ORIGINAL CONTRIBUTION

Transanal Local Excision for Distal Rectal Cancer and Incomplete Response to Neoadjuvant Chemoradiation – Does Baseline Staging Matter? Rodrigo O. Perez, M.D., Ph.D.1,2,3 • Angelita Habr-Gama, M.D., Ph.D.1,4 Guilherme P. São Julião, M.D.1 • Igor Proscurshim, M.D.1 Augusto Q. Coelho, M.S.1,4 • Marleny N. Figueiredo, M.D.1 Laura M. Fernandez, M.D.1 • Joaquim Gama-Rodrigues, M.D., Ph.D.1,4 1 Angelita & Joaquim Gama Institute, São Paulo, Brazil 2 University of São Paulo School of Medicine, Colorectal Surgery Division, São Paulo, Brazil 3 Ludwig Institute for Cancer Research, São Paulo Branch, São Paulo, Brazil 4 University of São Paulo School of Medicine, São Paulo, Brazil

BACKGROUND:  Local excision may offer the possibility of organ preservation for the management of select patients after neoadjuvant chemoradiation. The oncological outcomes of this strategy have been largely associated with the risk of nodal metastases. Therefore, in addition to final ypT status, baseline staging has been suggested to potentially influence the outcomes of this treatment modality.

chemoradiation. Assessment of response was performed at least 8 weeks from radiotherapy completion. Patients with a complete clinical response were not operated on immediately. Patients with an incomplete clinical response were managed by surgery. Those with small (≤3 cm) residual cancers (ycT1-2N0M0) were managed by transanal endoscopic microsurgery.

OBJECTIVE:  The aim of this study is to compare the pathological and oncological outcomes of patients following neoadjuvant chemoradiation and incomplete clinical response managed by transanal endoscopic microsurgery according to baseline staging.

MAIN OUTCOME MEASURES:  Patients undergoing local excision following chemoradiation were compared according to baseline staging.

DESIGN:  This study is a retrospective review of prospectively collected data. SETTINGS:  The study was conducted at a single center. PATIENTS:  Forty-six patients with distal rectal cancer cT24N0-2M0 underwent 5-fluorouracil-based neoadjuvant Financial Disclosure: None reported. Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s Web site (www.dcrjournal.com) Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Hollywood, FL, May 17 to 21, 2014. Correspondence: Angelita Habr-Gama, M.D., Ph.D., Rua Manoel da Nóbrega 1564, São Paulo – SP; Brazil, 04001-005. E-mail: gamange@ uol.com.br Dis Colon Rectum 2014; 57: 1253–1259 DOI: 10.1097/DCR.0000000000000215 © The ASCRS 2014 Diseases of the Colon & Rectum Volume 57: 11 (2014)

RESULTS:  Fifteen patients (32%) were cT2N0 at baseline. Final ypT status was ypT0 in 3 (20%) patients, ypT1 in 2 (13%) patients, ypT2 in 9 (60%) patients, and ypT3 in 1 (7%) patient. There were no differences in final ypT status in comparison with patients with baseline cT3-4 or cN+ undergoing chemoradiation followed by transanal endoscopic microsurgery (p = 0.38). Local recurrence was observed in 1 patient with baseline cT2N0 (7%) and in 7 patients (23%) with stage II and III (p = 0.18). LIMITATIONS:  This study was limited by the short followup, its limited sample size, and its retrospective and nonrandomized nature. CONCLUSIONS:  Patients with baseline cT2N0 that do not develop complete response to chemoradiation (ycT02N0; ≤3 cm) frequently present unfavorable pathological features for transanal local excision (ypT2 or 3 in >66%). In the presence of incomplete clinical response following chemoradiation, patients with baseline cT2N0 have pathological and oncological outcomes similar to patients with baseline stage II or III and are probably not ideal candidates for local excision (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A159).

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KEY WORDS:  Rectal cancer; Neoadjuvant chemoradiation; Transanal endoscopic microsurgery; Initial staging; Recurrence.

