Abstract
Background:
Our study aims to identify the minimum number of lymph nodes (LN) associated with improved survival in patients who underwent NRT for stage II-III rectal cancer.
Methods:
Adults with clinical stage II and III rectal adenocarcinoma in the National Cancer Data Base were stratified by NRT. Multivariable Cox regression modeling with restricted cubic splines was used to determine the minimum number of LNs associated with improved survival.
Results:
Of 38,363 patients, 76% received NRT. After adjustment, a LNY≥12 was associated with improved survival among patients receiving NRT (HR 0.79, p < 0.0001) and those without NRT (HR 0.88, p = 0.04). Among patients receiving NRT, factors independently associated with LNY≥12 were younger age, private insurance, low comorbidity score, a recent year of diagnosis, higher T stage and grade, APR resection, and academic institution.
Conclusions:
A minimum LNY of 12 confers a survival benefit for rectal cancer patients regardless of receiving neoadjuvant radiation therapy.
Keywords: Rectal adenocarcinoma, Lymphadenectomy, Lymph node yield, Neoadjuvant chemoradiation, Total mesorectal excision
1. Introduction
The importance of lymph node yield (LNY) in the resection of colon cancer is well defined.1,2 The literature dictates a minimum yield of 12 lymph nodes (LN) from surgical resection of malignant tumors to avoid the potential under staging of node positive disease.1-4 However, current guidelines on lymph node harvest for rectal cancers in the setting of neoadjuvant therapies are persistently called into question.1,5,6
Pre-operative neoadjuvant radiation therapy (NRT) plays an important role in the treatment of locally advanced rectal cancers. NRT is currently recommended for stage II and III rectal cancers, and it has been shown to reduce local recurrence, increase sphincter preservation, and improve overall survival.7,8 However, NRT decreases the LNY in subsequent resection.9-13 This is through a mechanism of lymphocyte depletion within the nodes in addition to atrophy and fibrosis of the stroma.14,15 There is robust prior literature describing the factors associated with decreased LNY and factors predictive of positive lymph node disease. However, the literature is contradicting, with no consensus answer, on the relationship between LNY and patient outcomes in the treatment of rectal cancer.12,16-22
Overall, the impact of neoadjuvant treatment on the adequacy of LN excision and its effect on survival in rectal cancer remains highly debated within the literature. Therefore, this study aims to identify the minimum number of resected lymph nodes associated with improved survival in patients who underwent NRT for stage II-III rectal adenocarcinoma by utilizing a large, nationwide database and novel statistical methods.
2. Methods
2.1. Data source
The National Cancer Database (NCDB) is a joint program of the American Cancer Society and the Commission on Cancer (CoC) of the American College of Surgeons. The NCDB is a nationwide, facility-based, comprehensive dataset which captures over 70% of newly diagnosed malignancies in the United States; established in 1989, it contains over 29 million cancer cases from >1500 CoC-accredited cancer programs across the U.S. It captures approximately 75% of all new colorectal cancer cases in the U.S.23 Institutional review board approval was obtained for the completion of this study utilizing the NCDB.
2.2. Study cohort
The NCDB Participant User File was used to identify all patients with rectal adenocarcinoma who underwent low anterior resection (LAR) or abdominoperineal resection (APR) between 1998 and 2012. Rectal adenocarcinoma patients were identified using the following ICD-O, Third Edition codes: 8140/3, 8141/3, 8143/3, 8144/3, 8145/3, 8147/3, 8150/3, 8210/3, 8211/3, 8220/3, 8221/3, 8260/3, 8261/3, 8262/3, 8263/3, 8310/3, 8320/3, 8323/3, 8380/3, 8401/3, 8410/3, 8440/3, 8460/3, 8470/3, 8490/3, 8500/3, 8503/3, 8510/3. Variables including patient age at diagnosis, race, gender, insurance status, and year of diagnosis were obtained from the database. Comorbidity data were documented as Charlson-Deyo scores. Hospital characteristics, such as type and location, were documented in the NCDB. Data on tumor characteristics included tumor size, status of lymph node metastases, receipt of neoadjuvant radiation and/or chemotherapy, and clinical and pathologic tumor stages were provided. Extent of surgery documented as LAR or APR was obtained directly from the database. Number of lymph nodes resected from each patient and receipt of adjuvant chemotherapy was determined. The study was granted exempt status by our Institutional Review Board.
