Abstract
Background:
Controversy exists regarding the ability of neoadjuvant chemoradiation (nCR) to diminish lymph node yield (LNY) and how that relationship is influenced by tumor response in patients undergoing proctectomy for locally advanced rectal cancer.
Study Design:
The National Cancer Database was used to identify patients with rectal adenocarcinomas from 2004 to 2014. Patients that received nCR were compared to those that underwent surgery alone. LNY was stratified into <12 and ≥12 groups to determine their differences in stage specific overall survival.
Results:
Of 56,812 patients 46.5% underwent surgery alone and 53.5% were administered nCR. There were more patients with LNY<12 in the nCR group compared to surgery alone, across all stages (44.1% vs. 36.5%, p<0.001). nCR improved OS regardless of LNY(p<0.001). Although patients with LNY≥12 had improved overall survival, patients that had a pCR achieved the greatest survival. In patients that did not achieve a pCR, LNY≥12 was a marker of improved OS but LNY did not impact OS in patients that attained pCR (p<0.001).
Conclusions:
Although nCR diminished LNY, LNY≥12 improved OS demonstrating the importance of quality TME. However, LNY did not impact patients that achieved pCR. These patients, who achieved the best OS, demonstrated that tumors’ biologic response to nCR had the greatest impact on patient outcomes.
Keywords: Nodal yield, Neoadjuvant chemoradiation, Rectal cancer, Survival, Pathologic Response
Introduction
The current standard of care for treatment of locally advanced rectal cancer (T3, T4 or node positive disease) is neoadjuvant chemoradiation (nCR) followed by surgery with total mesorectal excision (TME) (1). nCR has been shown to improve tumor resectability, aid in sphincter preservation and diminish the likelihood of local recurrence, with fewer long-term adverse effects than adjuvant chemoradiation (2–8). However, several randomized trials have shown conflicting data about improvement in survival after treatment with nCR (6,9–11).
American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) recommends a minimum of 12 lymph nodes in the pathologic specimen after resection to adequately stage colorectal cancer (CRC) (12). An inadequate lymph node yield (LNY) may result in poor tumor staging which has been associated with diminished overall and disease- free survival (DFS) (13–15). Several studies have reported a significantly diminished number of lymph nodes retrieved from patients after treatment with nCR (16,17). This may be explained by stromal atrophy, fibrosis and shrinkage of irradiated lymph nodes as well as decreased numbers of Tumor Infiltrating Lymphocytes (13,18).
We aimed to use a large cohort of patients within the National Cancer Database to evaluate the impact of nCR on LNY and to evaluate the correlation between LNY, overall survival (OS) and Pathologic Complete Response (pCR).
Material and Methods
The American College of Surgeons National Cancer Database (NCDB) was used to identify patients from 2004–2014 with a diagnosis of rectal adenocarcinoma. This study was deemed exempt by our Institutional Review Board. Patients were queried from the rectal Participant User Files (PUF) of the NCDB, code C209. Patients included were those who had tumors with invasive behavior and histologic adenocarcinoma. We compared the short- and long- term outcomes of patients who received nCR for locally advanced rectal cancer to those who underwent surgery alone. We also assessed LNY divided in to <12 and ≥ 12 lymph node groups and its impact on survival and the ability to concurrently gain a pCR.
Data collected included patient demographic variables (age, gender, race, insurance status, income, education level and distance from the hospital), tumor variables [tumor size, grade, clinical and pathologic TNM stage, pre-operative carcinoembryonic antigen (CEA), perineural invasion (PNI), microsatellite instability (MSI) status, KRAS mutation status, loss of heterozygosity (LOH), and resection margins]. Comorbidities are recorded as the Charlson-Deyo Comorbidity Score, derived from the sum of scores for each comorbid condition listed in the Charlson Comorbidity Score Mapping Table.
Of the 243,466 patients initially selected from the NCDB, 56,812 were included within the final analysis as we only included patients who underwent a standard nCR regimen within the United States as well as formal rectal cancer resection. Exclusion criteria included those who underwent no surgery or local excision, those who were missing chemotherapy or radiation data, patients who underwent intra-operative chemotherapy or radiation and patients treated with short course radiation (to maintain a consistent radiation treatment). Also, in order to examine the effect adjuvant chemotherapy (AC) on survival, we investigated an additional 18033 patients who received AC out of the original cohort of 243,466 patients.
