Nonoperative management of rectal cancer is an emerging treatment approach that aims to enable carefully selected patients to avoid the morbidity of radical surgical resection, while benefiting from the same excellent rates of tumor control achieved with radical surgery–based combined-modality therapy. The success of nonoperative management in this setting is based on the accurate assessment of tumor eradication after chemoradiotherapy, without pathologic verification. Therefore, clinical evidence of complete response—based on physical examination, endoscopic procedures, and imaging—must be utilized as a marker to predict for pathologic complete response and thus help select the patients who are most appropriate for nonoperative management. Initial evidence from retrospective and prospective single-arm and cohort studies has demonstrated high rates of local control and disease-free survival with nonoperative management of rectal cancer, compared with historical results of combined-modality therapy. Several trials and registries are prospectively investigating nonoperative management vs standard treatment of rectal cancer. At this time, combined-modality therapy with total mesorectal excision remains the standard of care for patients with locally advanced rectal cancer; nonoperative management should not be routinely offered outside of clinical trials.
The Current Standard of Care and Future Directions
The standard of care for locally advanced rectal cancer has evolved significantly over the past 3 decades. In 1990, the National Cancer Institute released a consensus statement that established surgery followed by combination chemotherapy and RT as standard treatment for stage II and III rectal cancer. After publication of the German Rectal Cancer Study Group trial in 2004, standard-of-care treatment for these patients shifted to neoadjuvant CRT followed by surgical resection. With a growing body of data supporting consideration of nonoperative management for select patients, recent professional society guidelines have addressed clinical scenarios in which a nonoperative management approach may be appropriate. The American Society for Radiation Oncology 2016 clinical practice guidelines considered CRT alone, CRT plus brachytherapy boost, and CRT plus external beam boost to be appropriate treatment options for patients with low-lying tumors who decline to undergo an APR. Nevertheless, the guidelines emphasize that neoadjuvant CRT followed by surgery remains the standard of care for patients with rectal cancer who are surgical candidates.
Current studies are prospectively investigating clinical outcomes among patients who achieve cCR after neoadjuvant CRT and who are managed without surgery (also see the ICESP trial). In addition to these efforts, patient-reported outcomes, including QOL metrics, will become increasingly important to support and justify the deintensification of therapy that nonoperative management entails. Prior QOL studies have focused on the impact of sphincter-preserving surgery vs APR, suggesting that while the former may avoid permanent colostomy, potential anorectal dysfunction has a significant negative impact on QOL.[56,57] Habr-Gama et al prospectively collected data and demonstrated that nonoperative management of patients with cCR after CRT results in better anorectal function (as measured by resting/squeeze pressure, rectal capacity, and incontinence scores) and overall QOL as compared with outcomes of patients with near-cCR who underwent transanal endoscopic microsurgery. No other prospective studies of rectal cancer treatment to date have investigated QOL outcomes in the setting of nonoperative management, but presumably anorectal functional outcomes after CRT alone should be comparable, if not superior, to outcomes of sphincter-preserving surgery and coloanal anastomosis. Further investigation is certainly warranted.
Rectal cancer patients who would otherwise achieve a pCR after neoadjuvant CRT derive less benefit from radical surgery and thus may be the most appropriate population for nonoperative management. As mentioned, intervals of at least 6 weeks between completion of neoadjuvant CRT and evaluation of tumor response were associated with improved rates of pCR, and this timeframe has been adopted accordingly in the assessment of clinical response after CRT in nonoperative management approaches. Additionally, as previously noted, investigators have demonstrated that intensive chemotherapy applied during the interval between the delivery of neoadjuvant long-course CRT and surgical treatment can further improve the pCR. This principle could similarly be applied to the setting of nonoperative management, potentially further improving the already excellent tumor control rates and increasing the number of patients who may be eligible for management by watchful waiting.
Besides generating robust data on clinical outcomes and QOL, future efforts should focus on the potential cost-effectiveness of nonoperative management of rectal cancer compared with standard trimodality therapy. While surgical resection imposes significant upfront costs on the healthcare system, close surveillance with the watch-and-wait approach following completion of CRT also has the potential to incur substantial costs over the patient’s lifetime, especially given the combined use of clinical examination, imaging, and laboratory testing. The results of a value analysis will depend heavily on the timing of follow-up, the diagnostic modalities employed, and the workup of abnormalities discovered on surveillance. These factors should be considered in the development of any standardized surveillance schedule. In the era of value-based healthcare, establishing significant clinical benefit will only be a part of the evidence base necessary for implementation and uptake of nonoperative approaches to the management of rectal cancer.
Nonoperative management, or watch and wait, is an emerging option in the treatment of rectal cancer. The goal is to spare select patients the morbidity of radical surgical resection while maintaining the excellent rates of tumor control afforded by traditional surgery-based trimodality therapy. Patient selection critically relies upon close and careful surveillance after a favorable response to CRT. To allow clinicians to optimally prognosticate which patients would derive the greatest benefit from the nonoperative management approach, patients must be able to provide the appropriate informed consent and undergo multiple and varied advanced diagnostic tests. The evidence supporting nonoperative management of rectal cancer continues to evolve, with several prospective trials and registries either directly or indirectly investigating outcomes of nonoperative approaches compared with traditional trimodality therapy. At this time, TME-based combined-modality therapy remains the standard of care for patients with locally advanced rectal cancer, and nonoperative management should not be routinely offered outside of clinical trials. With favorable results of this approach continuing to emerge, nonoperative management may represent a paradigm shift in the treatment of rectal cancer.
Financial Disclosure: Dr. Toesca holds an Investigator-Initiated Research Grant from the Varian Research Collaborations Program of Varian Medical Systems, Inc. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgment: Dr. Qian and Dr. Chin contributed equally to the writing of this article.
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