T

he introduction of neoadjuvant chemoradiation (CRT) into rectal cancer management has led to significant improvements in local disease control after radical surgery.1,2 In addition, preoperative CRT also results in significant tumor regression with frequent tumor downsizing and downstaging, including a lower risk for harboring lymph node metastases.1,3 In this setting, organpreserving strategies, including transanal full-thickness local excision (FTLE) or even no immediate surgery have been considered for the management of selected patients with significant response to CRT.4,5 This is because radical proctectomy is associated with significant functional consequences and the requirement of definitive stomas in a considerable proportion of these patients. Therefore, patients with significant small residual cancers, who are otherwise candidates for ultra-low anterior resections or abdominal perineal resections (APRs) exhibiting significant tumor downsizing and downstaging, would be ideal candidates for full-thickness transanal local excision.6,7 It has been suggested that patients with residual cancers restricted to the bowel wall (ycT2N0) would constitute appropriate candidates for this treatment strategy.8 However, the differences in regression of the residual primary tumor could affect oncological outcomes. First, because the risk of lymph node metastases seems to be correlated with final ypT status, and patients with residual ypT2 would be at considerably higher risk to allow safe management by FTLE alone.9,10 Also, the presence of tumor scatter away from the residual mucosal abnormality could also influence complete resection of the residual cancer.11 Perhaps baseline staging may play a significant role in this setting. Patients with baseline cT2N0 are usually managed or referred to surgery alone with total mesorectal excision (TME). However, this particular group of patients may constitute the best population for any local procedure after having being treated by long-course neoadjuvant CRT. First, the risk of lymph node metastases after CRT is already minimized when proper staging at baseline shows cN0 by using morphological features.12 Second, even if unsuspected mesorectal disease is present, CRT may be sufficient for microscopic disease eradication. In fact, the only randomized trial of patients with cT2N0 following neoadjuvant CRT to either TME or local excision (using transanal endoscopic microsurgery, TEM) suggests equivalent local disease control with both techniques regardless of primary tumor regression status.13 For these reasons, we decided to compare oncological outcomes and local disease control among patients with residual rectal cancer after neoadjuvant CRT and TEM according to baseline radiological staging specifically focusing on cT2N0 distal rectal tumors.

Perez et al: Role of TEM in cT2N0 Rectal Cancer After CRT

PATIENTS AND METHODS Patients and Neoadjuvant CRT

All patients with nonmetastatic rectal adenocarcinoma (cT2-4cN0-2) located up to 7 cm from the anal verge undergoing neoadjuvant CRT assessed at the Angelita & Joaquim Gama Institute between 2009 and 2013 were eligible for the study. Baseline assessment of the primary tumor included digital rectal examination (DRE), rigid proctoscopy, and abdominal and chest CT in all patients. In addition, endorectal ultrasound or high-resolution MR was performed for local staging. Patients with baseline cT2N0 (stage I) were compared with patients with baseline cT34N0/+ (stages II and III). In brief, all patients underwent 50.4 to 54 Gy during 6 weeks of radiation (45 Gy to the pelvis and 5.4–9 Gy boost to the primary tumor and perirectal fact) and 5-fluorouracil-based concomitant chemotherapy (450 mg/m2). Patients were reassessed for tumor response at least 8 weeks from the last dose of radiation including DRE, rigid proctoscopy, endorectal ultrasound, MR, or PET/CT as described elsewhere.14 Patients with complete clinical response (the absence of any irregularity of the rectal wall) were enrolled into a “Watch and Wait” protocol without immediate surgery.15 These patients were excluded from the study. Patients with small residual lesions (≤3 cm in diameter), restricted to the bowel wall (no evidence of perirectal fat invasion – ycT1-2), no evidence of nodal metastases (ycN0) that would otherwise require an APR or ultra-low anterior resection with coloanal anastomosis were considered for transanal FTLE. Restriction of TEM to ≤3 cm was made primarily for technical reasons (smaller lesions are more easily removed) and to minimize rectal wall defects and consequent postoperative morbidity. Patients were fully aware of the potential postoperative complications as well as the likelihood for the need of a definitive stoma in the event of a local recurrence after TEM and neoadjuvant CRT. Patients with incomplete clinical response ≥ycT3 or ≥3 cm or ycN+ were offered radical surgery and were also excluded from the study. Transanal Endoscopic Microsurgery

