Nonoperative Management of Rectal Cancer

Transcription

1 Review Article Nonoperative Management of Rectal Cancer Jordan A. Torok, MD; Manisha Palta, MD; Christopher G. Willett, MD; and Brian G. Czito, MD Surgery has long been the primary curative modality for localized rectal cancer. Neoadjuvant chemoradiation has significantly improved local control rates and, in a significant minority, eradicated all disease. Patients who achieve a pathologic complete response to neoadjuvant therapy have an excellent prognosis, although the combination treatment is associated with long-term morbidity. Because of this, a nonoperative management (NOM) strategy has been pursued to preserve sphincter function in select patients. Clinical and radiographic findings are used to identify patients achieving a clinical complete response to chemoradiation, and they are then followed with intensive surveillance. Incomplete, nonresponding and those demonstrating local progression are referred for salvage with standard surgery. Habr-Gama and colleagues have published extensively on this treatment strategy and have laid the groundwork for this approach. This watch-and-wait strategy has evolved over time, and several groups have now reported their results, including recent prospective experiences. Although initial results appear promising, several significant challenges remain for NOM of rectal cancer. Further study is warranted before routine implementation in the clinic. Cancer 2016;122: VC 2015 American Cancer Society. KEYWORDS: neoadjuvant therapy, nonoperative, radiation therapy, rectal cancer, watchful waiting. INTRODUCTION In 2015, an estimated 40,000 cases of rectal cancer will be diagnosed in the United States. 1 Surgical therapy, by either low anterior resection (LAR) or abdominoperineal resection (APR), has long been considered the primary curative modality for localized disease. In recent decades, a paradigm shift for locally advanced disease has occurred: postoperative chemoradiation therapy (CRT) has largely been supplanted by a neoadjuvant approach, either through short-course radiation therapy (RT) alone or long-course CRT. This shift has been paralleled by improvements in preoperative imaging and staging, including endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI), as well as advancements in surgical techniques. Although the initial rationale for neoadjuvant treatment was to decrease local recurrence rates, improve treatment tolerability, and increase sphincter-preserving surgery rates, a small but significant percentage of patients were found to be complete pathologic responders upon examination of the surgical specimen. Investigators have since explored definitive CRT and careful follow up, also called nonoperative management (NOM), as a curative approach for select patients, with surgery reserved as salvage therapy. This review aims to critically evaluate NOM of rectal cancer in the modern era. BACKGROUND The preferred surgical approach for rectal cancer depends on the location of the cancer in relation to the anal sphincter complex: a sphincter-preserving LAR is reserved for proximal and midrectal lesions, and an APR requiring a permanent stoma is reserved for distal lesions. Both types of resections now preferentially use total mesorectal excision (TME); this technique removes a circumferential envelope of perirectal tissue in its entirety and has been found to reduce local recurrence rates in comparison with the historical blunt dissection approach. 2 Numerous perioperative complications, including vascular injury and/or presacral bleeding, 3 infection, wound complications, ureteral injury, 4 and both urinary and sexual dysfunction, 5,6 have been associated with this procedure. In the Dutch TME prospective, randomized controlled trial, which allocated patients to TME alone or a short course of neoadjuvant RT followed by TME, observed in-hospital/ postoperative mortality and overall complication rates were 3% and 47%, respectively. 7,8 Complication rates from TME with or without RT were similar; complications included perioperative bleeding in approximately 13%, anastomotic leaks in approximately 11% (LAR patients), and operative reintervention in approximately 14%. Higher overall complication rates were seen in patients treated with APR versus LAR. Neoadjuvant RT was, however, associated with increased blood Corresponding author: Brian G. Czito, MD, Department of Radiation Oncology, Duke University Medical Center, Box 3085, Durham, NC 27710; Fax: (919) ; brian.czito@dm.duke.edu Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina. DOI: /cncr.29735, Received: August 4, 2015; Revised: September 16, 2015; Accepted: September 21, 2015, Published online November 24, 2015 in Wiley Online Library (wileyonlinelibrary.com) 34 Cancer January 1, 2016