Statistical Analysis
Patient characteristics were reported by nCR status using means, medians and standard deviations for continuous variables; and using relative frequencies for categorical variables. Comparisons were made using the Mann-Whitney U and Fisher’s exact or Pearson chi-square tests for continuous and categorical variables respectively. The LNY was reported by nCR status within each pathologic stage using frequencies and relative frequencies. Comparisons were made using the Pearson chi-square test. The short-term outcome rates (pathologic response and 30/90-day mortality) were summarized by stage (clinical for pCR and pathologic for mortality), neoadjuvant treatment status, and LNY using 95% confidence intervals obtained using Jeffrey’s prior method. For each stage, the outcomes were modeled as a function of treatment and LNY using logistic regression models. Odds ratios (ORs) comparing LNY within each treatment were obtained from model estimates; and were evaluated using standard tests (LN p-value). The LN yield ORs were then compared between treatments (Interaction p-value); which evaluated whether the association between a given outcome and LN yield depended on treatment status.
Overall survival (OS) from diagnosis was summarized by LNY and treatment groups using standard Kaplan-Meier methods; with comparisons made using the log-rank test. The median OS was also reported by pathologic stage, nCR status, and LNY using 95% confidence intervals obtained using standard methods. For each stage, OS was modeled as a function of treatment and LNY using Cox regression models. Hazard ratios (HRs) comparing LNY within each treatment were obtained from model estimates; and were evaluated using standard tests (LN p-value). The LNY HRs were then compared between treatments (Interaction p-value); which evaluates whether the association between OS and LNY depends on treatment status. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05.
Results
There were 56,812 patients identified in the NCDB rectal database from 2004 to 2014. Of these, 26,434 (46.5%) underwent surgery alone and 30,378 (53.5%) were treated with nCR. With short-course radiation excluded from analysis, 90.6% patients in the nCR group received 4000–6000 cGy radiation. 53.7 % of these patients also received a boost dose of radiation.
There was a propensity towards more female and white patients in the surgery alone group; with more black and Asian patients receiving nCR (Table 1). More patients were treated with nCR in academic/research centers (34.6% vs. 30.3%, p<0.001) compared to community cancer programs and had private rather than government insurance (Table 1). Patients who had more co-morbidities with a Charlson-Deyo score of 1 or 2 were significantly more likely to be treated with surgery alone compared to those with no co-morbidities who were more likely to be treated with nCR (70.9% vs. 78.7%, p<0.001). The recording of molecular markers was low overall but there was no difference in mutated KRAS between the two groups. There were more patients with MSI in the surgery alone group than nCR (14% vs. 12.2%, p=0.048).
Table 1-.
Demographic, Clinicopathologic and Treatment Information for Patients who received Surgery Alone vs. Neoadjuvant Chemoradiation
| Surgery Alone (%) | nCR (%) | p-Value | ||
|---|---|---|---|---|
| Age (N) | 68.3 | 61.3 | <0.001 | |
| Male/Female | 56.9/43.1 | 62.9/37.1 | <0.001 | |