The cohort was limited to patients who were diagnosed with clinical Stage II-III (non-metastatic) rectal adenocarcinoma and underwent formal surgical resection defined as LAR or APR between 1998 and 2012. The study was further limited to patients who underwent complete surgical resections with at least one lymph node removed during surgery.
2.3. Statistical analysis
The cohort was analyzed into two main groups: (1) patients who underwent neoadjuvant radiation therapy and (2) those who did not undergo neoadjuvant radiation therapy. Descriptive statistics were compared between these two groups by the Pearson Chi Square test for categorical variables and the Wilcoxon rank sum tests for continuous variables.
The association between the number of lymph nodes removed and overall survival was examined with the number of lymph nodes expressed as a continuous variable to determine if a threshold number of lymph nodes exists. Two multivariable Cox proportional hazards regression models with restricted cubic splines (RCS) were employed to examine the functional relationship between the number of lymph nodes removed and survival in patients who underwent neoadjuvant radiotherapy versus not. RCS provides a flexible model to examine the relationship between the number of lymph nodes removed and the natural logarithm (log) of the hazards ratio (HR). The relationship is established without prior knowledge of the form of the association, while adjusting for the effects of covariates. RCS allows for visual determination of the presence or absence of a linear relationship between a continuous predictor and the outcome. The following factors were accounted for in this multivariable model: patient gender, race, comorbidities, pathologic tumor T and N stages, extent of surgery, and receipt of adjuvant chemotherapy.
Factors associated with removal of ≥12 lymph nodes versus removal of <12 lymph nodes were then identified using a multivariable logistic regression model. A backward variable elimination method was used to produce the most parsimonious and fit model by removal of non-significant variables based on a cutoff p-value of ≤0.2.
All p-values reported are two-sided with the significance level set to 0.05. Statistical analyses were performed using SAS 9.4 (Cary, N.C., U.S.)
3. Results
3.1. Patient characteristics
A total of 38,363 patients with clinical stage II-III rectal adenocarcinoma who underwent complete resection via LAR or APR were included, of whom 29,149 (75.9%) received NRT. The median follow-up was 45 months (interquartile range 26–71). Of note, the use of NRT steadily increased over the study period from 50.7% in 1998 to 81.9% in 2012.
Patients receiving NRT were slightly younger (median 60 vs. 66 years, p < 0.001), more likely to have fewer comorbidities based on Charlson-Deyo Scores of ≥1 (17.7% vs. 20.5%, p < 0.001), and more likely to be treated at an academic center (37.9% vs. 30.8%, p < 0.001) (Table 1). The NRT cohort had fewer LNs removed (median 12 vs. 14, p < 0.001), a lower LNY ≥12 (65.7% vs 55.2%, p < 0.001), and more pathologically node negative tumors (57.8% vs. 47.1%, p < 0.001).
Table 1.
Patient Characteristics who underwent neoadjuvant radiation therapy versus no neoadjuvant radiation therapy.
