Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant Therapy

Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant... Abstract Background Neoadjuvant chemoradiation is currently standard of care in stage II–III rectal cancer, resulting in tumor downstaging for patients with treatment-responsive disease. However, the prognosis of the downstaged patient remains controversial. This work critically analyzes the relative contribution of pre- and post-therapy staging to the anticipated survival of downstaged patients. Methods The National Cancer Database (NCDB) was queried for patients with rectal cancer treated with transabdominal resection between 2004 and 2014. Stage II–III patients downstaged with neoadjuvant radiation were compared with stage I patients treated with definitive resection alone. Patients with positive surgical margins were excluded. Overall survival was evaluated using both Kaplan-Meier analyses and Cox proportional hazards models. All statistical tests were two-sided. Results A total of 44 320 patients were eligible for analysis. Survival was equivalent for patients presenting with cT1N0 disease undergoing resection (mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with those downstaged to pT1N0 from both cT3N0 (mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12) and cT3N1 disease (mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22). Survival statistically significantly improved in patients downstaged to pT2N0 from cT3N0 disease (mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001) and cT3N1 (mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001), compared with cT2N0 patients undergoing resection alone (mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months). Multiple survival analysis confirmed that final pathologic stage dictated long-term outcomes in patients undergoing neoadjuvant radiation (hazard ratio [HR] of pT2 = 1.24, 95% CI = 1.10 to 1.41; HR of pT3 = 1.81, 95% CI = 1.61 to 2.05; HR of pT4 = 2.72, 95% CI = 2.28 to 3.25, all P ≤ .001 vs pT1; HR of pN1 = 1.50, 95% CI = 1.41 to 1.59; HR of pN2 = 2.17, 95% CI = 2.00 to 2.35, both P < .001 vs pN0); while clinical stage at presentation had little to no predictive value (HR of cT2 = 0.81, 95% CI = 0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI = 0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI = 0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI = 0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI = 0.86 to 1.08, P = .48 vs cN0). Conclusions Survival in patients with rectal cancer undergoing neoadjuvant radiation is driven by post-therapy pathologic stage, regardless of pretherapy clinical stage. These data will further inform prognostic discussions with patients. Colorectal cancer is the third most common malignancy in the United States, with an anticipated 135 000 cases diagnosed in 2017 (1). Incidence and mortality rates continue to decline in both colon and rectal cancer, largely due to improvements in both early screening and multidisciplinary treatment modalities (2). Prior to the use of multimodality therapy, local recurrence was especially common in rectal cancer, resulting in poor long-term outcomes (3). The introduction of neoadjuvant radiotherapy has decreased local recurrence rates by approximately 50% to 60% (4), with chemotherapy further improving both progression-free and overall survival (5). The current standard of care for most patients with stage II and III rectal cancer is neoadjuvant chemotherapy with radiation, followed by complete surgical resection (6,7). As neoadjuvant chemoradiation regimens continue to improve, the patient population clinically benefitting from tumor downstaging prior to surgery is growing. It has been demonstrated that downstaged tumors are associated with improved survival compared with therapy-resistant tumors (8–13). However, estimates of overall survival in downstaged patients continue to vary, as recent studies have provided conflicting evidence (8,14,15). Specifically, it remains unclear whether long-term outcomes are tied more closely to baseline or postoperative disease stage. To address this gap in prognostic knowledge, we aimed to examine the prognostic utility of pathologic stage as compared with clinical stage in patients downstaged with neoadjuvant therapy. This work queries a large national database for patients with rectal cancer who underwent transabdominal resection over a 10-year time period. Methods Patients A retrospective review of the National Cancer Database (NCDB) was performed. The NCDB is a hospital-based national registry of cancer patients and a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data files used are compliant with the United States Health Insurance Portability and Accountability Act (HIPAA) and de-identified. The participant user file analyzed in this study included all patients diagnosed with rectal cancer from 2004 through 2014. Patient characteristics examined included age at diagnosis, sex, tumor grade, margin status, receipt of chemotherapy, receipt of neoadjuvant radiation, and clinical (c) and pathologic (p) TNM stage. Patients with incomplete data were excluded, with the exception of tumor grade, as this information was unavailable in over 2500 cases. High tumor grade was defined as poor differentiation. Margin status postresection was defined as positive or negative. Clinical and pathologic TNM staging was performed according to American Joint Committee on Cancer (AJCC) guidelines, with 54% and 46% of patients classified according to the 6th edition and 7th editions, respectively. Importantly, T stage according to depth of invasion and N stage according to nodal metastasis were largely unchanged between the AJCC editions for rectal cancer (16), and the data were therefore combined for the purposes of this manuscript. In total, 243 466 patients with rectal cancer diagnosed between 2004 and 2014 were eligible for analysis from the NCDB. Inclusion criteria for this analysis consisted of histologically proven rectal adenocarcinoma in patients undergoing curative-attempt surgical resection. Patients with metastatic disease were excluded. Patients who underwent local excision and those with positive surgical margins were excluded because these patients have higher rates of local recurrence. Finally, as adjuvant radiation was uncommon (10.9%) and the reasons for adjuvant radiation were unknown, these patients were also excluded. In addition, while the vast majority of patients undergoing neoadjuvant radiation received chemotherapy (97.5%), the timing of chemotherapy was unknown. Chemotherapy was therefore excluded as a separate variable in this analysis. A detailed inclusion diagram