| Race | White | 88.5 | 86.5 | <0.001 |
| Black | 7.6 | 8.7 | <0.001 | |
| Asian | 2.9 | 3.6 | <0.001 | |
| Other | 0.9 | 1.2 | <0.001 | |
| CDCI (0) | 70.9 | 78.7 | <0.001 | |
| CDCI (1 or 2) | 29.1 | 21.3 | <0.001 | |
| Insurance | Not insured | 2.0 | 5.0 | <0.001 |
| Private | 35.9 | 47.7 | <0.001 | |
| Government | 62.1 | 47.4 | <0.001 | |
| Facility Type | CCP | 10.9 | 10.1 | <0.001 |
| Comprehensive CCP | 47.5 | 44.2 | <0.001 | |
| Academic/Research | 30.3 | 34.6 | <0.001 | |
| Integrated Network | 11.4 | 11.0 | <0.001 | |
| Urban/Rural | Metro | 82.0 | 80.2 | <0.001 |
| Urban | 15.8 | 17.2 | <0.001 | |
| Rural | 2.2 | 2.7 | <0.001 | |
| CEA | Elevated | 32.7 | 46.2 | <0.001 |
| Normal | 67.3 | 53.8 | <0.001 | |
| Surgical Approach | Unknown | 4.3 | 17.7 | <0.001 |
| Robotic | 8.3 | 10.0 | <0.001 | |
| Laparoscopic | 28.4 | 19.5 | <0.001 | |
| Open/Converted | 59.0 | 52.9 | <0.001 | |
| MSI Positive | 14.0 | 12.2 | 0.048 | |
| KRAS Mutant | 29.9 | 33.7 | 0.081 | |
| Well Differentiated | 10 | 8.5 | <0.001 | |
| Moderately Differentiated | 77.9 | 79.2 | <0.001 | |
| Poorly Differentiated | 11.1 | 11.4 | <0.001 | |
| Undifferentiated | 1.0 | 0.9 | <0.001 | |
| Clinical T3/T4 | 26.1/3.4 | 78/7.6 | <0.001 | |
| Node Positive | 19.4 | 28.6 | <0.001 | |
| Lymphovascular Invasion | 19.3 | 14.7 | <0.001 | |
| Perineural Invasion | 9.5 | 11.9 | <0.001 | |
| Positive CRM | 2.7 | 3.6 | <0.001 | |
| Positive Surgical Margins | 5.4 | 5.9 | 0.01 | |
| Tumor Deposits | 4.3 | 7.2 | <0.001 | |
| No residual tumor/pCR | 1.3 | 3.4 | <0.001 |
CDCI- Charlson-Deyo Comorbidity Index, MSI- Microsatellite Instability, CRM-Circumferential Resection Margin, pCR- Pathologic Complete Response
Pathologic grade also differed between those treated with nCR versus surgery alone. Well differentiated tumors were significantly more likely to be treated with surgery alone (10.0% vs. 8.5%, p<0.001) while patients with moderately and poorly differentiated tumors were treated with nCR (Table 1). As expected, more clinical T3 (78% vs. 26.1%, p<0.001), T4 (7.6% vs. 3.4%, p<0.001) and node positive (28.6% vs. 19.4%, p<0.001) patients received nCR. 11.9% of nCR patients had PNI compared to 9.5% of surgery alone patients. Conversely, more patients in the surgery alone group had LVI compared to the nCR cohort (19.3% vs. 14.7%, p<0.001).
The nCR patients had more tumor deposits (7.2% vs. 4.3%, p<0.001) and were more likely to have positive circumferential resection margins (CRM) – (3.6% vs. 2.7%, p<0.001) as well as positive surgical margins (5.9 vs. 5.4%, p=0.01). 30-day (1.2% vs. 3.9%, p<0.001) and 90-day (2.7% vs. 7.2%, p<0.001) mortality were significantly reduced for the nCR group compared to the surgery alone cohort. Achieving an adequate LNY≥12 also appeared to directly correlate with being treated within an academic/research center (63.8%) or integrated network (64.2%) rather than community cancer programs (CCP- 48.6%) or comprehensive CCP’s (57%, p<0.001).
There were significantly more patients with LNY<12 in the nCR group compared to surgery alone in the overall cohort (44.1% vs. 36.5%, p<0.001) and particularly in pathologic stage 2 (41.5% vs. 28.6%, p<0.001) and stage 3 (31.1% vs. 24.9%, p<0.001), Table 2. The surgery alone group consistently had higher mean LNY than the nCR cohort overall (15 vs. 12.8 LNs) and at every stage. The greatest disparity was, again, seen in stage 2 and stage 3 (Table 2).
Table 2-.