| Characteristic | Total (N = 38,363) | No NRTa (N = 9214) | NRT (N = 29,149) | p-value |
|---|---|---|---|---|
| Age at Diagnosis (years) | 61 (52–71) | 66 (56–76) | 60 (51–69) | <0.0001 |
| Sex | <0.0001 | |||
| Female | 14,747 (38.44%) | 3806 (41.31%) | 10,941 (37.53%) | |
| Male | 23,616 (61.56%) | 5408 (58.69%) | 18,208 (62.47%) | |
| Race | 0.55 | |||
| Asian | 1333 (3.47%) | 301 (3.27%) | 1032 (3.54%) | |
| Black | 2873 (7.49%) | 685 (7.43%) | 2188 (7.51%) | |
| White | 33,360 (86.96%) | 8028 (87.13%) | 25,332 (86.91%) | |
| Other | 797 (2.08%) | 200 (2.17%) | 597 (2.05%) | <0.0001 |
| Insurance Status | ||||
| No | 1585 (4.13%) | 309 (3.35%) | 1276 (4.38%) | |
| Yes | 36,158 (94.25%) | 8721 (94.65%) | 27,437 (94.13%) | |
| Charlson-Deyo Score | <0.0001 | |||
| 0 | 26,602 (69.34%) | 5551 (60.25%) | 21,051 (72.22%) | |
| 1 | 5670 (14.78%) | 1458 (15.82%) | 4212 (14.45%) | |
| >/ = 2 | 1390 (3.62%) | 433 (4.7%) | 957 (3.28%) | <0.0001 |
| Facility Location | ||||
| Midwest | 11,426 (29.78%) | 2376 (25.79%) | 9050 (31.05%) | |
| Northeast | 7713 (20.11%) | 1840 (19.97%) | 5873 (20.15%) | |
| South | 12,359 (32.22%) | 3159 (34.28%) | 9200 (31.56%) | |
| West | 6865 (17.89%) | 1839 (19.96%) | 5026 (17.24%) | |
| Facility Type | <0.0001 | |||
| Academic | 13,880 (36.18%) | 2840 (30.82%) | 11,040 (37.87%) | |
| Community | 3883 (10.12%) | 1169 (12.69%) | 2714 (9.31%) | |
| Comprehensive | 20,551 (53.57%) | 5191 (56.34%) | 15,360 (52.69%) | <0.0001 |
| Year of Diagnosis | ||||
| 1998 | 795 (2.07%) | 392 (4.25%) | 403 (1.38%) | |
| 1999 | 825 (2.15%) | 337 (3.66%) | 488 (1.67%) | |
| 2000 | 890 (2.32%) | 332 (3.6%) | 558 (1.91%) | |
| 2001 | 1028 (2.68%) | 358 (3.89%) | 670 (2.3%) | |
| 2002 | 1163 (3.03%) | 353 (3.83%) | 810 (2.78%) | |
| 2003 | 1826 (4.76%) | 499 (5.42%) | 1327 (4.55%) | |
| 2004 | 2189 (5.71%) | 526 (5.71%) | 1663 (5.71%) | |
| 2005 | 2515 (6.56%) | 615 (6.67%) | 1900 (6.52%) | |
| 2006 | 2735 (7.13%) | 630 (6.84%) | 2105 (7.22%) | |
| 2007 | 3170 (8.26%) | 657 (7.13%) | 2513 (8.62%) | |
| 2008 | 3852 (10.04%) | 937 (10.17%) | 2915 (10%) | |
| 2009 | 4034 (10.52%) | 925 (10.04%) | 3109 (10.67%) | |
| 2010 | 4381 (11.42%) | 926 (10.05%) | 3455 (11.85%) | |
| 2011 | 4388 (11.44%) | 899 (9.76%) | 3489 (11.97%) | |
| 2012 | 4572 (11.92%) | 828 (8.99%) | 3744 (12.84%) | |
| Tumor Size (cm) | 4.0 (2.6–5.0) | 4.2 (3.0–5.5) | 4.0 (2.5–5.0) | <0.0001 |
| T stage, pathologic | <0.0001 | |||
| 1 | 5124 (13.36) | 495 (5.37%) | 4629 (15.88%) | |
| 2 | 8258 (21.53%) | 1524 (16.54%) | 6734 (23.1%) | |
| 3 | 17,781 (46.35%) | 6179 (67.06%) | 11,602 (39.8%) | |
| 4 | 895 (2.33%) | 352 (3.82%) | 543 (1.86%) | |
| N stage, pathologic | <0.0001 | |||
| 0 | 21,1185 (55.22%) | 4339 (47.09%) | 16,846 (57.79%) | |
| 1 | 8320 (21.69%) | 2725 (29.57%) | 5595 (19.19%) | |
| 2 | 3660 (9.54%) | 1523 (16.53%) | 2137 (7.33%) | |
| Pathologic Stage | <0.0001 | |||
| 1 | 7385 (19.25%) | 812 (8.81%) | 6573 (22.55%) | |
| 2 | 9794 (25.53%) | 3235 (35.11%) | 6559 (22.5%) | |
| 3 | 11,064 (28.84%) | 3947 (42.84%) | 7117 (24.42%) | |
| 4 | 475 (1.24%) | 125 (1.36%) | 350 (1.2%) | |