2 NOM of Rectal Cancer/Torok et al loss and increased perineal complications in those undergoing APR. 8,9 With longer follow up, patients treated with neoadjuvant RT were more likely to experience chronic bowel dysfunction, 10,11 urinary incontinence, 12 and small bowel obstruction. 13,14 Patients in the United States with American Joint Committee on Cancer stage I lesions (tumor invasion of the submucosa [T1] or muscularis propria [T2] and no regional lymph node [N0] or distant metastases [M0]) 15 are usually treated with surgery alone, whereas most patients with a T3-T4 stage (the tumor invades through the muscularis propria into pericolorectal tissues [T3], penetrates to the surface of the visceral peritoneum [T4a], or directly invades or is adherent to other organs or structures [T4b]) and/or any lymph node metastases are treated with a combined-modality approach followed by surgical resection. Uniform treatment of these patients exposes them to a risk of acute perioperative and long-term morbidity as seen in the Dutch TME trial, particularly with distal tumors planned for APR. A nonoperative strategy may avoid the complications associated with TME. This is of particular concern for elderly patients and for those with significant medical comorbidities. Another potential concern is the perceived reduction in quality of life with a permanent stoma. Compared with patients undergoing LAR, APR patients have an inferior perceived body image as well as impaired sexual and urinary function. 16,17 In contrast, LAR patients may experience worse gastrointestinal tract symptoms in comparison with APR patients, with similar overall quality-of-life scores. These factors have influenced the rationale for NOM. The potential clinical effectiveness of NOM is highlighted by pathologic response rates from neoadjuvant trials, particularly those using long-course CRT for locally advanced cancers. Pathologic complete response (pcr) rates in these trials range from 8% to 20% Subsequent recurrence in patients achieving a pcr is uncommon, 20,25 with several large meta-analyses reporting significantly lower cumulative rates of local recurrence ranging from 0.7% to 0.8% as well as improved overall survival (OS) and disease-free survival (DFS) in comparison to partial responders or nonresponders Although the majority of these studies have used TME, evidence also suggests a similarly favorable prognosis for those who undergo local excision. 29 Most of these studies use longcourse CRT regimens in which surgery is delayed by 6 to 8 weeks after treatment completion. Retrospective evidence suggests a higher incidence of pcr with longer intervals between CRT and surgery One prospective trial found that delaying surgery to 11 weeks after CRT with integration of intensified chemotherapy (mfol- FOX6) during the rest period increased the pcr rate to 25% versus 18% with the usual 6-week period. 33 A recent update of this study reported on 2 additional study groups with surgery delayed by 15 and 19 weeks (4 vs 6 intervening cycles of mfolfox6); this resulted in pcr rates of 30% and 38%, respectively. 34 In standard short-course RT, surgery is typically performed 1 week later, with pcr rarely observed (1%) with this interval. 35,36 Prolonging the interval from preoperative RT to surgery by 2 versus 6 to 8 weeks, as in the Lyon trial, improved the pcr rate from 7% to 14%. 37 Delayed surgery did not appear to compromise clinical outcomes in several studies. 38,39 Theoretically, if no viable tumor remains, then surgery may not add clinical benefit while potentially increasing morbidity. By definition, NOM precludes pathologic confirmation of the primary tumor and lymph node response. As a result, a clinical complete response (ccr) is used as a surrogate for pcr. The determination of a ccr is defined variably, but it is typically assessed with a combination of digital rectal examination (DRE), direct visualization by proctoscopy, and imaging studies with or without biopsy confirmation. Imaging modalities have been investigated to assess pcr. Fluorodeoxyglucose positron emission tomography and computed tomography (CT) appear limited in their ability to distinguish pcr from partial responses. 40 EUS and MRI are important techniques in the preoperative staging of rectal cancer. In one meta-analysis, EUS was found to have increased sensitivity for perirectal tissue invasion in comparison with MRI (90% vs 82%), although the 2 modalities had similar rates of sensitivity and specificity for nodal involvement (66%-67% and 76%-78%, respectively). 