Secondary Logo

Organ Preservation Among Patients With Clinically Node-Positive Rectal Cancer

Is It Really More Dangerous?

Habr-Gama, Angelita, M.D., Ph.D.1,2; São Julião, Guilherme Pagin, M.D.1; Vailati, Bruna Borba, M.D.1; Fernandez, Laura M., M.D.1; Ortega, Cinthia D., M.D.3; Figueiredo, Nuno, M.D., Ph.D.4; Gama-Rodrigues, Joaquim, M.D., Ph.D.1,2; Perez, Rodrigo Oliva, M.D., Ph.D.1,2,5

Diseases of the Colon & Rectum: June 2019 - Volume 62 - Issue 6 - p 675–683
doi: 10.1097/DCR.0000000000001337
Original Contributions: Colorectal Cancer
Free
CME
Denotes Associated Video Abstract
Denotes CME
Denotes Twitter Account Access

BACKGROUND: Select patients with complete clinical response to chemoradiation have been managed without radical surgery. The presence of radiologic evidence of nodal metastases at baseline could be a risk factor for local tumor regrowth, more advanced stage at the time of recurrence, and worse distant metastases-free survival.

OBJECTIVE: The purpose of this study was to compare the outcomes of patients with baseline node-positive and node-negative cancer after neoadjuvant chemoradiation and complete clinical response managed nonoperatively.

DESIGN: This was a retrospective review of consecutive patients with nonmetastatic distal rectal cancer undergoing neoadjuvant chemoradiation.

PATIENTS: Consecutive patients with clinical and radiologic evidence of complete clinical response at 8 to 10 weeks were managed nonoperatively and enrolled in a strict follow-up program (watch and wait). Patients with incomplete clinical response or tumor regrowth after initial complete clinical response were referred to surgery.

MAIN OUTCOMES MEASURES: Surgery-free and distant metastases-free survival were compared between patients according to nodal status at baseline.

RESULTS: A total of 117 patients with node-positive and 218 with node-negative cancer at baseline were reviewed. Overall, 62 (53.0%; node positive) and 135 (61.9%; node negative) achieved a complete clinical response and were managed nonoperatively (p = 0.13). Patients with baseline node-positive cancer had similar rates of pathologic nodal metastases at the time of recurrence. Five-year surgery-free (39.7% vs 46.8%; p = 0.2) and distant metastases–free survival (77.5% vs 80.5%; p = 0.49) were similar between baseline node-positive and node-negative patients.

LIMITATIONS: This was a retrospective study with a small sample size and possible inaccurate nodal staging.

CONCLUSIONS: Patients with rectal cancer with node-positive cancer at baseline who develop a complete clinical response after neoadjuvant chemoradiation are not at increased risk for local tumor regrowth or development of more advanced disease at the time of recurrence. These patients seem to be safe candidates for organ-preserving strategies after achieving complete clinical response. See Video Abstract at http://links.lww.com/DCR/A902.

1 Angelita & Joaquim Gama Institute, Sao Paulo, Brazil

2 Colorectal Surgery Division, University of São Paulo School of Medicine, Sao Paulo, Brazil

3 Radiology Division, University of São Paulo School of Medicine, Sao Paulo, Brazil

4 Champalimaud Foundation, Lisbon, Portugal

5 Ludwig Institute for Cancer Research São Paulo Branch, Sao Paulo, Brazil

Earn Continuing Education (CME) credit online at cme.lww.com.

Funding/Support: None reported.

Financial Disclosure: None reported.