| Neoadjuvant Chemotherapy | <0.0001 | |||
| No | 5955 (15.52%) | 4958 (53.81%) | 997 (3.42%) | |
| Yes | 21,085 (54.96%) | 779 (8.45%) | 20,306 (69.66%) | |
| Surgery | <0.0001 | |||
| APRb | 10,116 (26.37%) | 1977 (21.46%) | 8139 (27.92%) | |
| LARc | 28,247 (73.63%) | 7237 (78.54%) | 21,010 (72.08%) | |
| LNYd | <0.0001 | |||
| Total | 13 (8–18) | 14 (9–20) | 12 (8–17) | |
| < 12 | 16,202 (42.23%) | 3158 (34.27%) | 13,044 (44.75%) | |
| >/ = 12 | 22,161 (57.77%) | 6056 (65.73%) | 16,105 (55.25%) | <0.0001 |
| 90-Day Mortality | ||||
| No | 32,403 (84.46%) | 7932 (86.09%) | 24,471 (83.95%) | |
| Yes | 731 (1.91%) | 293 (3.18%) | 438 (1.5%) | |
| Adjuvant Chemotherapy | <0.0001 | |||
| No | 17,272 (45.02%) | 2903 (31.51%) | 14,369 (49.3%) | |
| Yes | 9768 (25.46%) | 2834 (30.76%) | 6934 (23.79%) | |
| Follow-up in Months | 45 (26–71) | 42 (23–69) | 46 (27–71) | <0.0001 |
Data is reported as median (interquartile range) or percentage (number) unless otherwise specified.
Neoadjuvant radiation therapy.
Abdominoperineal resection.
Low anterior resection.
Lymph node yield.
3.2. Survival
After multivariable adjustment for patient and clinicopathologic characteristics, increasing LNY was associated with improving survival up to 12 LNs regardless of receipt of NRT. Fig. 1 graphically demonstrates the critical threshold of 12 LNs with and without NRT by utilizing restricted cubic splines. With adjustment, a yield of ≥12 LNs versus <12 LNs is associated with improved survival among patients receiving NRT (HR 1.26, CI 1.17–1.37, p < 0.001) as well as those not receiving NRT (HR 1.14, CI 1.01–1.30, p = 0.04).
Fig. 1.
Smoothed restricted cubic splines of the log hazard ratio of (A) number of lymph nodes removed without neoadjuvant radiation therapy and (B) with neoadjuvant radiation therapy. The threshold of 12 lymph nodes is demonstrated. Variables adjusted for in the logistic regression model include patient gender, race, comorbidities, pathologic tumor T and N stages, extent of surgery, and receipt of adjuvant chemotherapy.
3.3. Lymph node yield
Based on the threshold of 12 LNs determined by the restricted cubic spline model, the entire cohort was stratified into two sub-groups: LNY <12 LNs (n = 16,202, 42.4%) and LNY ≥12 LNs (n = 22,161, 57.8%). Among patients receiving NRT, factors independently associated with a yield of ≥12 LNs compared to <12 LNs were younger age (OR 0.87, CI 0.84–0.90, p < 0.001), private insurance (OR 0.77, CI 0.66–0.91, p = 0.001), low comorbidity score (OR 0.78, CI 0.65–0.93, p = 0.005), a recent year of diagnosis (OR 1.20, CI 1.18–1.21, p < 0.001), higher T stage utilizing T2 and T3 vs. T1 (OR 1.1, CI 1.02–1.20, p = 0.017 and OR 1.46, CI 1.34–1.58, p < 0.001, respectively), high-grade tumors (OR 1.15, CI 1.0101.23, p = 0.030), APR resection (OR 0.867, CI 0.81–0.93, p < 0.001), treatment at an academic institution compared to community (OR 0.58, CI 0.52–0.65, p < 0.001) and comprehensive centers (OR 0.80, CI 0.74–0.86, p < 0.001), and treatment in the Midwest (OR 1.19, CI 1.09–1.29, p < 0.001) and Northeast (OR 1.19, CI 1.08–1.31, p < 0.001) compared to the South (Fig. 2).