Lymph Node Yield (LNY) in Surgery Alone compared to Neoadjuvant Chemoradiation (nCR) patients
| Pathologic Stage | LNY | Surgery Alone | nCR | Overall (%) | P-value |
|---|---|---|---|---|---|
| I | < 12 | 37.9 % | 43.2 % | 39.7 % | <0.001 |
| ≥ 12 | 62.1 % | 56.8 % | 60.3 % | <0.001 | |
| Mean No. | 14.7 | 12.8 | <0.001 | ||
| II | < 12 | 28.6 % | 41.5 % | 35.8 % | <0.001 |
| ≥ 12 | 71.4 % | 58.5 % | 64.2 % | <0.001 | |
| Mean No. | 16.8 | 13.2 | <0.001 | ||
| III | < 12 | 24.9 % | 32.1 % | 29.4 % | <0.001 |
| ≥ 12 | 75.1 % | 67.9 % | 70.6 % | <0.001 | |
| Mean No. | 17.6 | 15.1 | <0.001 | ||
| IV | < 12 | 33.2 % | 39.5 % | 37.2 % | <0.001 |
| > = 12 | 66.8 % | 60.5 % | 62.8 % | <0.001 | |
| Mean No. | 15.2 | 14.5 | <0.001 | ||
| Overall | < 12 | 36.5 % | 44.1 % | 40.5 % | <0.001 |
| ≥ 12 | 63.5 % | 55.9 % | 59.5 % | <0.001 | |
| Mean No. | 15 | 12.8 | <0.001 |
LNY- Lymph Node Yield, nCR- Neoadjuvant chemoradiation, Mean No. = Mean number of lymph nodes obtained
In examining survival for these patients, we found that patients who received nCR had significantly improved overall survival compared to the surgery alone cohort, regardless of their LNY (Figure 1). LNY≥12 was also associated with improved survival in both nCR and surgery alone groups. The highest median OS (108 months) was observed in the patients treated with nCR who had LNY≥12, followed by the nCR patients with LNY<12 (99.6 months). Survival was significantly poorer in surgery alone patients than the nCR group but was improved in patients who had LNY≥12 compared to LNY<12 (Table 3). A more marked discrepancy between OS in nCR and surgery alone groups was identified in patients with clinical stage 2 and 3 (Figure 2).
Figure 1-.
Overall Survival in total cohort associated with Lymph Node Yield in Neoadjuvant Chemoradiation and Surgery Alone groups
Table 3-.
3-year, 5-year and Median Overall Survival in Neoadjuvant chemoradiation compared to Surgery Alone patients stratified by Lymph Node Yield
| 3-year OS Rate (%) (95% CI) | 5-year OS Rate (%) (95% CI) | Median OS (months) (95% CI) | P-value | |
|---|---|---|---|---|
| Total | 77 (77,78) | 65 (65,66) | 99.2 (97.6,100.7) | <0.001 |
| nCR: LNY<12 | 80 (79,81) | 67 (66,68) | 99.6 (97.3, 102.1) | <0.001 |
| nCR: LNY≥12 | 82 (82,83) | 70 (69,71) | 108.0 (105.3, 110.5) | <0.001 |
| Surgery Alone: LNY<12 | 71 (70,72) | 60 (59,61) | 84.1 (80.6, 87.5) | <0.001 |
| Surgery Alone: LNY≥12 | 74 (73,75) | 62 (61,63) | 95.4 (92.9, 99.2) | <0.001 |
OS- Overall Survival, nCR- Neoadjuvant chemoradiation, LNY- Lymph Node Yield
Figure 2-.
Overall Survival in total cohort associated with Lymph Node Yield in Neoadjuvant Chemoradiation and Surgery Alone groups in a) Clinical Stage 2 and b) Clinical Stage 3
pCR was obtained in 3.4% of patients in the nCR group compared with 1.3% of patients without residual tumor identified within the surgery alone group. Of the patients in the nCR group who achieved a pCR, 57.9% had LNY≥12 and 42.1% had LNY<12. We found that patients who achieved a pCR had significantly better OS than those who did not, Table 4. In patients that did not achieve a pCR, LNY≥12 was a marker of improved OS. Patients with LNY≥12 had a median OS of 104 months, compared with 89 months in patients with LNY<12 (p<0.001). However, in those that had a pCR, LNY did not impact survival as all patients had a median OS which was not reached at 10 years (Figure 3).
Table 4-.