41 The sensitivity of EUS is highest for advanced disease and decreases to approximately 80% for T2 disease. 42 In contrast to a pretreatment evaluation, a systematic review and meta-analysis of studies investigating standard MRI and EUS for restaging after neoadjuvant treatment found that these techniques overstaged 73% and 66% of patients with ypt0 disease, respectively. 43 Both techniques had poor sensitivity for ypt0 disease (MRI, 15%; EUS, 37%) but high specificity (95% for both). Multiparametric MRI appears to have increased utility in predicting pcr Although visual and digital palpation can supplement the evaluation of the primary tumor, the response of clinically involved lymph node metastases relies solely on imaging. The nodal restaging accuracy for both standard MRI and EUS has been reported to be approximately 72%. 43 Several Cancer January 1,

3 Review Article studies have shown that nodal responses tend to mirror the response of the primary tumor, with ypn 1 rates 5% in patients with ypt0 disease. 47 Lymph node size, morphology, or both, typically based on MRI, appear to correlate with residual metastases. 48 The reported accuracy of MRI in assessing complete response in initially involved lymph nodes ranges from 80% to 90%, 49,50 with additional techniques such as contrast enhancement potentially improving these rates. 51 Because of the potential predictive value of MRI, it has been incorporated by some groups into the assessment of ccr. NOM Investigators from the Angelita and Joaquim Gama Institute (University of Sao Paulo School of Medicine) have published their NOM results for patients with potentially resectable rectal cancer. In one early report, Habr-Gama et al 52 reported the outcomes of 265 patients with distal ct2-t4 and/or N 1 rectal cancer (0-7 cm from the anal verge) treated with neoadjuvant CRT (5040 cgy with infusional 5-fluorouracil). Patients were re-evaluated at least 8 weeks after the completion of CRT with clinical, endoscopic, and radiologic studies with biopsies obtained during proctoscopy for pathologic confirmation of a response. An incomplete response was defined as a residual ulcer/mass or positive biopsies, and these patients were subsequently managed with immediate surgery. Initial clinical complete responders underwent a strict watchand-wait strategy, including monthly physical/digital rectal examinations, proctoscopy, biopsy of any suspicious areas, and serum carcinoembryonic antigen (CEA) monitoring with abdominal pelvic CT every 6 months for the first year. Only patients with sustained tumor regression for at least 12 months were considered to have a ccr. After CRT, 71 patients (26.8%) of the patients met the criteria for a ccr. These patients had a mean follow-up of 57 months, during which 2 patients (2.8%), 0 patients, and 3 patients (4.2%) developed an endoluminal, pelvic, or systemic recurrence, respectively. Both local failures were treated successfully with salvage therapy. These results were updated with a larger patient cohort, and the feasibility of this approach was further described. 53 Importantly, this publication describes the numbers of both initial and sustained responders, with 20% of the initial complete responders developing tumor regrowth within 12 months. When only those patients who retained a ccr after 12 months were selected, the endorectal recurrence rate was 6% (all were treated with salvage therapy except for 1 patient with both local and systemic recurrence), and the 5-year OS and DFS rates were 93% and 85%, respectively. In the most recent report, the outcomes of all patients initially enrolled for the watch-andwait strategy, including those with early tumor regrowth, were reported. 54 An assessment 8 weeks after CRT found that 49% of the patients had a ccr. With a median follow-up of 60 months, 31% of the patients with an initial ccr developed a local recurrence. Of these recurrences, 60% occurred within the first 12 months. Salvage therapy was possible and effective for most local recurrences, with 7% of patients not amenable to salvage. Sphincter preservation was achieved in 86% of all patients with this strategy. Systemic recurrence was seen in 14% of patients, with 5-year cause-specific OS and DFS rates of 91% and 68%, respectively. These results are summarized in Table 1. It should be noted that these authors offered full-thickness local excision (FTLE) for small residual lesions and used radical resection for adverse pathologic findings or a strict surveillance program for patients with ypt0 disease. 