Fig. 2.
Predictors of removing ≥12 lymph nodes among patients who underwent neoadjuvant radiation therapy. Black circles represent odds ratios for the independent association of each factor with the removal of ≥12 lymph nodes. CI of 95% are represented by the corresponding horizontal lines.
4. Discussion
Per National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that locally advanced rectal cancers be treated with pre-operative chemoradiation to achieve tumor downstaging prior to resection. However, numerous studies have demonstrated a reduced LNY in pathologic specimens of these patients.8-12 In this large nationwide analysis utilizing a novel statistical method, a minimum LNY of 12 remains essential to confer a survival benefit for patients with rectal cancer regardless of receiving neoadjuvant radiation therapy. This critical value of 12 LNs remained the threshold following adjustment for patient, clinical, and pathological factors. This is an important validation given the recent introduction of the National Accreditation Program for Rectal Cancer (NAPRC) to ensure compliance with guidelines. The retrieval of 12 lymph nodes is in line with NCCN guidelines and should be included within the NAPRC standards. Additionally, this is consistent with prior studies and recommendations for resection of colon cancer.1-3
Prior studies have attempted to create a consensus on the critical threshold of lymph nodes required for examination during the resection of rectal cancer; however, the results have been inconsistent. Ha and colleagues reported that lymph node retrieval decreased by approximately 33% among patients who received neoadjuvant chemoradiation due multiple factors including the neoadjuvant treatment, surgeon, pathologist, patient, and tumor characteristics.10 However, this difference in LNY was not associated with superior perioperative outcomes or survival. This analysis was also limited by the retrospective nature and small cohort. In a 2008 analysis of 216 patients, Doll and colleagues again identified the reduced LNY in patients receiving neoadjuvant therapy, but this difference did not impact survival.12 Investigators concluded that guidelines should be revised, but this study was limited by the small number of patients restricting generalizability.
Damin and colleagues also recognized the decrease in LNY after preoperative chemotherapy which was affected by the degree of tumor response to the therapy.13 Therefore, they concluded that LNY should not be used as a surrogate to measure the adequacy of resection in this patient population. In 2015, Lykke and colleagues suggested that a minimum of 12 lymph nodes is indeed needed to ensure node negative disease regardless of neoadjuvant therapy.17 However, this analysis was performed in a Danish database with only a fraction of the patients included in the current study. Additionally, their statistical methods included LNY as a categorical variable which is inferior to the restricted cubic splines utilized in this study.
In our study, all patients with LNY >12 had an associated survival benefit. However, survival was improved to a greater degree for those who received NRT. This finding suggests that the lymph node yield alone is an essential factor in the pathologic staging of patients at the time of resection providing a critical impact on the allocation of adjuvant therapy and subsequent overall survival.
Patients with a LNY of less than 12 lymph nodes had inferior survival. It is likely that patients below the threshold of 12 lymph nodes resected had under-staged node-positive disease which is associated with lower likelihood of adjuvant chemotherapy use. Additionally, the lower LNY might be a surrogate for an incomplete total mesorectal excision which is known to result in poorer survival.18-22 Evaluating fewer than 12 lymph nodes cannot guarantee pathologically node-negative disease with or without NRT.
Furthermore, this study defined the predictors of obtaining 12 or more lymph nodes after NRT which included expected factors such as younger age, lower comorbidity scores, and APR resection. However, location (Midwest and Northeast), insurance status (private), and type of hospital (academic medical centers) were also predictors of adequate lymph node evaluation suggesting we need to continue to develop standardized techniques for diagnosis and treatment in order to identify and provide appropriate care to those patients at risk of understaging due to low lymph node yield.
There are limitations to our analysis in a population based study utilizing a large, nationwide database. First, in a retrospective study, selection bias is always possible although we attempted to control for known covariates via our analysis. Remaining inherent differences between the cohorts could still occur which would be best addressed with a prospective study. Second, our analysis does not include the amount and duration of radiation actually received by each patient. It is possible that some patients received incomplete courses of either chemotherapy or radiation. Therefore, how that might relate to the number of lymph nodes resected and subsequent survival remains unknown. Additionally, we were unable to determine if low LNY is actually a surrogate variable for inadequate surgical resection which would also lead to inferior survival. Clinically, these important questions remain to be answered.
