Nonoperative Management of Rectal Cancer: A Modern Perspective

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.

Introduction

An estimated 39,910 patients in the United States will be diagnosed with rectal cancer in 2017.[1] Surgery is the primary component of curative therapy, either alone for early-stage disease (T1N0 or T2N0) or as part of combined-modality therapy for locally advanced disease (T3/T4, or node-positive).[2] The standard of care is total mesorectal excision (TME) with sharp dissection of the mesorectum en bloc, which completely removes mesorectal nodal tissue; this procedure reduces positive radial margins and improves local control compared with blunt dissection techniques.[3] TME is performed with either low anterior resection or abdominoperineal resection (APR); in the latter procedure, the anal sphincter is removed, leaving patients with a permanent colostomy. In the current era of TME, the German Rectal Cancer Study Group demonstrated the superiority of preoperative over postoperative chemoradiotherapy (CRT).[4,5] Based on the outcomes of their studies,[4,5] neoadjuvant CRT-which consists of long-course radiation therapy (RT) with concurrent fluorouracil (5-FU)–based chemotherapy-followed by surgical resection then adjuvant chemotherapy was established as the standard of care in advanced rectal cancer. Neoadjuvant short-course RT using 25 Gy in 5 fractions with chemotherapy is an effective alternative to standard neoadjuvant CRT.[6,7]

It is important to bear in mind, however, that radical surgery combined with pelvic RT is associated with serious early and late effects. Long-term toxicities of surgery plus RT for rectal cancer can include chronic diarrhea, bowel obstruction, and permanent stoma, as well as significant rates of stoma reconstruction (for patients who undergo APR[8]), urinary dysfunction, anastomotic strictures, and sexual dysfunction.[4,9] Further, the mortality risk of surgery should be considered; for example, the rate of mortality was 1.3% in the postoperative treatment arm of the German Rectal Cancer Study Group trial.[4] Therefore, there is increasing interest in treatment de-escalation for lower-risk patients, with the hope of maintaining disease control in a subset of patients while sparing them from the toxicities and quality-of-life (QOL) effects associated with combined-modality therapy.

One such approach is nonoperative management, in which patients who have a clinical complete response (cCR) to CRT undergo close clinical surveillance, with surgery reserved as salvage treatment only. Nonoperative management may represent an appropriate option for select patients who have multiple comorbidities, are unable to tolerate a radical surgery, or want to avoid the potential adverse effects of TME. The rate of pathologic complete response (pCR) in patients who received neoadjuvant CRT was 8% in the German Rectal Cancer Study Group trial,[4] but pCR rates as high as 20% have been reported in other trials of neoadjuvant CRT.[10-13] Investigators have also demonstrated that intensive chemotherapy applied during the interval between the delivery of neoadjuvant CRT and surgical treatment can further improve the pCR. A recent phase II trial demonstrated the feasibility of delivering an increasing number of chemotherapy cycles of modified FOLFOX6 (5-FU, leucovorin, oxaliplatin; mFOLFOX6) after CRT and before TME; the highest pCR rate, 38%, was reported in patients who received the greatest number of cycles of mFOLFOX6.[14] Studies have shown that patients with rectal cancer who achieve a pCR have better long-term outcomes-including local control, distant control, disease-free survival (DFS), and overall survival (OS)-than patients who do not.[15-17] Patients who achieve a pCR after receiving neoadjuvant CRT would derive less benefit from radical surgery and may be the most appropriate candidates for nonoperative management. Table 1 highlights patient-related factors to consider when selecting patients for nonoperative management.

An inherent conundrum exists in that, by definition, nonoperative management does not involve pathologic confirmation of tumor response, so clinicians must rely on using cCR as a surrogate for pCR. Typically, clinical evaluation of tumor response is not based on any single test but rather on the combination of physical examination, endoscopic procedures, and imaging. Advances in diagnostic technologies have allowed physicians to improve prognostication for tumor response and pCR, and thereby have further optimized selection of appropriate patients for nonoperative management.