All patients underwent TEM with the use of a Storz device (TEO; Karl Storz, Germany). Two surgeons performed all procedures together, and the technique was uniform. Under general anesthesia, circumferential marking of the resection area was performed by using regular electrocautery with an estimated 1-cm lateral margin. The depth of resection always attempted to reach the mesorectal fascia to provide maximal radial margin. The full excision was made according to the visible residual mucosal abnormality and was not based on the primary tumor. The speci-

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TABLE 1.   Patients demographics N Age, y Sex, M–F, n (%) Distance anal verge, cm Tumor size, mm Initial staging, n (%) cT cN After CRT staging, n (%) ycT

Final pathological staging, n (%) Final tumor size, mm ypTb

Local relapse, n (%) Pelvic relapse, n (%) Systemic relapse, n (%) Cancer-specific mortality, n (%)

TABLE 2.   Features according to initial staging 46 61.0 ± 12.4 26–20 (56.5–43.5) 3.6 ± 1.6 37.0 ± 12.9 2 3 1

19 (41.3) 27 (58.7) 7 (15.2)

0 1 2 3a

8 (17.4) 12 (26.1) 25 (54.3) 1 (2.2)

0 1 2 3

19.9 ± 13.3 8 (17.4) 6 (13.0) 22 (47.8) 10 (21.7) 8 (17.4) 3 (6.5) 10 (21.7) 8 (17.4)

CRT = chemoradiation; ERUS = endorectal ultrasound; TEM = transanal endoscopic microsurgery. a One patient underwent ERUS and MRI for the assessment of response with discordant findings (ycT2 at MRI and ycT3 at ERUS). b yp is exclusively related to ypT status since ypN status is not available for TEM resection specimens.

men, fixed on a cardboard with appropriate indication of laterality, was sent to the pathologist. The closure of the wound defect with a running or interrupted suture was always attempted by using PDS3-0. Follow-up

Patients were followed regularly every 3 months for the first 2 years and every 6 months thereafter; follow-up included CEA level determination, DRE, flexible proctoscopy, chest and abdominal CT scans, and pelvic high-resolution MR. Digital rectal examination, CEA levels, and proctoscopy were performed at all visits. Computed tomography scans and MRI were performed every 6 months during the first 2 years and yearly thereafter or whenever there was any suspicion of recurrence. Local recurrence was defined in the presence of adenocarcinoma within the rectal lumen. Pelvic recurrence was defined as the presence of an extra rectal mass (radiologically), and systemic recurrences were defined as radiological evidence of recurrent disease outside the pelvis. None of the patients received adjuvant systemic chemotherapy following TEM. Statistical Analysis

Statistical analysis was performed by the χ2 and Fisher exact tests for categorical variables and the Student t test for numerical variables. Results were considered significant for

cT2N0 n 15 Sex, M–F 9–6 (60.0–40.0) Age, y 62.1 ± 8.9 Tumor size, mm 33.3 ± 16.3 Distance anal 3.7 ± 2.2 verge, cm Staging after CRT, n (%) ycT 0 3 (20.0) 1 8 (53.3) 2 4 (26.7) 3a 0 (0.0) Pathological staging, n (%) ypTb 0 3 (20.0) 1 2 (13.3) 2 9 (60.0) 3 1 (6.7) Final tumor 21.3 ± 18.2 size, mm Local relapse, n (%) 1 (6.7) Systemic relapse, n (%) 1 (6.7) Cancer-specific 1 (6.7) mortality, n (%)