3-year, 5-year and Median Overall Survival in patients that achieved a Pathologic Complete response (pCR) compared to Non-pCR patients stratified by Lymph Node Yield
| 3-year OS Rate (%) (95% CI) | 5-year OS Rate (%) (95% CI) | Median OS (Months) (95% CI) | P-Value | ||
|---|---|---|---|---|---|
| Non-pCR | Total | 80 (79,81) | 65 (65,66) | 97.3 (95,100.2) | <0.001 |
| LNY<12 | 78 (77,79) | 62 (61,64) | 89.4 (85.8,93.9) | <0.001 | |
| LNY≥12 | 81 (80,82) | 68 (67,69) | 104.4 (100.2,108) | <0.001 | |
| pCR | Total | 91 (88,93) | 84 (80,87) | NR (NR,NR) | 0.092 |
| LNY<12 | 87 (82,91) | 80 (74,85) | NR (NR,NR) | 0.092 | |
| LNY≥12 | 94 (90,96) | 87 (81,92) | NR (NR,NR) | 0.092 | |
pCR- Pathologic Complete Response, LNY- Lymph Node Yield, OS- Overall Survival, NR- Not reached at 120 months
Figure 3-.
Overall Survival comparing LNY<12 and LNY≥12 in patients who achieved a pathologic complete response (pCR) compared to those who did not achieve a pCR.
An additional 18,033 patients were evaluated who were treated with adjuvant chemotherapy (AC) to assess its impact on survival in both nCR and surgery groups. Of these, 5368 (29.8%) were treated with surgery + AC and 12665 patients (70.2%) were treated with nCR + surgery + AC. Patients who received nCR + surgery + AC had significantly better median OS, 5-year and 3-year OS than those treated with surgery + AC (Table 5). Those who received surgery + AC had higher pathologic T3 stage (65.8% vs. 49.9%, p<0.001), T4 stage (13.5% vs. 4.5%, p<0.001) and node positivity (74.2% vs. 37.8%, p<0.001) than patients also treated with nCR. These patients also had more tumor deposits (17.4% vs. 9.6%, p<0.001), positive surgical margins (14.4% vs. 5.9%, p<0.001) and more positive CRM (7.0% vs. 4.1%, p<0.001).
Table 5-.
3-year, 5-year and Median Overall Survival in Neoadjuvant chemoradiation compared to Surgery Alone patients with the addition of Adjuvant Chemotherapy stratified by Lymph Node Yield
| 3-yr OS Rate (%) (95% CI) | 5-yr OS Rate(%) (95% CI) | Median OS (Months) (95% CI) | P-value | |
|---|---|---|---|---|
| Total | 82 (81,82) | 68 (67,69) | 109.2 (107.6,114.2) | <0.001 |
| nCR+ Surgery+ AC: LNY<12 | 87 (86,88) | 75 (74,77) | NR (113.2, NR) | <0.001 |
| nCR+ Surgery+ AC: LNY≥12 | 89 (88,90) | 77 (76,79) | 114.2 (109.2, NR) | <0.001 |
| Surgery+ AC: LNY<12 | 62 (58,65) | 39 (36,43) | 48.0 (45.1,51.1) | <0.001 |
| Surgery+ AC: LNY≥12 | 68 (67,70) | 51 (49,53) | 63.0 (59,68.1) | <0.001 |
nCR- Neoadjuvant chemoradiation, AC- Adjuvant Chemotherapy, LNY- Lymph Node Yield, OS- Overall Survival, NR- Not reached at 120 months
Discussion
Lymph node yield after surgical resection has been demonstrated to be an important prognostic factor in CRC. Obtaining an adequate LNY≥12 is important to avoid under-staging and stage migration of CRC which can affect whether adjuvant chemotherapy is administered and alter long term prognosis (14,19). A number of studies have identified a diminished LNY in patients with rectal cancer who have received nCR (13,16,20–22). We identified this same trend within our cohort, which was particularly pronounced in patients with locally advanced disease. Damin et al. (13) noted a 26.8% decrease in the mean number of lymph nodes retrieved in rectal cancer specimens after nCR. They hypothesized that this phenomenon was secondary to radiation-induced apoptosis of lymphocytes in the meso-rectum resulting in stromal atrophy, fibrosis and nodal shrinkage with replacement by adipocytes (13,20).