55 Other reports of NOM have included patients who were medically inoperable or refused surgery. Lim et al 56 retrospectively reviewed 48 such patients in a multiinstitutional database in Australia. The median age of these patients was 76 years, and the majority had distal tumors (<8 cm from the anal verge) with T3 disease and were treated with CRT. In contrast to the Habr-Gama studies, follow-up was not as rigorous, and ccr was defined solely on the basis of the visual appearance at examination. In addition, salvage was not possible for many of these patients because of medical comorbidities. A ccr was reported for 56% of the patients, and after a median follow-up of 49 months, progression was seen in 37% (local component in 60%). Patients who achieved a ccr had significantly longer progression-free survival than incomplete responders. Maas et al 57 aimed to prospectively replicate the results from Sao Paulo with modern MRI techniques as part of a strict selection process. Patients were treated with a neoadjuvant regimen similar to that of the Habr-Gama studies, although capecitabine was used as part of the CRT regimen. According to their strict definition of a ccr, only 11% of patients were determined to be eligible for their wait-and-see policy. These patients were compared with a group that achieved a pcr (approximately half of whom required a permanent colostomy and 35% of whom had major operative complications). The 2-year DFS (89% vs 93%) and OS rates (100% vs 91%) were similar for the ccr and pcr patients. The 1 recurrence in the wait-and-see approach group was successfully salvaged with surgery. In addition, long-term bowel dysfunction 36 Cancer January 1, 2016

4 NOM of Rectal Cancer/Torok et al TABLE 1. Published Experience of Habr-Gama and Colleagues Time Period Source No. ccr Rate: Initial/Sustained, % Local/Pelvic Failures, % Salvage Rate, n/n (%) Systemic Recurrence, % Survival, % a Habr-Gama NR/27 3 2/2 (100) (5-y OS) a Habr-Gama /27 6 5/5 (100) 8 93 (5-y OS) b Habr-Gama / /28 (93) (5-y CSS) Abbreviations: ccr, clinical complete response; CSS, cancer-specific survival; NR, not reported; OS, overall survival. a Failure, salvage, and survival rates were based on sustained responders. Sustained response was defined as a ccr at 12 months. b Failure, salvage, and survival rates were based on initial responders was worse in operatively managed patients. The low ccr rate in this study versus Habr-Gama et al s study was likely a result of strict imaging criteria, which classified a ccr in only 5 of the 20 patients found to have a pcr in the operative group. Another prospective experience from Denmark evaluated patients with primary, resectable T2 or T3, N0-1 adenocarcinoma of the distal rectum (<6 cm). Patients were treated with high-dose radiotherapy (60 Gy in 30 fractions with a 5-Gy endorectal brachytherapy boost) and oral tegafur-uracil. Patients who achieved complete clinical regression according to endoscopy/biopsy and had no evidence of regional/distant metastases according to MRI/CT 6 weeks after treatment were prospectively observed. This watchful-waiting approach consisted of clinical examination and endoscopy every 2 months for year 1, every 3 months for year 2, every 6 months for year 3, and then annually, with biopsy reserved for suspicious lesions. Positron emission tomography/ct was performed 3 times in the first year, twice in the second year, and annually thereafter. Out of 51 eligible patients, 40 met the criteria for watchful waiting (78% ccr rate). 58 With a median follow-up of 24 months, the 1- and 2-year cumulative local recurrence rates for these patients were 15% and 26%, respectively. The median time to recurrence was 10.4 months, and all patients with local recurrence were surgically salvaged without additional recurrence. Approximately 70% of the patients retained sphincter function without fecal incontinence. Memorial Sloan Kettering Cancer Center investigators have reported further experience with NOM of rectal cancer. Smith et al 60 reviewed the outcomes of 32 patients achieving a ccr, and as in Maas et al s study, 57 they compared the outcomes with those of contemporaneous patients achieving a pcr with resection. The response assessment after CRT was not standardized during this period but was primarily based on the absence of a palpable tumor on digital rectal examination (DRE) or any visual pathology at endoscopy. With a median follow-up of 28 months, the actuarial local recurrence for NOM was 21% versus 0% in the pcr group. 