In this article, we provide a summary of nonoperative management of locally advanced rectal cancer in the modern era. Our focus is on technical details of tumor response and patient assessment after CRT, as well as a review of existing clinical data.

Tumor Response and Patient Assessment After Neoadjuvant CRT

The success of nonoperative management for rectal cancer is predicated on the accurate assessment of tumor eradication after CRT, without pathologic verification. Therefore, clinical evidence of complete response must be utilized as a marker to predict the likelihood of pCR. However, controversy exists over the appropriate duration of time between completion of CRT and assessment of clinical response, as well as the question of which nonsurgical diagnostic modalities most accurately detect the presence, or lack of, residual tumor.

The current standard of care for patients with rectal cancer typically involves tumor assessment 6 to 8 weeks after a patient has completed CRT.[18,19] Lack of consensus on the ideal timing of response assessment arises from data suggesting that longer time intervals between the end of treatment and the initial posttreatment patient assessment are perhaps associated with improved pCR rates.[20,21] Lyon R90-01 was a randomized trial comparing surgery performed 2 weeks after completion of RT vs surgery performed 6 to 8 weeks post treatment.[22] The investigators found significantly improved rates of pathologic downstaging without any differences in treatment-related toxicities, including anastomotic complications, reoperation rates, or postoperative mortality, in the patients who waited a longer period before surgery. Importantly, the combined pCR and near-pCR rate was 26% in the long-interval group and 10% in the short-interval group. These data provide strong evidence that a posttreatment time interval of at least 6 weeks must be allowed prior to the patient follow-up assessment, in order to capture delayed tumoricidal effects of RT.

More recent studies have investigated the hypothesis that even longer time intervals between treatment and clinical assessment of patients with rectal cancer may result in greater improvements in response rates. Tulchinsky et al found that an interval greater than 7 weeks between completion of CRT and surgery was associated with improved rates of pCR and near-pCR (35% vs 17% with intervals ≤ 7 weeks),[20] while Kalady et al demonstrated similar findings with a cutoff of 8 weeks.[21] In a recent meta-analysis of 13 studies investigating neoadjuvant CRT followed by surgical resection for rectal cancer, time intervals greater than 6 to 8 weeks between combined-modality treatment and surgery were associated with significantly improved pCR rates (19.5% vs 13.7% with intervals of ≤ 6 weeks).[23] Longer time intervals did not appear to negatively impact survival or surgical complication rates.

Sloothaak et al, in analyzing treatment information and clinical outcomes data on 1,593 rectal cancer patients in a large Dutch population database, found that an interval of 10 to 11 weeks between completion of RT and the date of surgery resulted in the highest pCR rate-18%, compared with pCR rates of 10% to 13% for patients undergoing surgery less than 10 weeks after RT.[24] However, they found that the pCR rate for patients whose surgery was performed more than 11 weeks after RT was also lower, at 11.8%. GRECCAR-6 was a prospective randomized trial evaluating intervals of 7 weeks vs 11 weeks between the end of RT and the performance of surgery in 265 patients; the investigators found no significant difference in pCR rates between the two groups (15% for the 7-week group vs 17.4% for the 11-week group; P = .6).[25] Based on the available data, the optimal timing of assessment of tumor response is likely approximately 7 to 10 weeks after completion of CRT.

