3]. MC has a distinct clinicopathological entity with an aberrant molecular background, and it has been reported uniformly associated with younger patient populations, a later stage of presentation, and worse outcomes compared to non-MC [ 4, 5]. Several studies have reported a poor response of rectal MC to neoadjuvant chemoradiotherapy (NCRT) in terms of downstaging and tumor regression grade [ 2, 6], while others found a similar survival benefit for MC and non-MC [ 3].

Although NCRT is the current standard of care for patients with locally advanced rectal cancer, a substantial number of locally advanced rectal cancers have not received NCRT due to understage limited by preoperative evaluation. Data from pooled analyses, as well as from recent smaller studies revealed that the sensitivity of endorectal ultrasound (ERUS) in detecting lymph node metastasis ranges from 50 to 83%, comparable with that of magnetic resonance imaging (MRI) (sensitivity, 45-79%) [ 7– 9]. Adjuvant radiation therapy is recommended for patients with T3, T4, or N+ rectal cancer to decrease the risk of local failure [ 10], which is reported that about 37% lower in those who had postoperative treatment than those who had surgery alone [ 11].

Although histopathological type is an important factor predicting tumor response to NCRT [ 12], the value of adjuvant radiotherapy in MC has not been investigated. Thus, we conducted this study to investigate the prognostic importance of adjuvant radiotherapy in rectal MC.

In the 1990s, a number of clinical trials found significantly improved rates of local recurrence, cancer-related deaths, and overall survival with adjuvant radiotherapy compared to surgery alone [ 15– 17]. Since then, radiotherapy has become the cornerstone of adjuvant therapy for advanced rectal cancer. During the first decade of the 21st century, preoperative radiochemotherapy with 5-FU became the standard perioperative therapy for locally-advanced rectal cancer due to its higher efficacy in reducing local recurrences and improving disease free survival compared with postoperative radiotherapy, but with no significant advantage in overall survival [ 18– 20]. But for limitation in preoperative assessment, a relative number of patients were understaged, and postoperative radiotherapy was an important complementary. Moreover, most clinical trial only included rectal adenocarcinoma, and the therapy strategies for MC referred to adenocarcinoma. It has been clearly demonstrated that MC is a distinct group of tumors which shows different natural history, biological behavior, different oncogenic and molecular pathways which may make them respond differently to chemoradiation compared to adenocarcinoma [ 21– 23]. However, no current guidelines describe MC as a clinical factor that should influence the therapeutic algorithm. In the era of precise medicine and personalized treatment, it is urgent to know the prognosis value of postoperative radiotherapy in rectal MC.

For low incidence rate of MC in rectal cancer, it will be difficult to accumulate an adequate number of patients treated at a single center. Therefore, we used a large, nationwide, population-based cancer registry, the SEER database, to guarantee power effect for determining the postoperative radiotherapy value of the MC subtype of stage II and III rectal cancer. For there has been great advancements advances in modern radiotherapy in the last decade for rectal cancer [ 3], we limited the diagnosis from 2004 to 2011 to minimize the confusion. Our study demonstrated that only stage II rectal MC benefit from postoperative radiotherapy, and postoperative radiotherapy was an independently prognostic factor in MC rectal cancer. Considering the toxicity of radiotherapy, postoperative radiotherapy should be recommended with caution for stage III rectal MC.

To our knowledge, the present study is the largest and the first study analyzing the prognostic value of postoperative radiotherapy for MC in stage II and stage III rectal cancer patients. Pooled analysis data from different SEER register centers enabled us to systemically know the protective effect of postoperative radiotherapy in stage II rectal MC. Although this is a large population based study, it should be acknowledged that the result should be interpreted in the light of several limitations. First, there were no information about radiotherapy dosage and additional adjuvant chemotherapy, which may cause confusion. Second, we only selected patients who were pathologically diagnosed as stage II and III rectal cancer and with at least 1 lymph node retrieval to speculate that they had received radical resection. The quality of surgery cannot be assessed in this retrospective study. Third, patients with postoperative radiotherapy has a higher rate of young patients probably with better health and less comorbidities, and therefore, with a better prognosis, which may cause bias to analysis. Fourth, the SEER data lacks the information of local control and relapse free survival, which were the main benefits for radiotherapy in rectal cancer. However, there was defined CSS benefit in stage II rectal MCs who received postoperative radiotherapy, which was sufficient to support the advantage of postoperative radiotherapy in such subgroup of patients. For stage III rectal MC, the possible of local control cannot be converted to CSS advantage.

According to the findings in our study, we suggest that postoperative radiotherapy should be routinely applied to patients with stage II rectal MC for significantly improved CSS. For stage III patients, considering the losing of CSS advantage and potential radiotherapy toxicity, radiotherapy should be recommended with great caution.