60 All local failures, however, were successfully salvaged with surgery, and clinical outcomes were otherwise similar and favorable between the 2 groups. This experience was recently updated, now with 73 patients achieving ccr. A ccr in this update was defined on the basis of DRE, proctoscopy, and imaging criteria as assessed approximately 8 weeks after CRT. Patients with a ccr were followed with endoscopy and DRE at intervals of 3, 4, 6, and 12 months in year 1, year 2, years 3-5 and beyond 5 years, respectively. Imaging was performed every 6 months in years 1 and 2, followed by every 6 to 12 months in years 3 to 5. With a median follow-up of 3.5 years, local tumor regrowth was seen in 26%. 59 Nearly all patients with regrowth were salvaged with surgery, with preservation of the rectum in 77% of the patients. OS and disease-specific survival were again similar and favorable between the NOM and pcr groups. These experiences are summarized in Table 2. CRITICAL EVALUATION The experience with NOM for potentially resectable rectal cancer (primarily the experience of investigators at the University of Sao Paulo) has evolved with time. The majority of the patients in early studies were not initially staged or followed with modern imaging techniques, including MRI and endorectal ultrasound, so the assessment of ccr was based primarily on clinical examination. In the Habr-Gama studies, the definition of ccr necessitated intensive monthly follow-up beginning 8 weeks after CRT completion, and a 1-year disease-free interval was required for classification as a complete clinical responder. This effectively resulted in a highly selected patient population with favorable tumor biology. Not surprisingly, these patients had an excellent prognosis. Additionally, many of the previously discussed series have relatively short median follow up, and should be considered preliminary given the sometimes long natural history seen in rectal cancer recurrence. Cancer January 1,

5 Review Article TABLE 2. Additional Published Experience of Patients With Clinical Complete Responses Managed Nonoperatively Source No. Follow-Up, mo Local/Pelvic Failures, % Salvage Rate, n/n (%) Systemic Recurrence, % Overall Survival, % Maas /1 (100) (2 y) Smith /19 (95) (4 y) Appelt /9 (100) (2 y) The definition of ccr and how it predicts pcr requires further clarification. A pcr assessment requires an operative intervention; therefore, it is problematic to extrapolate the favorable results of patients with a pcr to those with a ccr. In a series from Memorial Sloan Kettering Cancer Center evaluating patients treated with neoadjuvant CRT followed by a planned resection in 6 weeks, pcr was seen in only 25% of patients deemed as ccr by preoperative proctoscopy. 61 Although longer post-crt intervals may result in higher response rates, delayed surgery may be associated with inferior survival, 62 although this remains controversial. According to the Habr-Gama and Memorial Sloan Kettering series, most recurrences for patients with an initial ccr occur within the first 12 months. Although local salvage therapy may be possible for most of these patients, 30% of those with early regrowth developed systemic recurrence. 54 These patients likely had an unfavorable biology and/or subclinical residual disease that was not appreciated on re-evaluation. Whether early surgery would have benefited these patients is unknown. The process of selecting operative versus nonoperative strategies based on clinical assessment is also confounded by the fact that patients with residual abnormalities may have in fact responded well, with 8% of nonresponders demonstrating a pcr in the Habr- Gama series 52 and 75% demonstrating a pcr in the more restrictive Maas series. 57 The latter series particularly emphasizes the potential mismatch between clinical and imaging criteria for a ccr and an actual response. Habr- Gama and colleagues offer FTLE for patients with small (<3-cm) residual abnormalities. In one report, 20% of these patients were found to have ypt0 disease, 63 and this further highlights the inaccuracy of clinical restaging. FTLE allows confirmation of the pathologic response but has several drawbacks, including the potential for morbidity 63 and higher local failure rates. 64 Another important consideration is the toxicity and quality of life after definitive CRT for rectal cancer. Although the report from Maas et al 57 suggests improved bowel function with NOM, there is little additional evidence documenting the toxicity and quality of life following definitive CRT. Although a different treatment regimen is used, definitive CRT for anal canal carcinoma is associated with adverse effects on quality of life, including long-term sexual and bowel dysfunction. 