There is also uncertainty regarding the appropriate diagnostic modalities for assessment of tumor response post treatment. Clinical evaluation of the patient post treatment may include digital rectal examination (DRE), endoscopy, and biomarker measurements. Preferred imaging modalities include CT, MRI, and positron emission tomography (PET). In general, DRE is the most important tool for assessment of primary tumor response, since this procedure may reveal findings that are not readily apparent on radiographic imaging. While DRE has fairly poor sensitivity for predicting complete response, its specificity is high. For example, one prospective study found that only 21% of patients with pCR had a negative preoperative DRE. Conversely, there were no instances in which DRE findings were negative and residual tumor was then discovered on pathology.[26] Endoscopy with biopsy has also been studied, although the positive and negative predictive values of this approach may also be suboptimal, due to sampling error.[27] In addition, the presence of residual mucosal abnormalities may not correlate well with pCR: in one series, investigators found that 19 of 31 pathologic specimens (61%) classified as ypT0 after CRT contained visible mucosal lesions, including ulceration or a polypoid mass, that precluded defining the tumor response as cCR.[28] Another limitation of DRE and endoscopy relates to the evaluation of nodal response. The accuracy of endoscopic ultrasound in restaging nodal involvement after CRT has been reported to range between 39% and 83%.[29]

Radiographic imaging serves as a potentially noninvasive means of evaluating both the primary site and any nodal disease. PET/CT imaging has been of particular interest, given its theoretical benefit of detecting metabolically active disease and distinguishing it from posttreatment tumor changes. Guillem et al conducted a prospective study investigating its utility in this setting but concluded that fluorodeoxyglucose-PET or CT alone did not provide adequate predictive value for distinguishing pCR from incomplete response.[30] Among patients with a pCR, the investigators found that PET accurately detected complete response in 54% of patients and CT did so in 19%. Among 95 patients with less than a pCR, PET and CT accurately identified 66% and 95%, respectively, as incomplete responders. CT has been reported to be 62% and 82% accurate when using size cutoffs of 5 mm and 10 mm, respectively, for nodal involvement.[31,32] Although the majority of studies of PET/CT restaging after neoadjuvant CRT have focused on the primary tumor and not specifically on nodal involvement, Maffione et al reported the overall accuracy of PET/CT, with sensitivity and specificity rates of 73% and 77%, respectively.[33] A study investigating the use of positron emission tomography (PET) for evaluation of response to neoadjuvant CRT in rectal cancer showed that after 6 weeks post CRT completion, a subset of patients demonstrated an increase in tumor metabolism, suggestive of tumor repopulation; they concluded that these “bad” responders-whom they defined as patients with an early increase in maximum standardized uptake volume at 6-week PET/CT-might benefit from individually tailored selection of CRT/surgery intervals.[34]

MRI, including the addition of diffusion-weighted imaging (DWI), holds significant promise for accurately detecting pCR. In one prospective study, Lambregts et al found that the use of DWI in addition to standard MRI sequences improved the sensitivity of pCR detection from 0% to 40% to between 52% and 64%, while specificity remained high at 89% to 98%.[35] These results were validated in a larger multi-institutional study, which reported sensitivity and specificity rates of 70% and 98%, respectively, for DWI.[36] The accuracy of MRI with standard imaging sequences has been reported to be 65% for nodal staging after neoadjuvant CRT.[37] van Heeswijk et al have shown that restaging MRI with DWI sequences can reliably predict for yN0 status after CRT, with 100% sensitivity, 14% specificity, 24% positive predictive value, and 100% negative predictive value, when differentiating between yN0 and yN-positive patients.[38] Overall, imaging studies are useful in the restaging of primary tumor and nodal lymph nodes after neoadjuvant CRT; recent and emerging evidence support the value of PET/CT and MRI in this setting, especially with the addition of DWI sequences.

The utility of tumor markers, primarily carcinoembryonic antigen (CEA), has previously been studied in rectal cancer. Perez et al investigated the prognostic value of serum CEA levels prior to and after neoadjuvant CRT and observed a significant association between post-CRT CEA levels < 5 ng/dL and increased rates of both cCR and pCR.[39] However, they did not find any association between pre- and post-CRT CEA level differences and rates of either cCR or pCR. Low CEA levels after CRT may indicate a higher likelihood of pCR, but this test result should be interpreted in the context of clinical and imaging data to guide management decisions. Results of the aforementioned studies suggest that multiple modalities should be used for patient assessment, in order to most accurately identify patients with pCR who may not require surgical resection after CRT.