Stage II or III UICC

p

31 17–14 (54.8–45.2) 60.6 ± 14.1 38.8 ± 10.7 3.7 ± 1.3

0.74 0.68 0.25 0.99

5 (16.7) 3 (10.0) 21 (70.0) 1 (3.3)

0.009

5 (16.1) 4 (12.9) 13 (41.9) 9 (29.0) 19.2 ± 10.8

0.38 0.68

7 (22.6) 9 (29.0) 7 (22.6)

0.18 0.08 0.18

CRT = chemoradiation; ERUS = endorectal ultrasound; TEM = transanal endoscopic microsurgery; UICC = International Union Against Cancer. a One patient underwent ERUS and MRI for the assessment of response with discordant findings (ycT2 at MRI and ycT3 at ERUS). b yp is exclusively related to ypT status, because ypN status is not available for TEM resection specimens.

p values of 40%. Even when only good responders were considered (ypT0 or ypT1), there was an 8% local recurrence rate. It is curious that, in that study, local recurrence was higher for ypT0 than for ypT1 (10% vs 4%).17 In the Italian study, patients with cT2-3N0-1 underwent CRT, and those with residual ypT2 were also referred for salvage radical TME. Only 9 patients refused TME and 2 developed local recurrence (22%). It seems that there are enough data to suggest that residual ypT2 cancers, even among baseline cT2N0, are inappropriate candidates for TEM or FTLE alone.16 Immediate salvage or completion of TME could potentially minimize the adverse oncological outcomes and provide safe management of unexpected ypT2 after FTLE. However, these same studies report the difficulties of the

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salvage procedures performed. In the Italian study, major postoperative complications were quite significant after CRT and TEM. Five of 7 patients developed anastomotic leaks, and 2 of 11 patients required reoperation.16 In the Polish study, 2 of 6 patients undergoing salvage APR were originally candidates for a sphincter-preserving procedure.17 In fact, salvage TME or completion of TME after FTLE may be quite challenging and frequently result in suboptimal TME specimens. In a recent review of patients undergoing this procedure following FTLE without previous CRT, 3 features were independent predictors of a worse TME specimen: TEM full-thickness excision, distal location of the tumor, and an interval longer than 7 weeks between local excision and completion of TME.22 Ultimately, all of these features are expected to be present in the vast majority of patients being considered for an alternative approach to radical TME. Finally, the postoperative morbidity of TEM after neoadjuvant CRT may also be an issue.23,24 In this setting, patients may experience significantly higher rates of postoperative pain, wound dehiscence, and hospital readmission in comparison with patients undergoing TEM alone.23 These healing difficulties may in part be associated with the challenges in proper surgical salvage with completion TME.25 A number of factors may contribute to the inappropriateness of FTLE for ypT2 even among baseline cT2N0 cancers. First, nodal upfront staging may still be insufficiently accurate, particularly for earlier tumors.26 Second, nodal restaging after CRT may fail to identify small residual lymph nodes, an inherent limitation of any radiological imaging modality.27 Even the assessment of the primary tumor regression was inaccurately determined by standard radiological restaging in our series. Even though patients with baseline cT2N0 staging were expected to have ycT0-1 in the majority of cases, final pathology revealed ypT2-3 in over 67% of the patients. Also, the primary tumor may regress after CRT in a fragmented pattern leaving cancer cells (tumor scatter) considerably away from the residual mucosal abnormality and, therefore, out of reach of the standard 1-cm lateral margins and at potential additional risk for local recurrence.11,28 Finally, the omission of adjuvant chemotherapy, particularly for patients with baseline stage II/ III, could have influenced local and distant relapse rates. A recent update of the EORTC trial suggested that there is no survival benefit among patients with rectal cancer following neoadjuvant CRT and radical surgery with or without adjuvant 5-fluorouracil.29 However, more data with the use of current adjuvant regimens is required before this is definitively implemented into clinical practice.30 In fact, it has been our practice to offer no adjuvant systemic therapy to patients with complete clinical response managed nonoperatively, to those with pCR after radical surgery, or to those managed by FTLE. However, observation of systemic recurrence rates among patients with pCR after radical surgery or complete clinical response after no immediate surgery

