A carefully monitored, multidisciplinary watch-and-wait strategy can result in excellent rectal preservation and pelvic tumor control for a large majority of select patients with rectal cancer who show a clinical complete response after neoadjuvant therapy, according to our recent retrospective study, which was published in January 2019 in JAMA Oncology.
The study included 249 patients who were diagnosed with rectal adenocarcinoma at Memorial Sloan Kettering Cancer Center over a nine-year period starting in early 2006. Patients who had a clinical complete response after completing neoadjuvant therapy either agreed to the watch-and-wait strategy and possible salvage surgery (113 patients) or underwent total mesorectal excision with a subsequent pathological complete response (pCR) (136 patients). (1)
In the watch-and-wait group, 93 of 113 patients (82 percent) avoided total mesorectal excision. All 22 local regrowths were detected on routine surveillance, and 20 of 22 (91 percent) were successfully removed. Five-year disease-specific survival was excellent for both groups: 90 percent for the watch-and-wait group and 98 percent for the pCR group. (1)
Overall survival at five years was 73 percent in the watch-and-wait group, much lower than the 94 percent in the pCR group. The watch-and-wait patients, however, were a decade older on average. In the overall survival analysis, 70 percent of the watch-and-wait group died of causes unrelated to cancer. (1)
Our results indicate that when the rectal tumor disappears after radiation and chemotherapy treatments, the watch-and-wait strategy works well for most patients, providing very significant cost savings and improved quality of life. However, not all patients are cured of cancer and close follow-up must be maintained over a five-year period to initiate treatment should the rectal tumor recur.
Optimizing Rectal Cancer Treatment
The watch-and-wait strategy is a nonstandard approach that has become more popular with the advent of neoadjuvant therapy (2) and due to an increasing demand by patients who want to keep their rectums after achieving a clinical complete response to neoadjuvant therapy. (3) The goal is to spare selected patients from unnecessary resection and improve quality of life while maintaining or improving pelvic tumor control and survival outcomes.
The most recent National Comprehensive Cancer Network (NCCN) guidelines mention the watch-and-wait approach (4) in response to international reports, including a recent meta-analysis in the United Kingdom (5) and a large international multicenter registry. (6) However, the NCCN cannot formally endorse it until more rigorous evidence is available in prospective clinical trials.
Our group previously reported that the watch-and-wait strategy could be safe and efficacious following clinical complete response to neoadjuvant therapy; however, follow-up intervals were short, and there were a small number of patients in these prior analyses. (7), (8)
MSK Study Findings
Between January 1, 2006, and January 31, 2015, 1,070 patients with resectable, nonmetastatic rectal adenocarcinoma were treated at MSK. For our study, we retrospectively evaluated oncologic outcomes for 113 patients who were treated with the off-protocol watch-and-wait strategy compared to 136 patients who underwent total mesorectal excision with subsequent pCR. (1)
In total, 91 of 113 patients (81 percent) in the watch-and-wait cohort remained free of disease in the rectum after neoadjuvant therapy. Together with two patients salvaged by transanal excision, 93 of 113 patients (82 percent) avoided total mesorectal excision. (1)
Five-year survival rates are summarized in Table 1:
| Table 1: Five-Year Survival Outcomes by Patient Cohort (1) | ||
| Watch-and-Wait (n=113) | pCR (n=136) | |
| Overall survival | 73% (95% CI, 60–89%) |
94% (95% CI, 90–99%) |
| Disease-free survival | 75% (95% CI, 62–90%) |
92% (95% CI, 87–98%) |
| Disease-specific survival | 90% (95% CI, 81–99%) |
98% (95% CI, 95–100%) |
1 Adapted from Smith JJ, Strombom P, Chow OS, et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncology. Published online January 10, 2019.
At the end of the follow-up, 11 patients (10 percent) in the watch-and-wait group had a permanent stoma compared to 21 patients (15 percent) in the pCR group. (1)
Nine patients (8 percent) in the watch-and-wait cohort developed distant metastases compared to five patients (4 percent) in the pCR cohort. Notably, within the watch-and-wait group, we noted a significant difference in the rate of distant metastases among patients with local regrowth versus those who did not experience local regrowth (36 versus 1 percent, P < 0.001). (1)
Our study represented our experience of the watch-and-wait strategy at a single large institution with sufficient cases and a follow-up period to assess cancer recurrence and survival outcomes. In addition to the limitations inherent in a retrospective study, limitations included some notable differences between groups. Patients in the watch-and-wait group were a decade older compared to the pCR group (67.2 years versus 57.3 years, respectively). The watch-and-wait patients also had lower-situated tumors (5.5 centimeters from the anal verge versus 7.0), and patients in the pCR group were more likely to have received chemoradiation therapy compared to the watch-and-wait group (83 patients versus 31, accounting for 61 versus 27 percent, respectively).
Advancing Rectal Cancer Research
Similar to other large case-series analyses, our data support the benefit and overall safety of the watch-and-wait strategy. However, we also identified worse survival and more distant metastases in the watch-and-wait group, suggesting a higher oncologic risk of local regrowth that may not be mitigated by aggressive surveillance and surgical salvage.
Our data also add weight to the assertion that a pathologically verified complete response in patients undergoing total mesorectal excision is associated with a reduced risk of both local and systemic failure.
Rectal cancer treatment remains challenging as we balance reducing the risk of distant metastases, preserving quality of life, and tailoring treatments to individual patients by identifying those who respond to neoadjuvant therapy. Overall, our study highlights that we must proceed with caution as we weigh oncologic risks with the benefits of organ preservation for each patient.
At MSK, we continue to research how to help patients with rectal cancer achieve the best possible outcomes while minimizing the adverse effects of cancer treatment. For example, we are leading the Organ Preservation in Rectal Adenocarcinoma (OPRA) trial, (9) a multi-institutional phase II study that is evaluating the use of a watch-and-wait approach for rectal cancer patients who achieve a clinical complete response after total neoadjuvant therapy compared to those who have an incomplete response and undergo total mesorectal excision. The trial has accrued more than 300 patients to date and is comparing two novel neoadjuvant approaches that could shed light on the best options for rectal preservation. We are also conducting 23 clinical trials investigating new chemoradiation, chemotherapy, surgical, and combination approaches for rectal cancer.
Funding/Support:
This work was supported by National Cancer Institute grants (P30-CA008748 and 5R01-CA182551-04), an American Society of Colon and Rectal Surgeons Career Development Award and Limited Project Grant, an Association of Academic Surgery Joel J. Roslyn Faculty Research Award, an MSK Department of Surgery Junior Faculty Award, the Wasserman Colon and Rectal Cancer Fund, and the Berezuk Colorectal Cancer Fund. It was also supported in part by a Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C: AACR-DR22-17).
The funders had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Conflict of Interest Disclosures:
Dr. Smith has received travel support from Intuitive Surgical. Dr. Garcia-Aguilar has received honoraria from Medtronic, Johnson & Johnson, and Intuitive Surgical. Dr. Paty reported no disclosures. For more information, refer to the study.