Clinical Data Supporting Nonoperative Management of Rectal Cancer

The nonoperative management of rectal cancer was initiated in 2004, through the pioneering work of Habr-Gama et al at the University of São Paulo School of Medicine. These investigators evaluated patients with resectable distal rectal cancer treated with neoadjuvant CRT to 50.4 Gy, retrospectively comparing the long-term results of 71 patients who achieved cCR after CRT without further surgery vs outcomes in 22 patients who underwent resection for clinical partial response (cPR) after CRT but ultimately were found to have achieved pCR. The OS and DFS rates at 5 years were 88% and 83% in the surgical cohort (in which 16 of the 22 patients underwent a definitive colostomy or diverting temporary ileostomy) and 100% and 92% in the nonoperative cohort, respectively.[40] Table 2 outlines outcomes of selected trials of nonoperative management of rectal cancer.

An expanded analysis confirmed these findings in 99 patients with sustained cCR after 12 months following neoadjuvant therapy who were managed nonoperatively. The authors reported a 13% recurrence rate; 5% had local recurrence, 7% had systemic recurrence, and 1% had both local and systemic recurrence. All local recurrences were successfully salvaged with surgery. Similar to the original results, in the expanded analysis, rates of 5-year OS and DFS were favorable, at 93% and 85%, respectively.[41] In 2014, results were expanded further to include 183 patients; 90 (49%) of these patients demonstrated a cCR after neoadjuvant CRT and were followed with nonoperative management. Seventeen (19%) patients experienced a recurrence within 12 months after receiving CRT, highlighting the need for close surveillance in the immediate posttreatment period. Nevertheless, successful salvage was possible for 93% of the patients with local recurrences. The reported overall rate of local disease control was 94% after salvage surgery, with a 78% rate of organ preservation at 5-year follow-up for the 90 patients who were managed nonoperatively.[42]

Another group from the National Institute of Cancer of Brazil, led by Araujo et al, conducted a separate retrospective analysis of disease recurrence in 42 patients who were managed nonoperatively, compared with 69 patients who had pCR after undergoing surgical resection. After 47 months of follow-up, overall recurrence rates were 28% in patients who received nonoperative management and 12% in surgically managed patients; isolated local recurrence rates in the nonoperatively vs surgically managed patients were 11% and 1.4%, respectively. Nonoperatively managed patients had a local control rate of 81%, and 80% of the patients who experienced isolated local relapse were surgically salvaged. Although no statistically significant difference in OS was found (71.6% with nonoperative management vs 89.9% with surgery), the DFS outcomes favored the surgical group (82.8% vs 60.9% with nonoperative management), leading the authors to caution against routine use of nonoperative management of rectal cancer outside of the clinical trial setting.[43]

Similar to the Brazilian experience, an Australian group retrospectively analyzed long-term outcomes of 48 patients with potentially resectable rectal cancer who underwent neoadjuvant therapy but not surgery, due to medical inoperability or refusal. There was a 56% rate of cCR after neoadjuvant CRT or long-course RT alone, with over half of the patients free from progression after 5 years.[44] As might be expected, the rates of progression-free survival and OS were lower than those reported by the Brazilian studies, since patients in the Australian study were generally elderly and frail, with a subset receiving RT without chemotherapy. Overall, the Brazilian and Australian trials introduced the concept of nonsurgical management of distal rectal cancer after long-course CRT as an alternative strategy for patients with cCR. The outcomes of these trials also provided evidence that high rates of long-term local control of rectal cancer could be achieved with nonoperative approaches. The seminal work of the Habr-Gama group in Brazil has spurred further interest in nonoperative management of rectal cancer through prospective cohort studies, large-scale population-based studies, and randomized prospective clinical trials.