Correspondence: Rodrigo Oliva Perez, M.D., Ph.D., Rua Manoel da Nóbrega 1564, São Paulo, Brazil 04001-005. E-mail: rodrigo.operez@gmail.com. Twitter: @R_Perez_MD

Achievement of complete clinical response (cCR) to neoadjuvant chemoradiation (nCRT) among patients with rectal cancer has led to organ-preserving strategies in an attempt to avoid potentially unnecessary surgery and its associated morbidity and mortality.1–5 No immediate surgical resection and enrollment into a strict surveillance program (watch and wait (WW)) may result in acceptable oncologic and excellent functional outcomes.6,7 However, local tumor regrowth or recurrence may develop, most frequently within the first 2 years of follow-up, requiring immediate salvage resection in <35% of cases.8 Although most series have reported high rates of successful salvage, patients with specific baseline features may be at high risk for the development of recurrence after WW and may warrant special surveillance strategies. In addition, these patients could represent a distinct subgroup of candidates for even more aggressive treatment regimens to maximize the chances for organ preservation and minimize the risk for systemic relapse.8–10

Baseline T status has been shown to be associated with increased risk for early local regrowth (at 1 and 2 y) among patients achieving a cCR after extended nCRT with 54 Gy and consolidation chemotherapy during the waiting period. Although cT3 and cT4 patients were more likely to develop local regrowth in this setting, there was nearly always an endoluminal component, and salvage was frequently successful.9

In the presence of clinical lymph node metastases at baseline (cN+), however, development of cCR could potentially mislead surgeons to an organ-preserving strategy in a setting of no residual endoluminal disease but at high risk for residual microscopic nodal disease. The lack of clinical or endoscopic findings and limitations in radiologic assessment of residual microscopic mesorectal disease in these patients could potentially lead to disastrous clinical outcomes after WW. These patients could be at higher risk for local regrowth and also more advanced disease stage at the time of recurrence. As a consequence, this could affect the rates of successful salvage or even result in worse distant metastases–free survival. For these reasons, we decided to review the outcomes of patients with clinically node-positive rectal cancer undergoing nCRT who achieved a cCR and were managed by WW.

Back to Top | Article Outline

PATIENTS AND METHODS

All of the patients with nonmetastatic rectal cancer located ≤7 cm from the anal verge measured by rigid proctoscopy undergoing nCRT were eligible for the study after local institutional review board approval. Baseline local staging included CT scans (before MRI and endorectal ultrasound (ERUS) became available), MRI, or ERUS. Distant metastases were assessed by abdominal and chest CT. All of the patients with cT3/T4 or cN+ at baseline were referred to nCRT. Candidates for abdominoperineal resection or anterior resection with coloanal anastomosis were also referred to nCRT, even when local staging was cT2N0.

Staging of nodal status was performed according to staging modality used. Nodal size (using ≥10 mm for cN+) and border regularity (irregular borders considered as cN+) were used for patients who underwent ERUS and CT. For patients undergoing MRI, border regularity (irregular borders considered as cN+) and intranodal signal intensity (mixed signal intensity of heterogeneity considered as cN+) were used. In the presence of any of the above-mentioned features, the nodal status was considered as positive (cN+).9

Back to Top | Article Outline

Neoadjuvant CRT

Standard Chemoradiation

Consecutive patients between 1991 and 2005 were treated with the standard chemoradiation regimen. Treatment consisted of 50.4 Gy of radiation and concomitant chemotherapy (5-fluorouracil (5-FU)/leucovorin; 5-FU, 425 mg/m2/d; folinic acid, 20 mg/m2/d) delivered in 2 cycles (beginning and end of radiation therapy, 3 d each). A total of 45.0 Gy in daily doses of 180.0 cGy was delivered to the pelvis, and an additional boost of 5.4 Gy was delivered to the primary tumor. Patients managed in other institutions with identical chemoradiation regimens referred to surgical management after 2005 were also included in the standard chemoradiation group.

