Comparing the Oncologic Efficacy of Radical Versus Local Excision for Rectal Cancer With Clinically Complete Remission to Neoadjuvant Chemoradiation Therapy: A Randomized Controlled Clinical Trial

In Taiwan, patients with stage Ⅱ or Ⅲ rectal cancer represented around 30% of all cases of colorectal cancer(n=15,000 annually). Standard treatment of locally advanced rectal cancer consists of neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME), and postoperative adjuvant chemotherapy. This intensive treatment leads to good local tumor control and patient survival, but is associated with short- and long-term morbidity that impairs each patient's quality of life permanently. Although nCRT followed by adjuvant chemotherapy are associated with specific toxicity and may compound surgery-related morbidity, most of the side effects of multimodal treatment that impair the patient's quality of life are attributable to TME with sphincter-preservation or abdomino-perineal resection (APR). Even with the technological advances of robotic and transanal TME, some patients with distal rectal cancer will still require a permanent colostomy. In addition, patients who undergo a sphincter-saving procedure develop a combination of defecatory symptoms known as low anterior resection syndrome. These symptoms are associated with significant impairment of patients' quality of life. With the age-adjusted incidence of rectal cancer increasing steadily in young patients, alternatives to TME are needed.

Some patients with locally advanced rectal cancer have a pathological complete response (pCR) to nCRT. Because patients with pCR have excellent prognosis,8 surgeons question the added value of TME for patients with a clinical complete response (cCR) to CRT. Several institutional case series have reported that a watch-and-wait strategy can result in sustained organ preservation in patients with a cCR to nCRT. Remarkably, up to 30% of patients entered in watch-and-wait protocols eventually experienced tumor re-growth, but most of the cases were surgically salvageable.9 In some series, the survival rate in patients with clinical complete response (cCR) entered in a watch-and-wait protocol was equivalent to that in patients found to have a pCR after TME. However, most of these series, recently published together as an international multicenter registry study, are heterogeneous in terms of tumor stages, radiation dosage, sensitizing chemotherapy, the criteria and timing for assessment of response, and surveillance follow-up protocols. Because these series included only selected patients entering in the watch-and-wait protocol without reporting the total number of patients with similar-stage rectal tumors treated with neoadjuvant therapy during the study period, the possibility of selection bias cannot be excluded. Without a reference denominator, the number of patients who would have potentially benefited from organ preservation by using a watch-and-wait strategy is unknown.

With above-mentioned reasons, most of the patients, including the international case series and our previous case reports, still receive radical surgery for their rectal cancer with cCR to neoadjuvant CRT; some patients with cCR even received a theoretically unnecessary APR procedure and wore a colostoma for life. To enhance the life quality for such patients with cCR to nCRT, the guidelines of the National Comprehensive Cancer Network for treatment of rectal cancer included total neoadjuvant therapy (TNT; systemic chemotherapy before rather than after TME), which was developed in part as a strategy to increase the rate of tumor response. However, to date, the impact of TNT on the potential for organ preservation through avoidance of surgery is unknown.

There is no denying that the organ preservation with no immediate surgery, i.e., the watch-and-wait strategy, in selected patients with a cCR after nCRT is currently at the forefront of rectal cancer management. This strategy is considered as an attractive option to avoid major surgery and the associated morbidity and mortality risks, and functional consequences. However, with the watch-and-wait approach, there is a risk for the development of local regrowth, systemic recurrence, or both, despite the initial achievement of a clinical complete response. Overall, the risk of local re-growth within 3 years from attaining a clinical complete response is 25-30%, and even the occurrence of local re-growth at as long as 7 years from the completion of neoadjuvant chemoradiotherapy has been reported. Therefore, long-term and intensive surveillance protocols have been recommended for patients managed by a watch-and-wait strategy. Remarkably, in consideration of the watch-and-wait policy requires intensive medical resources, it has been not adopted in Taiwan and most of the centers of excellence worldwide.

On the other hand, the GRECCAR2 multicenter randomized trial showed that no evidence of difference in oncological outcomes between local excision and total mesorectal excision in term of 5-year overall survival. Local excision can be proposed in selected patients having a small T2-T3 low rectal cancer with a good clinical response after chemoradiotherapy. However, their study subjects were not limited to rectal cancer with cCR to preoperative CCRT.