Continuing their effort to characterize outcomes of nonoperative management of distal rectal cancer, Habr-Gama et al tested a more intensive neoadjuvant CRT regimen in a prospective single-arm study of 70 patients. Neoadjuvant treatment consisted of 54 Gy of RT and 6 cycles of 5-FU/leucovorin (with 3 cycles delivered concurrently and 3 delivered after RT). Patients were assessed for tumor response at 10 weeks after completion of RT. Initially, 47 (68%) patients presented with cCR, but 8 (17%) developed early tumor regrowth within the first 12 months of follow-up. Ultimately, 39 (57%) maintained a sustained cCR beyond 12 months. There were 4 (10%) cases of late recurrences, all of which were successfully salvaged by surgery. The 3-year OS rate was 94%, including a 51% rate of organ preservation.[45]

In a small prospective study, Maas et al, from Maastricht University Medical Centre in the Netherlands, evaluated a policy of “wait and see” rather than surgery post RT for rectal cancer (Table 3). A total of 21 patients with rectal cancer who achieved cCR after neoadjuvant CRT were followed with MRI and endoscopy with biopsies without surgery. Functionality and outcomes in the wait-and-see group were compared with those of a control group of 20 patients who achieved pCR after neoadjuvant CRT and TME. Among the 21 wait-and-see patients, 20 (95%) were free from disease at a mean follow-up of 25 months; a single patient had a local recurrence and underwent salvage surgery. The control group had 2-year DFS and OS rates of 93% and 91%, respectively.[46] Also in the Netherlands, Appelt et al conducted a single-institutional, prospective, single-arm, observational trial of high-dose CRT (RT at 60 Gy in 30 fractions to tumor, 50 Gy in 30 fractions to elective lymph nodes, a 5-Gy endorectal brachytherapy boost, and concomitant tegafur-uracil) and watchful waiting to determine the proportion of patients with resectable T2–T3 lower rectal cancers who can be managed nonoperatively. Of 51 eligible patients who were treated with high-dose CRT, 40 (78%) patients achieved cCR and underwent watchful waiting, with local recurrence rates of 15.5% and 25.9% at 1 year and 2 years, respectively.[47] Posttreatment sphincter preservation rates were excellent: 72% at 1 year and 69% at 2 years. All patients in the study were alive at 2 years. The authors concluded that high-dose definitive CRT could be a safe alternative to APR for patients with distal rectal cancer.[47]

Given that the majority of prior evidence supporting nonoperative management of rectal cancer with watch-and-wait approaches has been derived from retrospective, single-institutional, or noncomparative studies, Renehan et al from the United Kingdom sought to prospectively assess oncologic outcomes of nonoperative management of rectal cancer in patients achieving cCR. Their OnCoRe study was a propensity score–matched cohort analysis of patients with nonmetastatic rectal cancer treated with neoadjuvant CRT (45 Gy in 25 fractions with concurrent fluoropyrimidine-based chemotherapy). A total of 129 patients who had cCR after CRT were offered nonoperative management and were compared one-to-one with paired cohorts of patients who underwent surgical resection using propensity score matching. The rate of local recurrence at 3-year follow-up was 34% for patients managed nonoperatively, and 88% of the nonmetastatic locally recurrent tumors were salvageable. There were no significant differences in 3-year DFS rates (88% with watch and wait vs 78% with surgery) and OS rates (96% vs 87%, respectively); nonoperatively managed patients had better rates of colostomy-free survival than surgical patients, with a 26% absolute difference in avoidance of permanent colostomy at 3 years.[48] This UK population–based matched cohort analysis further affirmed that many patients with rectal cancer managed by a nonoperative watch-and-wait approach could avoid major surgery and permanent colostomy, without compromising local control.