Back to Top | Article Outline

Extended Chemoradiation

Since 2005, the nCRT regimen changed to a total dose of 54.0 Gy (2 additional doses of 1.8 Gy), including the same 45.0 Gy (pelvis) but with a 9.0 Gy of boost to the primary tumor or perirectal tissue (instead of 5.4 Gy). This regimen is now routinely offered for all of the patients managed at our institution.10 Concomitant chemotherapy (5-FU, 450 mg/m2 and leucovorin, 50 mg fixed dose) was delivered in a total of 6 cycles (3 d each). Three (of the 6 cycles) were delivered every 21 days during radiotherapy, whereas 3 remaining cycles were delivered during the resting period (after radiotherapy completion), as described previously.10

Back to Top | Article Outline

Assessment of Tumor Response

Two colorectal surgeons clinically assessed tumor response in all of the patients. Clinical assessment was performed ≥8 weeks from radiotherapy completion among patients undergoing the standard chemoradiation regimen and ≥10 weeks among those undergoing the extended chemoradiation. The last day of radiotherapy was considered for the interval between chemoradiation completion and assessment of tumor response. Clinical assessment consisted of complete physical examination, digital rectal examination, rigid proctoscopy, CEA level, and radiologic imaging (CT, MRI, or ERUS). In the presence of clinical and radiologic findings consistent with a cCR, patients were offered no immediate surgery and enrolled in a follow-up program (ie, the WW strategy). This was considered irrespective of baseline features (including cN status). The definition of a cCR included the absence of residual ulcers, stenosis, or masses within the rectal lumen. The presence of white scars and teleangiectasias was considered an acceptable finding for a cCR, as described previously.11 Radiologic studies with findings consistent with no residual disease within the rectal wall and mesorectum were also required for the definition of cCR. In the presence of incomplete clinical response of the primary tumor or exclusively within the mesorectal compartment, patients were recommended radical surgery.

Back to Top | Article Outline

Follow-up

In the setting of a cCR managed by WW, follow-up included rigid proctoscopy, CEA level determination, and digital rectal examination every visit (every 2 mo for the first 2 years; 3 mo in the third year, and 6 mo thereafter). Radiologic imaging for the pelvis (CT, MRI, or ERUS) and distant metastases (CT scans) was performed every 6 months during the first 2 years and yearly afterward, unless suspicious findings were identified. None of the patients underwent adjuvant chemotherapy after a cCR and WW. Adjuvant chemotherapy (mFOLFOX) was only offered to patients undergoing radical surgery based on the presence of metastatic lymph nodes (ypN+) in the resected specimen.

Back to Top | Article Outline

Local Recurrences

Local recurrence was defined in the presence of pathologically confirmed adenocarcinoma within the rectum or mesorectum during follow-up or after subsequent radical salvage resection. Salvage resection was offered to all of the patients with exclusively local recurrences.

Back to Top | Article Outline

Surgery-Free Survival

Patients undergoing each nCRT regimen (standard or extended) were compared according to the time elapsed between the last day of radiation therapy and the indication for surgery. This included surgery for primary incomplete response to nCRT or for patients with initial cCR under WW and subsequent local recurrence.

Back to Top | Article Outline

Distant Metastases–Free Survival

The time elapsed between the last day of radiation and radiologic or pathologic confirmation of distant metastases was used for the estimation of distant metastases–free survival in patients undergoing each nCRT regimen.

Back to Top | Article Outline

Statistical Analysis

Patients were compared according to baseline cN status. Groups were compared for numerical variables using the Student t test, whereas categoric variables were compared according the χ2 or Fisher exact test. Kaplan–Meier actuarial curves were created for the comparison of surgery-free survival between subgroups of patients using a log-rank test. P values <0.05 were considered statistically significant. We also compared patients according to the need for surgical resection for incomplete response or local regrowth or recurrence (after WW) at any time during follow-up. All of the statistical analyses were performed using SPSS (IBM Corp, Armonk, NY) or GraphPad (Prism, San Diego, CA).

Back to Top | Article Outline

RESULTS

Between 1991 and 2016, 409 patients with distal rectal cancer underwent nCRT for nonmetastatic disease at our institution. Overall, 335 patients had cN status information available for review (117 were cN+ and 218 were cN0) and constitute the population of our study. Median follow-up was 55 ± 94 months. No minimum follow-up was required. Clinical and radiologic features of these patients are available in Table 1.