65 Although NOM may improve sphincter-preservation rates, a nonfunctioning or poorly functioning sphincter will result in a significantly detrimental impact on quality of life. The intensity of follow-up and resources necessary to assess and monitor a ccr may also have a significant impact on quality of life and health care costs. FUTURE DIRECTIONS Further study of radiographic and biologic predictors of ccr/pcr may ultimately facilitate improved selection of patients eligible for NOM instead of a waiting period for all patients. Radiographic techniques, particularly MRI, have already shown promise for defining favorable outcomes after neoadjuvant CRT. 66 Additional improvements are necessary to improve the accuracy of ccr assessment. Biomarkers and gene expression profiles may also serve as predictive tools. Low pretreatment CEA levels have been associated with an improved pathologic response Low posttreatment CEA levels (<5-6 ng/ ml) may indicate significant pathologic downstaging when the pretreatment level was elevated. 70,71 Certain genetic expression profiles have also been correlated with tumor response, 72 but reproducing these results in independent cohorts has been challenging. 73 Prospective trials are ultimately needed before routine implementation of the NOM approach. Two randomized, multicenter clinical trials are currently ongoing that will help to further clarify the role of NOM. Investigators from Sao Paulo are conducting a prospective phase 2 trial randomizing patients achieving a ccr 12 weeks after chemoradiotherapy to TME or close observation (NCT ). The primary endpoint will be 3- year DFS. Memorial Sloan Kettering Cancer Center investigators are also conducting a prospective phase 2 trial (NCT ), although the study design is more complex and does not directly address the question of 38 Cancer January 1, 2016

6 NOM of Rectal Cancer/Torok et al NOM. Patients will be randomized to 1 of 3 arms: 2 experimental arms investigating the use and timing of neoadjuvant chemotherapy (before or after neoadjuvant CRT but before surgery) and a standard arm consisting of neoadjuvant CRT, TME, and adjuvant chemotherapy. The experimental arms include TME or NOM as treatment approaches. As before, the primary endpoint will be 3- year DFS. In the United Kingdom, a single-arm prospective study is underway to determine the safety of NOM after a response to preoperative CRT. Patients will have MRI performed 4 weeks after long-course CRT, and if no viable disease or a partial response is seen, MRI will be repeated at 8 weeks. Patients who remain disease-free or continue to respond will be eligible for continued observation. Taken together, these trials will further help to identify a select population appropriate for NOM and provide further clinical information regarding its safety and efficacy. Because of the intensive follow-up of NOM, costeffectiveness research will also be important in the future evaluations and development of this approach. CONCLUSIONS Initial reports of NOM for selected rectal cancer patients appear promising. The optimal tools for assessing ccr remain to be determined. Overly stringent criteria may exclude patients who may have or will respond to treatment, whereas broader criteria will require increased utilization of salvage surgery and the morbidity associated with resection. The intensive follow-up and extensive surgical and radiologic experience necessary for an NOM program may limit its widespread use. In addition, robust prospective experiences and prospective quality-of-life and toxicity data are currently lacking. At present, combined-modality therapy including TME should remain the standard of care for locally advanced rectal cancer pending further prospective validation of a nonoperative approach. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, CA Cancer J Clin. 2015;65: MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341: D Ambra L, Berti S, Bonfante P, Bianchi C, Gianquinto D, Falco E. Hemostatic step-by-step procedure to control presacral bleeding during laparoscopic total mesorectal excision. World J Surg. 2009;33: Halabi WJ, Jafari MD, Nguyen VQ, et al. Ureteral injuries in colorectal surgery: an analysis of trends, outcomes, and risk factors over a 10-year period in the United States. Dis Colon Rectum. 2014;57: Tekkis PP, Cornish JA, Remzi FH, et al. Measuring sexual and urinary outcomes in women after rectal cancer excision. Dis Colon Rectum. 2009;52: Ho VP, Lee Y, Stein SL, Temple LK. Sexual function after treatment for rectal cancer: a review. Dis Colon Rectum. 2011;54: Kapiteijn E, Kranenbarg EK, Steup WH, et al. Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Dutch Colo- Rectal Cancer Group. Eur J Surg. 1999;165: Marijnen CA, Kapiteijn E, van de Velde CJ, et al. Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol. 2002;20: Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345: Peeters KC, van de Velde CJ, Leer JW, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients a Dutch Colorectal Cancer Group study. J Clin Oncol. 2005;23: Birgisson H, Pahlman L, Gunnarsson U, Glimelius B; Swedish Rectal Cancer Trial Group. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol. 2005;23: Pollack J, Holm T, Cedermark B, et al. Late adverse effects of shortcourse preoperative radiotherapy in rectal cancer. Br J Surg. 2006;93: Holm T, Singnomklao T, Rutqvist LE, Cedermark B. Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Adverse effects during long term follow-up of two randomized trials. Cancer. 1996;78: Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Late gastrointestinal disorders after rectal cancer surgery with and without preoperative radiation therapy. Br J Surg. 2008;95: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Manual. 7th ed. New York, NY: Springer; Camilleri-Brennan J, Steele RJ. Objective assessment of morbidity and quality of life after surgery for low rectal cancer. Colorectal Dis. 2002;4: Russell MM, Ganz PA, Lopa S, et al. Comparative effectiveness of sphincter-sparing surgery versus abdominoperineal resection in rectal cancer: patient-reported outcomes in National Surgical Adjuvant Breast and Bowel Project randomized trial R-04. Ann Surg. 2015; 261: Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004; 351: Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results EORTC J Clin Oncol. 2005;23: 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: Gerard 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: Park JH, Yoon SM, Yu CS, Kim JH, Kim TW, Kim JC. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer. 2011;117: Cancer January 1,

7 Review Article 23. 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: Rodel C, Liersch T, Fietkau R, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: results of the German CAO/ARO/AIO-04 randomized phase III trial [abstract]. J Clin Oncol. 2014;32(suppl): Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypcr patients. Int J Radiat Oncol Biol Phys. 2008;72: 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: 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: 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: Belluco C, De Paoli A, Canzonieri V, et al. Long-term outcome of patients with complete pathologic response after neoadjuvant chemoradiation for ct3 rectal cancer: implications for local excision surgical strategies. Ann Surg Oncol. 2011;18: Wolthuis AM, Penninckx F, Haustermans K, et al. Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome. Ann Surg Oncol. 2012;19: 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: Tulchinsky H, Shmueli E, Figer A, Klausner JM, Rabau M. 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: Garcia-Aguilar J, Smith DD, Avila K, et al. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg. 2011;254: 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: Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of shortcourse radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans- Tasman Radiation Oncology Group trial J Clin Oncol. 2012; 30: Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Kryj M. 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: 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: Habr-Gama A, Perez RO, Proscurshim I, et al. Interval between surgery and neoadjuvant chemoradiation therapy for distal rectal cancer: does delayed surgery have an impact on outcome? Int J Radiat Oncol Biol Phys. 2008;71: Kerr SF, Norton S, Glynne-Jones R. Delaying surgery after neoadjuvant chemoradiotherapy for rectal cancer may reduce postoperative morbidity without compromising prognosis. Br J Surg. 2008;95: 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: Bipat S, Glas AS, Slors FJ, Zwinderman AH, Bossuyt PM, Stoker J. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging a meta-analysis. Radiology. 2004;232: Puli SR, Bechtold ML, Reddy JB, Choudhary A, Antillon MR, Brugge WR. How good is endoscopic ultrasound in differentiating various T stages of rectal cancer? Meta-analysis and systematic review. Ann Surg Oncol. 2009;16: Memon S, Lynch AC, Bressel M, Wise AG, Heriot AG. Systematic review and meta-analysis of the accuracy of MRI and endorectal ultrasound in the restaging and response assessment of rectal cancer following neoadjuvant therapy. Colorectal Dis. 2015;17: Curvo-Semedo L, Lambregts DM, Maas M, et al. Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy conventional MR volumetry versus diffusion-weighted MR imaging. Radiology. 2011;260: Hotker AM, Garcia-Aguilar J, Gollub MJ. Multiparametric MRI of rectal cancer in the assessment of response to therapy: a systematic review. Dis Colon Rectum. 2014;57: Lambregts DM, Vandecaveye V, Barbaro B, et al. Diffusionweighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study. Ann Surg Oncol. 2011;18: Smith FM, Waldron D, Winter DC. Rectum-conserving surgery in the era of chemoradiotherapy. Br J Surg. 2010;97: Oh HK, Kang SB, Lee SM, et al. Neoadjuvant chemoradiotherapy affects the indications for lateral pelvic node dissection in mid/low rectal cancer with clinically suspected lateral node involvement: a multicenter retrospective cohort study. Ann Surg Oncol. 2014;21: Ryu KH, Kim SH, Yoon JH, et al. Diffusion-weighted imaging for evaluating lymph node eradication after neoadjuvant chemoradiation therapy in locally advanced rectal cancer. Acta Radiol. In press. 50. Koh DM, Chau I, Tait D, Wotherspoon A, Cunningham D, Brown G. Evaluating mesorectal lymph nodes in rectal cancer before and after neoadjuvant chemoradiation using thin-section T2-weighted magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2008;71: Lambregts DM, Beets GL, Maas M, et al. Accuracy of gadofosvesetenhanced MRI for nodal staging and restaging in rectal cancer. Ann Surg. 2011;253: 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: 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: Habr-Gama A, Gama-Rodrigues J, Sao Juliao 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: Habr-Gama A, Sao Juliao GP, Perez RO. Nonoperative management of rectal cancer: identifying the ideal patients. Hematol Oncol Clin North Am. 2015;29: 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: 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: Appelt AL, Ploen J, Harling H, et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015;16: Smith JJ, Chow OS, Eaton A, et al. Organ preservation in patients with rectal cancer with clinical complete response after neoadjuvant therapy. ASCO Meet Abstr. 2015;33(3 suppl): Cancer January 1, 2016

8 NOM of Rectal Cancer/Torok et al 60. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg. 2012;256: Hiotis SP, Weber SM, Cohen AM, et al. Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients. J Am Coll Surg. 2002;194: Huntington CR, Boselli D, Hill JS, Salo JC. Optimal timing of surgical resection after radiation therapy in locally advanced rectal adenocarcinoma: an analysis of the National Cancer Database (NCDB). ASCO Meet Abstr. 2015;33(3 suppl): Perez RO, Habr-Gama A, Sao Juliao GP, Proscurshim I, Scanavini Neto A, Gama-Rodrigues J. Transanal endoscopic microsurgery for residual rectal cancer after neoadjuvant chemoradiation therapy is associated with significant immediate pain and hospital readmission rates. Dis Colon Rectum. 2011;54: Perez RO, Habr-Gama A, Lynn PB, et al. Transanal endoscopic microsurgery for residual rectal cancer (ypt0-2) following neoadjuvant chemoradiation therapy: another word of caution. Dis Colon Rectum. 2013;56: Bentzen AG, Balteskard L, Wanderas EH, et al. Impaired healthrelated quality of life after chemoradiotherapy for anal cancer: late effects in a national cohort of 128 survivors. Acta Oncol. 2013;52: Yu SK, Tait D, Chau I, Brown G. MRI predictive factors for tumor response in rectal cancer following neoadjuvant chemoradiation therapy implications for induction chemotherapy? Int J Radiat Oncol Biol Phys. 2013;87: Das P, Skibber JM, Rodriguez-Bigas MA, et al. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer. 2007;109: Wallin U, Rothenberger D, Lowry A, Luepker R, Mellgren A. CEA a predictor for pathologic complete response after neoadjuvant therapy for rectal cancer. Dis Colon Rectum. 2013;56: Park YA, Sohn SK, Seong J, et al. Serum CEA as a predictor for the response to preoperative chemoradiation in rectal cancer. J Surg Oncol. 2006;93: Yang KL, Yang SH, Liang WY, et al. Carcinoembryonic antigen (CEA) level, CEA ratio, and treatment outcome of rectal cancer patients receiving pre-operative chemoradiation and surgery. Radiat Oncol. 2013;8: Perez RO, Sao Juliao 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: Palma P, Cano C, Conde-Muino R, et al. Expression profiling of rectal tumors defines response to neoadjuvant treatment related genes. PLoS One. 2014;9:e Lopes-Ramos C, Koyama FC, Habr-Gama A, et al. Comprehensive evaluation of the effectiveness of gene expression signatures to predict complete response to neoadjuvant chemoradiotherapy and guide surgical intervention in rectal cancer. Cancer Genet. 2015;208: Cancer January 1,