Perez et al: Role of TEM in cT2N0 Rectal Cancer After CRT

has raised the issue of offering routine adjuvant chemotherapy to patients regardless of primary tumor response.31,32 The limitations of the present study include the small number of patients and also the short follow-up. However, studies with highly selected patients always suffer from small numbers, and none of the previous studies have reached 100 patients. Also, when complete pathological responses are included in the denominator, reported local recurrence rates are underestimated for those that truly need resection (ypT1-2) and are at higher risk for recurrence. Ultimately, all studies reported ≤4 patients with local recurrences each. In terms of follow-up, the study that randomized TME and TEM suggested that patients undergoing TEM were more likely to develop earlier recurrences (within 24 months of follow-up), whereas the Italian study suggested that 3-year survival was probably a clinically valid end point.13,16 Therefore, 22 months of median follow-up is acceptable even though additional recurrences may still develop after longer follow-up.

CONCLUSION Even patients with baseline cT2N0 are at risk for harboring residual ypT2 after neoadjuvant CRT, particularly in the setting of poor or incomplete clinical response. The local recurrence rates after FTLE of these patients may depend less on the baseline staging classification or radiological reassessment of response and be more related to final ypT status. When most patients with complete response are removed, outcomes between cT2N0 and stages II/III become very similar. Ultimately, patients with incomplete response to CRT and residual ycT1-2N0 (confirmed to be ypT2 at pathology) are not ideal candidates for local excision alone regardless of primary baseline staging. Patients with baseline stages II/III are not only at significant risk for local, but also for distant recurrence. This may raise the issue of offering these patients routine aggressive adjuvant chemotherapy. Radiological staging and reassessment of response are still insufficient to allow the safe selection of patients for TEM after neoadjuvant CRT. The careful selection of patients for this treatment/diagnostic strategy is crucial, and the final oncological outcome is still highly dependent on the final pathological features, often unavailable during the assessment of tumor response, and available only after the resection of the primary specimen. REFERENCES 1. Sauer R, Becker H, Hohenberger W, et al; German Rectal ­Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740. 2. 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;30:1926–1933.