TABLE 1

TABLE 1

Patients with baseline cN+ (versus cN0) were more likely to have a larger initial tumor size (4.2 vs 3.9 cm; p = 0.04), more advanced cT status (cT3/4 in 99 (85%) vs 135 (62%) patients; p < 0.001), and to have undergone the extended chemoradiation regimen (55 (47%) vs 63 (29%) patients; p = 0.001; Table 2). Initial cCR was observed in 62 (53%) and 135 patients (62%) with baseline cN+ and cN0 (p = 0.13). When only patients who achieved a cCR after chemoradiation are considered, those with baseline cN+ were more likely to have more advanced baseline cT status (cT3/4 in 50 (81%) vs 79 (58%); p = 0.001) and higher pretreatment CEA levels (9.4 vs 2.2; p = 0.009; Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

Back to Top | Article Outline

Risk Factors for Local Regrowth

At univariate analysis, none of the pretreatment characteristics (including baseline cN status) were associated with the risk of local recurrence at any time after achieving an initial cCR and being managed nonoperatively. Baseline cN+ was not a predictive factor for the development of local regrowth after initial cCR. In addition, local regrowth rates were similar across all of the different baseline staging modalities (Table 4).

TABLE 4

TABLE 4

Back to Top | Article Outline

Disease Stage at the Time of Local Recurrence

Patterns of regrowth and salvage therapy strategies are available in Table 5. Briefly, of the 55 patients with local regrowth, 46 underwent salvage treatment. Three were considered palliative (concomitant systemic recurrences or unresectable) and were treated with systemic chemotherapy. Two patients were salvaged at a different institution. Four were considered medically unfit for salvage resection (Table 5).

TABLE 5

TABLE 5

To investigate the risk of more advanced disease at the time of recurrence after initial cCR and WW, we compared the rates of pathologic positive nodes at the time of salvage resection among these patients. However, there were no ypN+ differences among patients with local recurrences between patients with baseline cN+ or cN0 status (1 (10.0%) vs 5 (16.6%); p = 1.0) undergoing this organ preservation strategy (Table 3).

Back to Top | Article Outline

Survival Curves in All Patients According to Baseline cN Status

There were no differences in overall cancer-specific, distant metastases–free, or surgery-free (organ-preservation) survival between all cN+ and cN0 patients (Fig. 1).

FIGURE 1

FIGURE 1

Back to Top | Article Outline

Survival Curves in Patients Achieving Initial cCR Managed by WW According to Baseline cN Status

When only patients who achieved initial cCR and were managed by WW are considered, there were also no differences in overall cancer-specific, distant metastases–free, or surgery-free (organ-preservation) survival between cN+ and cN0 patients (Fig. 2).

FIGURE 2

FIGURE 2

Back to Top | Article Outline

cN+ and Extended nCRT

Patients with baseline cN+ undergoing standard or extended nCRT developed similar rates of initial cCR (28 (51%) vs 34 (54%); p = 0.7; Table 6). In addition, there were no differences in overall cancer-specific, distant metastases–free, or surgery-free (organ-preservation) survival according to the type of nCRT. Extended nCRT did not result in higher organ-preservation rates or lower risk for distant metastases (Fig. 3).

TABLE 6

TABLE 6

FIGURE 3

FIGURE 3

Back to Top | Article Outline

DISCUSSION

The present study suggests that patients with radiologic evidence of baseline nodal metastases may be safely offered organ-preservation strategies (WW) after the achievement of initial cCR after nCRT. First, these patients achieve similar rates of initial cCR when compared with those with baseline cN0 disease. Second, nonoperative management after a cCR among baseline cN+ is not associated with higher risk for local regrowth. Third, even when patients with baseline cN+ develop local regrowths, pathologic stage (ypN+) is not more advanced when compared with those with baseline cN0. In addition, these patients are not at increased risk for systemic relapse. Finally, there is no apparent benefit from more aggressive nCRT regimen (with radiotherapy dose escalation or interval or consolidation chemotherapy) in terms of chances of organ preservation and distant disease control.