Although a large proportion of the data supporting nonoperative management of rectal cancer originated outside of the United States, JD Smith et al retrospectively analyzed outcomes in 32 patients with stage I to III rectal cancer managed nonoperatively after achieving a cCR. At a median follow-up of 28 months, there was an 18.8% rate of local failure; all cases were controlled by salvage surgery, with no further local recurrence. The 2-year rates of DFS (88% vs 98%) and OS (96% vs 100%) were similar between the nonoperatively managed patients and a comparative cohort who underwent standard TME and achieved pCR.[49] In an expanded and updated comparative analysis of 73 patients managed nonoperatively after cCR vs 72 patients who achieved pCR after surgery, 4-year disease-specific survival (91% vs 96%) and OS (91% vs 95%) were similar, with a 72% rate of rectal preservation in the nonoperatively managed cohort. Therefore, the authors concluded that in a highly selected group of patients with cCR to neoadjuvant therapy, nonoperative management in combination with salvage surgery, if necessary, could achieve oncologic outcomes similar to those of patients with a pCR after resection.[50]

Nonoperative management of rectal cancer is under active investigation. Investigators from Memorial Sloan Kettering Cancer Center on behalf of the OSTRiCh (Optimizing the Surgical Treatment of Rectal Cancer) Consortium are leading a multi-institutional phase II study (ClinicalTrials.gov identifier: NCT02008656) of the efficacy of total neoadjuvant CRT with induction vs consolidation chemotherapy with FOLFOX or CAPOX (capecitabine and oxaliplatin), followed by observation for patients who achieve cCR and TME for patients with residual tumor.[51] Although the treatment randomization in this trial is not specifically between nonoperative management and TME, the goal is to compare rates of 3-year DFS in a large population of patients with locally advanced rectal cancer, analyzing clinical outcomes of patients with cCR managed nonoperatively vs those with pCR after TME. In addition, an ongoing prospective randomized phase II trial (ClinicalTrials.gov identifier: NCT02052921) has been opened by the Instituto do Câncer do Estado de São Paulo (ICESP) in Brazil, comparing a watch-and-wait (nonoperative) approach vs surgery in patients with locally advanced rectal cancer who achieve a cCR after neoadjuvant CRT.

Overall, the nonoperative management approach pioneered by the Brazilian ICESP group has emerged as an attractive alternative for patients who are medically unfit for, or want to avoid, surgery. The initial retrospective evidence from the Brazilian Group[40-42] demonstrates local control and DFS outcomes similar to those of patients who achieve a pCR after neoadjuvant CRT and surgery. Prospective single-arm protocols and cohort analyses have affirmed the feasibility of this approach, with a prospective single-arm study demonstrating an especially high cCR rate of 68%.[47] Current prospective comparison trials (including the ICESP study) directly address the question of benefit from nonoperative management in a randomized fashion. In addition, the International Watch & Wait database is an initiative to prospectively register all patients with rectal cancer managed nonoperatively, with the intention of accruing a dataset large enough to reduce confounding and bias, in order to assess long-term outcomes of nonoperative management.[52] The most recent update from this database provides preliminary outcomes data: in 679 patients with cCR after induction therapy (90% managed with CRT), local control and OS rates at 3 years were 75% and 91%, respectively. Across all patients, the imaging surveillance protocol after therapy was variable, with 64%, 25%, and 6% of patients evaluated with MRI, CT, or endorectal ultrasound, respectively. Given the heterogeneity in induction therapy techniques and follow-up imaging strategies, the authors commented that collection of more data from this registry is necessary to determine the oncologic safety of omitting surgery.[53]

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.[54] After publication of the German Rectal Cancer Study Group trial in 2004,[4] 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.[55] 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[51] (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.[58] 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,[23] and this timeframe has been adopted accordingly in the assessment of clinical response after CRT in nonoperative management approaches.[14] 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.[14] 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.[59] 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.

Conclusions

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.

References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7-30.

2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Rectal cancer. Version 3.2017. Updated March 13, 2017. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed July 6, 2017.

3. MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341:457-60.

4. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-40.

5. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926-33.

6. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215-23.

7. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012; 30:3827-33.

8. Luna-Pérez P, Rodríguez-Ramírez S, Vega J, et al. Morbidity and mortality following abdominoperineal resection for low rectal adenocarcinoma. Rev Invest Clin. 2001;53:
388-95.

9. Hendren SK, O’Connor BI, Liu M, et al. Prevalence of male and female sexual dysfunction is high following surgery for rectal cancer. Ann Surg. 2005;242:212-23.

10. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29:2773-80.

11. Gérard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010;28:1638-44.

12. Rödel C, Graeven U, Fietkau R, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16:979-89.

13. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27:5124-30.

14. Garcia-Aguilar J, Chow OS, Smith DD, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015;16:957-66.

15. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835-44.

16. Zorcolo L, Rosman AS, Restivo A, et al. Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis. Ann Surg Oncol. 2012;19:2822-32.

17. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012;99:918-28.

18. Goodman KA. Definitive chemoradiotherapy (“watch-and-wait” approach). Semin Radiat Oncol. 2016;26:205-10.

19. Habr-Gama A, São Julião GP, Perez RO. Nonoperative management of rectal cancer: identifying the ideal patients. Hematol Oncol Clin North Am. 2015;29:135-51.

20. Tulchinsky H, Shmueli E, Figer A, et al. An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol. 2008;15:2661-7.

21. Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009; 250:582-9.

22. Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol. 1999;17:2396.

23. Petrelli F, Sgroi G, Sarti E, Barni S. Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies. Ann Surg. 2016;263:458-64.

24. Sloothaak DA, Geijsen DE, van Leersum NJ, et al. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2013;100:933-9.

25. Lefevre JH, Mineur L, Kotti S, et al. Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer: a multicenter, randomized, controlled trial (GRECCAR-6). J Clin Oncol. 2016 Jul 18. [Epub ahead of print]

26. Guillem JG, Chessin DB, Shia J, et al. Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate end point. J Clin Oncol. 2005; 23:3475-9.

27. Perez RO, Habr-Gama A, Pereira GV, et al. Role of biopsies in patients with residual rectal cancer following neoadjuvant chemoradiation after downsizing: can they rule out persisting cancer? Colorectal Dis. 2012;14:714-20.

28. Smith FM, Chang KH, Sheahan K, et al. The surgical significance of residual mucosal abnormalities in rectal cancer following neoadjuvant chemoradiotherapy. Br J Surg. 2012; 99:993-1001.

29. De Nardi P, Carvello M. How reliable is current imaging in restaging rectal cancer after neoadjuvant therapy? World J Gastroenterol. 2013;19:5964-72.

30. Guillem JG, Ruby JA, Leibold T, et al. Neither FDG-PET nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study. Ann Surg. 2013;258:289-95.

31. Pomerri F, Pucciarelli S, Maretto I, et al. Prospective assessment of imaging after preoperative chemoradiotherapy for rectal cancer. Surgery. 2011;149:56-64.

32. Maretto I, Pomerri F, Pucciarelli S, et al. The potential of restaging in the prediction of pathologic response after preoperative chemoradiotherapy for rectal cancer. Ann Surg Oncol. 2007;14:455-61.

33. Maffione AM, Marzola MC, Capirci C, et al. Value of 18F-FDG PET for predicting response to neoadjuvant therapy in rectal cancer: systematic review and meta-analysis. Am J Roentgenol. 2015;204:1261-8.

34. Perez RO, Habr-Gama A, São Julião GP, et al. Optimal timing for assessment of tumor response to neoadjuvant chemoradiation in patients with rectal cancer: do all patients benefit from waiting longer than 6 weeks? Int J Radiat Oncol Biol Phys. 2012;84:1159-65.

35. Lambregts DM, Vandecaveye V, Barbaro B, et al. Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study. Ann Surg Oncol. 2011;18:2224-31.