5. Conclusion
Our study utilizes one of the largest databases available and a novel statistical method to validate the metric of 12 lymph nodes resected as appropriate for patients who receive neoadjuvant radiation prior to resection of clinical stage II or III rectal adenocarcinoma. This is especially important in rectal cancer given the large number of patients who complete NRT for tumor downstaging prior to resection. Additionally, the identification of risk factors for a lymph node yield less than 12 requires further investigations to standardize treatment regimens across regions and facility types to improve LNY and reach the critical threshold of 12 for an overall survival benefit.
Acknowledgements
The data used in this study are derived from a de-identified National Cancer Data Base file. The American College of Surgeons has executed a Business Associate Agreement that includes a data use agreement with each of its Commission on Cancer accredited hospitals. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators.
Funding
This was an institutionally supported study. This research did not receive specific grant funding from public, commercial, or not-for-profit sectors.
Abbreviations
- LNY
lymph node yield
- LN
lymph node
- NRT
neoadjuvant radiation therapy
- NCDB
National Cancer Database
- CoC
Commission on Cancer
- LAR
low anterior resection
- APR
abdominoperineal resection
- RCS
restricted cubic splines
- HR
hazards ratio
- NCCN
National Comprehensive Cancer Network
- NAPRC
National Accreditation Program for Rectal Cancer
Footnotes
Conflicts of interest
The authors have no declared conflicts of interest.
Meeting Presentation: The American Society of Colon and Rectal Surgeons Annual Scientific Meeting, Los Angeles, CA, April–May 2016
References
- 1.Nelson H, Petrelli N, Carlin A, et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst. 2001;93(8):583–596. 10.1093/JNCI/93.8.583. [DOI] [PubMed] [Google Scholar]
- 2.Chang GJ, Kaiser AM, Mills S, et al. Standards practice task force of the American society of colon and rectal surgeons. Practice parameters for the management of colon cancer. Dis Colon Rectum. 2012;55(8):831–843. 10.1097/DCR.0b013e3182567e13. [DOI] [PubMed] [Google Scholar]
- 3.Lee S, Hofmann LJ, Davis KG, Waddell BE. Lymph node evaluation of colon cancer and its association with improved staging and survival in the Department of Defense Health Care System. Ann Surg Oncol. 2009;16(11):3080–3086. 10.1245/s10434-009-0620-4. [DOI] [PubMed] [Google Scholar]
- 4.National Comprehensive Cancer Network. Rectal Cancer. https://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf.
- 5.Lykke J, Jess P, Roikjaer O, Group O behalf of the DCC. A minimum yield of twelve lymph nodes in rectal cancer remains valid in the era of neo-adjuvant treatment. Int J Colorectal Dis. 2015;30(3):347–351. 10.1007/s00384-015-2145-6. [DOI] [PubMed] [Google Scholar]
- 6.Govindarajan A, Gonen M, Weiser MR, et al. Challenging the feasibility and clinical significance of current guidelines on lymph node examination in rectal cancer in the era of neoadjuvant therapy. J Clin Oncol. 2011;29(34):4568–4573. 10.1200/JCO.2011.37.2235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.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(9):638–646. 10.1056/NEJMoa010580. [DOI] [PubMed] [Google Scholar]
- 8.Berho M, Oviedo M, Stone E, et al. The correlation between tumour regression grade and lymph node status after chemoradiation in rectal cancer. Colorectal Dis. 2009;11(3):254–258. 10.1111/j.1463-1318.2008.01597.x. [DOI] [PubMed] [Google Scholar]