Although nodal status has been considered a relevant prognostic factor in rectal cancer, our study has failed to demonstrate the influence of cN status in any clinically relevant outcome after nCRT. These results may be explained by at least 2 important aspects. First, inherent limitations in accurate nodal staging with any radiologic imaging study are well recognized and may ultimately have contributed to the observed outcomes.12–14 Second and possibly even more important is the inclusion of an additional variable to these patients: excellent response to nCRT. The inclusion of only patients with initial cCR, and therefore excellent response to treatment, may have selected those patients in that nodal metastases were either overestimated (false positives) or biologically irrelevant. Ultimately, response to nCRT may be such an important prognostic feature that it may override others, such as baseline nodal status, in the prediction of long-term organ preservation (surgery-free survival) and even in the prediction of distant dissemination of the disease (distant metastases–free survival). Previous studies in rectal cancer already suggest that response to nCRT is one of the most relevant prognostic factors, frequently overriding other baseline staging features in clinically relevant oncologic outcomes.2,15,16

These findings may support the idea that, once a cCR is achieved for these patients, baseline cN status may become of little relevance. In this setting, organ-preservation strategies should clearly not be denied to these patients. In addition, there is no need for specific concern about nodal recurrence among these patients.

Finally, the concept to offer adjuvant systemic treatment exclusively based on pretreatment staging features may be at least challenged here. It has been recommended that we offer adjuvant systemic chemotherapy to these patients with baseline cN+ irrespective of response to nCRT.17,18 Our data suggest that, in the event of cCR, baseline cN+ becomes at least questionable for the indication for adjuvant therapy. Importantly, these findings do not suggest that adjuvant systemic therapy is not required or is not beneficial. Instead, it suggests that nodal status should not be used exclusively and independently to direct additional treatment.

Interestingly, only 10% to 16% of local recurrences after initial cCR were found to harbor nodal metastases in the specimen obtained after salvage resection. It may be virtually impossible to understand the exact mechanism for these local recurrences. However, solely blaming nodal metastases for the cause of the local recurrences is clearly inappropriate, because none of the recurrences were exclusively mesorectal. Therefore, although the presence of residual cancer cells within mesorectal nodes is a possible explanation for regrowths, microscopic residual foci of cancer cells within the rectal wall appear to be more relevant in this setting. In fact, the 10% to 16% risk for ypN+ among local regrowths undergoing salvage resection is very close to the risk of lymph node metastases (9%) among patients with complete primary tumor response (ypT0N1).19 These findings suggest considerably high rates of false-negative findings in nodal status by radiologic imaging. This could challenge the role of radiologic imaging during follow-up of patients undergoing organ-preserving strategies. However, although not frequent (≤10%), exclusively mesorectal recurrences may develop among these patients.20,21 In addition, patients undergoing organ-preservation strategies may benefit from radiologic surveillance, particularly of areas not included in the radiation therapy field. Historically, radiation oncologists have attempted to focus and concentrate radiation therapy doses within the area of interest in rectal cancer, progressively narrowing the volume to minimize toxicity.22 By reviewing the patterns of local recurrence after total mesorectal excision, it has been suggested that lowering the upper limits of radiation would have been appropriate in the vast majority of patients.22 However, if organ preservation becomes an option and total mesorectal excision is not necessarily going to be performed, lowering the level of radiation therapy fields may actually leave an area for high risk of mesorectal recurrence (or perhaps persistence) of disease because of inappropriate doses of radiation being delivered to potentially micrometastatic disease. Therefore, caution should be taken when imaging patients during follow-up for the surveillance of mesorectal recurrent disease. Areas above S2 among these patients should be considered not only for routine inclusion in radiation therapy fields but also for routine radiologic evaluation for the risk of high mesorectal recurrences.