36. Lambregts DM, Rao SX, Sassen S, et al. MRI and diffusion-weighted MRI volumetry for identification of complete tumor responders after preoperative chemoradiotherapy in patients with rectal cancer: a bi-institutional validation study. Ann Surg. 2015;262:1034-9.

37. Kim DJ, Kim JH, Lim JS, et al. Restaging of rectal cancer with MR imaging after concurrent chemotherapy and radiation therapy. Radiographics. 2010;30:503-16.

38. van Heeswijk MM, Lambregts DM, Palm WM, et al. DWI for assessment of rectal cancer nodes after chemoradiotherapy: is the absence of nodes at DWI proof of a negative nodal status? AJR Am J Roentgenol. 2017;208:W79-W84.

39. Perez RO, São Julião GP, Habr-Gama A, et al. The role of carcinoembriogenic antigen in predicting response and survival to neoadjuvant chemoradiotherapy for distal rectal cancer. Dis Colon Rectum. 2009;52:1137-43.

40. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240:711-7.

41. Habr-Gama A, Perez RO, Proscurshim I, et al. Patterns of failure and survival for nonoperative treatment of stage c0 distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg. 2006;10:1319-28.

42. Habr-Gama A, Gama-Rodrigues J, São Julião GP, et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys. 2014;88:822-8.

43. Araujo RO, Valadão M, Borges D, et al. Nonoperative management of rectal cancer after chemoradiation opposed to resection after complete clinical response: a comparative study. Eur J Surg Oncol. 2015;41:1456-63.

44. Lim L, Chao M, Shapiro J, et al. Long-term outcomes of patients with localized rectal cancer treated with chemoradiation or radiotherapy alone because of medical inoperability or patient refusal. Dis Colon Rectum. 2007;50:2032-9.

45. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management? Dis Colon Rectum. 2013;56:1109-17.

46. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29:4633-40.

47. Appelt AL, Pløen J, Harling H, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015;16:919-27.

48. Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2016;17:174-83.

49. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg. 2012;256:965-72.

50. Smith JJ, Chow OS, Eaton A, et al. Organ preservation in patients with rectal cancer with clinical complete response after neoadjuvant therapy. J Clin Oncol. 2015;33(suppl 3):abstr 509.

51. Smith JJ, Chow OS, Gollub MJ, et al. Organ preservation in rectal adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer. 2015;15:767.

52. Breugom AJ, van de Velde CJ. Is it time for watchful waiting for rectal cancer? Lancet Oncol. 2015;16:875-6.

53. van der Valk M; International Watch and Wait Database Consortium. The International Watch & Wait database (IWWD) for rectal cancer: an update. J Clin Oncol. 2017;35(suppl 4S):abstr 521.

54. National Institutes of Health consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-50.

55. Goodman KA, Patton CE, Fisher GA, et al. Appropriate customization of radiation therapy for stage II and III rectal cancer: executive summary of an ASTRO Clinical Practice Statement using the RAND/UCLA Appropriateness Method. Pract Radiat Oncol. 2016;6:166-75.

56. Allal AS, Bieri S, Pelloni A, et al. Sphincter-sparing surgery after preoperative radiotherapy for low rectal cancers: feasibility, oncologic results and quality of life outcomes.
Br J Cancer. 2000;82:1131-7.

57. Kasparek MS, Hassan I, Cima RR, et al. Quality of life after coloanal anastomosis and abdominoperineal resection for distal rectal cancers: sphincter preservation vs quality of life. Colorectal Dis. 2011;13:872-7.

58. Habr-Gama A, Lynn PB, Jorge JM, et al. Impact of organ-preserving strategies on anorectal function in patients with distal rectal cancer following neoadjuvant chemoradiation. Dis Colon Rectum. 2016;59:264-9.

59. van der Stok EP, Spaander MCW, Grünhagen DJ, et al. Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol. 2017;14:297-315.