Pathologic complete response has been reported in 8–30% of patients treated with nCR and subsequent TME and has been associated with an improvement in DFS and OS (1,23–25). Dinaux et al. (26) also found an association between pCR and lower clinical T and N stage, higher radiation dose and absence of mutations such as KRAS; with lower rates of local recurrence and higher 5-year OS in these patients than those with residual disease. In our evaluation of patients that did not achieve a pCR, we found that LNY≥12 significantly improved OS (by 15 months) compared to those with LNY<12. However, LNY did not appear to significantly impact OS in those who achieved a pCR. This is likely because survival in patients who achieved a pCR was universally excellent (>10 years) and in patients that did not achieve this response, better operative standards and appropriate staging improved patient outcomes.
In this study, we demonstrated a survival advantage in patients with LNY≥12 compared to patients with LNY<12 in both surgery alone (median OS- 95.4 vs. 84.1 months) and nCR (median OS-108 vs. 99.6 months) groups which has been demonstrated in previous studies (27,28). There was, however, also a significant survival advantage in patients treated with nCR rather than surgery alone, even in patients who were found to have LNY<12, indicating that response to nCR is likely more predictive of improved survival than LNY alone. We also found that the addition of adjuvant chemotherapy did not significantly improve survival in the surgery alone patients but did have a positive effect on OS in patients that did receive nCR. This is likely because patients that did not receive nCR had higher stage disease, worse tumor biology and more margin positive surgical resections, for which AC was unable to compensate.
Additionally, the attainment of a pCR in the nCR cohort, had a significantly positive impact on OS, regardless of LNY (29). Results may provide additional justification for optimizing response rates with management strategies such as the use of total neoadjuvant therapy for locally advanced rectal cancers (30). In addition, there has been increasing use of “watch and wait” or organ preservation strategies after attaining complete clinical response (cCR) after nCR with excellent salvage rates for recurrences (31–34).
There are some limitations to this study. This a retrospective review of data from the NCDB with variability between institutions in the amount of clinical data provided. Patients with significantly missing data were excluded from analysis. This may have resulted in selection bias in analysis of some of the included data. There is also potential for variability between institutions in the completeness of TME surgical specimens as well as differences in pathologic evaluation of these specimens which may alter LNY between institutions. Some factors have also been under reported within the database including the status of molecular markers as well as incidence of PNI, CEA, tumor regression grade and pathologic M (metastasis) stage. The NCDB also reports OS as a prognostic outcome but does not report either cancer specific survival or DFS. Further limitations of this study are that the NCDB does not report the location (distance from the anal verge) of the tumors recorded within the database, which may have impacted margin positivity or indications for nCR and also does not report granular details about specific chemotherapy regimens used. Another limitation may be that given the differences in the clinicopathologic features between the nCR and surgery alone groups, strictly comparing outcomes between them may be difficult given confounding variables.
Conclusions
Lymph node yield is important in the prevention of stage migration to allow for appropriate treatment of locally advanced cancer and LNY≥12 has been demonstrated to improve survival. We used a large database of patients within the NCDB to assess clinical and pathologic outcomes of patients treated with surgery alone compared to those treated initially with nCR. We found that despite the reduction in LNY after treatment with nCR, LNY≥12 was still a positive prognostic factor in both nCR and surgery alone groups likely related to the positive impact of quality TME, diminished stage migration as well as intrinsic tumoral biology. However, the patients that had superior OS were those who attained a pCR, regardless of LNY, thereby demonstrating that the best indicator of positive prognostic outcomes in patients is the tumoral response to nCR. Optimizing this response appears to be the key to achieving enhanced outcomes in the future treatment of locally advanced rectal adenocarcinoma.
Acknowledgements
This work was supported by Roswell Park Cancer Institute and National Cancer Institute (NCI) grant P30CA016056. This article has not been published in its full form previously. It was presented as an oral presentation at the American College of Surgeons, San Diego, California October, 2017 and the abstract was included within the JACS supplement.
Footnotes
Disclosures: The authors have no disclosures
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