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3. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for ­ rectal cancer: preliminary results–EORTC 22921. J Clin Oncol. 2005;23:5620–5627. 4. 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;56:1109–1117. 5. Smith FM, Waldron D, Winter DC. Rectum-conserving surgery in the era of chemoradiotherapy. Br J Surg. 2010;97:1752–1764. 6. Lezoche E, Guerrieri M, Paganini AM, Feliciotti F. Transanal endoscopic microsurgical excision of irradiated and nonirradiated rectal cancer: a 5-year experience. Surg Laparosc Endosc. 1998;8:249–256. 7. Marks JH, Frenkel JL, D’Andrea AP, Greenleaf CE. Maximizing rectal cancer results: TEM and TATA techniques to expand sphincter preservation. Surg Oncol Clin N Am. 2011;20:501–520. 8. Engelen SM, Beets-Tan RG, Lahaye MJ, et al. MRI after chemoradiotherapy of rectal cancer: a useful tool to select patients for local excision. Dis Colon Rectum. 2010;53:979–986. 9. Perez RO, Habr-Gama A, Proscurshim I, et al. Local excision for ypT2 rectal cancer–much ado about something. J Gastrointest Surg. 2007;11:1431–1438. 10. Park IJ, You YN, Skibber JM, et al. Comparative analysis of lymph node metastases in patients with ypT0-2 rectal cancers after neoadjuvant chemoradiotherapy. Dis Colon Rectum. 2013;56:135–141. 11. Hayden DM, Jakate S, Pinzon MC, et al. Tumor scatter after neoadjuvant therapy for rectal cancer: are we dealing with an invisible margin? Dis Colon Rectum. 2012;55:1206–1212. 12. Brown G, Richards CJ, Bourne MW, et al. Morphologic predictors of lymph node status in rectal cancer with use of high-spatial-resolution MR imaging with histopathologic comparison. Radiology. 2003;227:371–377. 13. Lezoche E, Baldarelli M, Lezoche G, Paganini AM, Gesuita R, Guerrieri M. Randomized clinical trial of endoluminal locoregional resection versus laparoscopic total mesorectal excision for T2 rectal cancer after neoadjuvant therapy. Br J Surg. 2012;99:1211–1218. 14. Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H, GamaRodrigues J. Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization. Dis Colon Rectum. 2010;53:1692–1698. 15. Habr-Gama A, Perez RO, São Julião GP, Proscurshim I, GamaRodrigues J. Nonoperative approaches to rectal cancer: a critical evaluation. Semin Radiat Oncol. 2011;21:234–239. 16. Pucciarelli S, De Paoli A, Guerrieri M, et al. Local excision after preoperative chemoradiotherapy for rectal cancer: results of a multicenter phase II clinical trial. Dis Colon Rectum. 2013;56:1349–1356. 17. Bujko K, Richter P, Smith FM, et al. Preoperative radiotherapy and local excision of rectal cancer with immediate radical reoperation for poor responders: a prospective multicentre study. Radiother Oncol. 2013;106:198–205. 18. Yeo SG, Kim DY, Kim TH, et al. Local excision following preoperative chemoradiotherapy-induced downstaging for selected cT3 distal rectal cancer. Jpn J Clin Oncol. 2010;40:754–760.

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19. 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;56:6–13. 20. Garcia-Aguilar J. Transanal endoscopic microsurgery following neoadjuvant chemoradiation therapy in rectal cancer: a word of caution about patient selection? Dis Colon Rectum. 2013;56:1–3. 21. 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;240:711–717. 22. Hompes R, McDonald R, Buskens C, et al; Association of Coloproctology of Great Britain and Ireland Transanal Endoscopic Microsurgery Collaboration. Completion surgery following transanal endoscopic microsurgery: assessment of quality and short- and long-term outcome. Colorectal Dis. 2013;15:e576–e581. 23. Perez RO, Habr-Gama A, São Julião 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;54:545–551. 24. Marks JH, Valsdottir EB, DeNittis A, et al. Transanal endoscopic microsurgery for the treatment of rectal cancer: comparison of wound complication rates with and without neoadjuvant radiation therapy. Surg Endosc. 2009;23:1081–1087. 25. Habr-Gama A, São Julião GP, Perez RO. Pitfalls of transanal endoscopic microsurgery for rectal cancer following neoadjuvant chemoradiation therapy. Minim Invasive Ther Allied Technol. 2014;23:63–69. 26. Landmann RG, Wong WD, Hoepfl J, et al. Limitations of early rectal cancer nodal staging may explain failure after local excision. Dis Colon Rectum. 2007;50:1520–1525. 27. Perez RO, Pereira DD, Proscurshim I, et al. Lymph node size in rectal cancer following neoadjuvant chemoradiation: can we rely on radiologic nodal staging after chemoradiation? Dis Colon Rectum. 2009;52:1278–1284. 28. Perez RO, Habr-Gama A, Smith FM, et al. Fragmented pattern of tumor regression and lateral intramural spread may influence margin appropriateness after TEM for rectal cancer following neoadjuvant CRT. J Surg Oncol. 2014;109:853–858. 29. Bosset JF, Calais G, Mineur L, et al; EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15:184–190. 30. Bosset JF, Collette L, Calais G, et al; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123. 31. 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;11:835–844. 32. 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;88:822–828.