- 9.de la Fuente SG, Manson RJ, Ludwig KA, Mantyh CR. Neoadjuvant chemoradiation for rectal cancer reduces lymph node harvest in proctectomy specimens. J Gastrointest Surg. 2009;13(2):269–274. 10.1007/s11605-008-0717-2. [DOI] [PubMed] [Google Scholar]
- 10.Ha YH, Jeong S-Y, Lim S-B, et al. Influence of preoperative chemoradiotherapy on the number of lymph nodes retrieved in rectal cancer. Ann Surg. 2010;252(2):336–340. 10.1097/SLA.0b013e3181e61e33. [DOI] [PubMed] [Google Scholar]
- 11.Miller ED, Robb BW, Cummings OW, Johnstone PAS. The effects of preoperative chemoradiotherapy on lymph node sampling in rectal cancer. Dis Colon Rectum. 2012;55(9):1002–1007. 10.1097/DCR.0b013e3182536d70. [DOI] [PubMed] [Google Scholar]
- 12.Doll D, Gertler R, Maak M, et al. Reduced lymph node yield in rectal carcinoma specimen after neoadjuvant radiochemotherapy has No prognostic relevance. World J Surg.2009;33(2):340–347. 10.1007/s00268-008-9838-8. [DOI] [PubMed] [Google Scholar]
- 13.Damin DC, Rosito MA, Contu PC, et al. Lymph node retrieval after preoperative chemoradiotherapy for rectal cancer. J Gastrointest Surg. 2012;16(8):1573–1580. 10.1007/s11605-012-1916-4. [DOI] [PubMed] [Google Scholar]
- 14.Fajardo LF. Effects of ionizing radiation on lymph nodes. A review. Front Radiat Ther Oncol. 1994;28:37–45. http://www.ncbi.nlm.nih.gov/pubmed/7982602. Accessed May 26, 2017. [DOI] [PubMed] [Google Scholar]
- 15.Shvero J, Koren R, Marshak G, et al. Histological changes in the cervical lymph nodes after radiotherapy. Oncol Rep. 8(4):909–911. http://www.ncbi.nlm.nih.gov/pubmed/11410808. Accessed May 26, 2017. [DOI] [PubMed] [Google Scholar]
- 16.Morcos B, Baker B, Al Masri M, et al. Lymph node yield in rectal cancer surgery: effect of preoperative chemoradiotherapy. Eur J Surg Oncol. 2010;36:345–349. 10.1016/j.ejso.2009.12.006. [DOI] [PubMed] [Google Scholar]
- 17.Lykke J, Roikjaer O, Jess P. Danish Colorectal Cancer Group. Tumour stage and preoperative chemoradiotherapy influence the lymph node yield in stages I-III rectal cancer: results from a prospective nationwide cohort study. Colorectal Dis. 2014;16(4):O144–O149. 10.1111/codi.12521. [DOI] [PubMed] [Google Scholar]
- 18.Moro-Valdezate D, Pla-Martí V, Martín-Arévalo J, et al. Factors related to lymph node harvest: does a recovery of more than 12 improve the outcome of colorectal cancer? Color Dis. 2013;15(10):1257–1266. 10.1111/codi.12424. [DOI] [PubMed] [Google Scholar]
- 19.Newton AD, Li J, Jeganathan AN, et al. A nomogram to predict lymph node positivity following neoadjuvant chemoradiation in locally advanced rectal cancer. Dis Colon Rectum. 2016;59(8):710–717. 10.1097/DCR.0000000000000638. [DOI] [PubMed] [Google Scholar]
- 20.McDonald JR, Renehan AG, O'Dwyer ST, Haboubi NY. Lymph node harvest in colon and rectal cancer: current considerations. World J Gastrointest Surg. 2012;4(1):9–19. 10.4240/wjgs.v4.i1.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Awwad GEH, Tou SIH, Rieger NA. Prognostic significance of lymph node yield after long-course preoperative radiotherapy in patients with rectal cancer: a systematic review. Color Dis. 2013;15(4):394–403. 10.1111/codi.12011. [DOI] [PubMed] [Google Scholar]
- 22.Kidner TB, Ozao-Choy JJ, Yoon J, Bilchik AJ. Should quality measures for lymph node dissection in colon cancer be extrapolated to rectal cancer? Am J Surg. 2012;204(6). 10.1016/j.amjsurg.2012.05.003, 843–847-8. [DOI] [PubMed] [Google Scholar]
- 23.Raval MV, Bilimoria KY, Stewart AK, et al. Using the NCDB for cancer care improvement: an introduction to available quality assessment tools. J Surg Oncol. 2009;99(8):488–490. 10.1002/jso.21173. [DOI] [PubMed] [Google Scholar]