Our study has several limitations and should be interpreted with caution. First, there is an uncontrolled risk for selection bias among patients referred to 1 single institution. Also, the relatively small sample size may have accounted for the lack of differences between groups. A considerably larger sample size would have been required to appropriately address this question in a prospective study (514 patients; considering ≤10% in local regrowth rates between subgroups and 80% power). Considering the difficulties in running such a trial prospectively, perhaps large databases will be able to address this question in future studies.21 In addition, inherent limitations associated with accurate nodal staging may also have contributed to the lack of significant differences between cN+ and cN0, particularly with the use of different staging modalities (CT, MRI, and ERUS) available over time. In fact, improvements in locoregional radiologic staging may have occurred overtime and are difficult to measure. Finally, the ideal scenario would have been the comparison of WW versus radical surgery for patients with baseline cN+ and cCR after nCRT. Because we offered WW to all of the patients in this scenario, we lack a comparator group (undergoing radical surgery) for this analysis.

Back to Top | Article Outline

CONCLUSION

Patients with rectal cancer with baseline cN+ appear to be appropriate candidates for organ-preserving strategies after achieving a cCR after nCRT. These patients are not at increased risk for developing local regrowths or for developing more advanced (ypN+) local regrowths when compared with patients with baseline cN0. Finally, radiotherapy dose escalation and consolidation chemotherapy appear to offer no significant benefit to these patients in terms of organ preservation or distant metastases. Altogether, our data do not support the discrimination of patients for adjuvant systemic treatment based on baseline cN status in the setting of cCR.

Back to Top | Article Outline

REFERENCES

1. 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.
2. 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.
3. 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;17:174–183.
4. 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;16:919–927.
5. Martens MH, Maas M, Heijnen LA, et al. Long-term outcome of an organ preservation program after neoadjuvant treatment for rectal cancer. J Natl Cancer Inst. 2016;108:.
6. 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;59:264–269.
7. 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;29:4633–4640.
8. Dossa F, Chesney TR, Acuna SA, Baxter NN. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2017;2:501–513.
9. Habr-Gama A, São Julião GP, Gama-Rodrigues J, et al. Baseline T classification predicts early tumor regrowth after nonoperative management in distal rectal cancer after extended neoadjuvant chemoradiation and initial complete clinical response. Dis Colon Rectum. 2017;60:586–594.
10. 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.
11. Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H, Gama-Rodrigues 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.
12. 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.
13. 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;232:773–783.
14. Al-Sukhni E, Milot L, Fruitman M, et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2012;19:2212–2223.
15. Quah HM, Chou JF, Gonen M, et al. Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer. 2008;113:57–64.
16. Mace AG, Pai RK, Stocchi L, Kalady MF. American Joint Committee on Cancer and College of American Pathologists regression grade: a new prognostic factor in rectal cancer. Dis Colon Rectum. 2015;58:32–44.
17. Jung KU, Kim HC, Park JO, et al. Adjuvant chemotherapy after neoadjuvant chemoradiation and curative resection for rectal cancer: is it necessary for all patients? J Surg Oncol. 2015;111:439–444.
18. Kiran RP, Kirat HT, Burgess AN, Nisar PJ, Kalady MF, Lavery IC. Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? Ann Surg Oncol. 2012;19:1206–1212.
19. 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.
20. 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.
21. van der Valk MJM, Hilling DE, Bastiaannet E, et al; IWWD Consortium. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet. 2018;391:2537–2545.
22. Kusters M, Marijnen CA, van de Velde CJ, et al. Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial. Eur J Surg Oncol. 2010;36:470–476.
Keywords:

Lymph node metastases; Organ preservation; Rectal cancer; Watch and wait

Supplemental Digital Content

Back to Top | Article Outline
© 2019 The American Society of Colon and Rectal Surgeons