is shown in Figure 1. Figure 1. View largeDownload slide Inclusion algorithm for National Cancer Database analysis (NCDB). All patients diagnosed with rectal cancer between 2004 and 2014 were initially included in the study, representing data obtained directly from the NCDB. Diagnosis was narrowed to adenocarcinoma, excluding neuroendocrine and other uncommon rectal tumors. Stage IV patients, defined by either clinical or pathologic M1 stage, were excluded. Patients who had positive surgical margins or who did not proceed to definitive transabdominal resection were then excluded, including nonoperative patients and those undergoing local excision. Patients with missing data were excluded, most of whom had incomplete clinical staging. Finally, patients undergoing adjuvant radiation were excluded, as the primary purpose was to compare patients who downstaged with neoadjuvant therapy with patients presenting with stage I disease undergoing surgery without neoadjuvant radiation. Figure 1. View largeDownload slide Inclusion algorithm for National Cancer Database analysis (NCDB). All patients diagnosed with rectal cancer between 2004 and 2014 were initially included in the study, representing data obtained directly from the NCDB. Diagnosis was narrowed to adenocarcinoma, excluding neuroendocrine and other uncommon rectal tumors. Stage IV patients, defined by either clinical or pathologic M1 stage, were excluded. Patients who had positive surgical margins or who did not proceed to definitive transabdominal resection were then excluded, including nonoperative patients and those undergoing local excision. Patients with missing data were excluded, most of whom had incomplete clinical staging. Finally, patients undergoing adjuvant radiation were excluded, as the primary purpose was to compare patients who downstaged with neoadjuvant therapy with patients presenting with stage I disease undergoing surgery without neoadjuvant radiation. Statistical Analysis All statistical analyses were performed using IBM SPSS Statistics version 24. A P value of less than .05 was considered statistically significant. Categorical variables were compared using the exact chi-square test, and continuous variables were compared using the two independent samples t test. Survival curves were estimated using Kaplan-Meier methodology and compared between two groups using the log-rank test. Univariate analysis of overall survival was performed using a Cox proportional hazards regression model. The proportional hazards assumption was validated graphically using model checking (log minus log) plots for each variable. All variables that were statistically significant on univariate analysis (P < .05) were included in a multivariable Cox proportional hazards regression model. To adjust for selection bias, inverse probability weighting was performed based on the predicted probability of inclusion in the main study population for an expanded population including subjects with local excision, positive margins, metastatic disease, and adjuvant radiotherapy. Weights were applied to logistic regression analyses to predict three-year and five-year mortality using covariates included in the original analysis. All statistical tests were two-sided unless otherwise indicated. Results Patient Population A total of 44 320 patients were included in the final analysis: 13 736 patients undergoing surgical resection up front and 30 584 patients who received neoadjuvant radiation prior to surgical resection. Baseline characteristics of each group are detailed in Table 1. Patients who underwent neoadjuvant radiation tended to be younger and female. Neoadjuvant radiation was used most commonly in clinical stage II–III disease, while those patients who did not undergo radiation were largely clinical stage I, consistent with National Comprehensive Cancer Network (NCCN) guidelines (7). Importantly, of the 13 736 patients who did not undergo radiation, 3872 were pT1N0 and 4287 were pT2N0, accounting for only 59.4% of this cohort. Thus, 40.6% of the patients who underwent surgery without radiation had pathologic stage II–III disease, discordant with NCCN guidelines. Table 1. Patient demographics and clinicopathologic data Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  * P values were calculated using two-sided independent samples t tests for continuous variables and the exact chi-square test for categorical variables. † Tumor grade was unavailable for 4208 tumors (9.5%). Table 1. Patient demographics and clinicopathologic data Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  * P values were calculated using two-sided independent samples t tests for continuous variables and the exact chi-square test for categorical variables. † Tumor grade was unavailable for 4208 tumors (9.5%). Clinical and Pathologic Staging Concordance We first sought to evaluate the accuracy of clinical staging in this group of patients. As such, the concordance between clinical and pathologic staging was assessed in patients undergoing surgery up front. In the absence of neoadjuvant radiation, clinical T staging was found to be approximately 70% to 80% accurate when compared with postoperative pathologic T stage (Supplementary Figure 1A, available online). In contrast, clinical T stage predicted pathologic T stage only 30% to 65% of the time in patients undergoing neoadjuvant radiation. This disparity suggests a downstaging effect (Supplementary Figure 1B, available online). Clinical N staging proved to be 87.8% and 89.4% accurate for N0 and N2 disease, respectively, but relatively poor at predicting N1 disease (60.3%) (Supplementary Figure 1C, available online). Clinical N stage was a poor indicator of pathologic N stage in patients undergoing neoadjuvant radiation, again suggesting a downstaging effect (Supplementary Figure 1D, available online). Outcomes While it has been previously demonstrated that patients responding to neoadjuvant radiation fare better than nonresponders, it remains unclear whether patients survive in a manner that most closely associates with either their pre- or postneoadjuvant therapy stage. To assess this, we compared outcomes of patients resected without neoadjuvant therapy (ie, pStageX) with those downstaged with neoadjuvant radiation to a similar stage (ie, ypStageX). All patients with final pT1N0 disease demonstrated similar overall survival, regardless of their clinical stage prior to therapy (mean survival of cT1N0 = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months; mean survival of cT2N0 = 110.9 months, 95% CI = 104.1 to 117.6 months; mean survival of cT3N0 = 114.9 months, 95% CI = 110.4 to 119.3 months; P = .18 cT1N0 vs cT2N0, P = .12 cT1N0 vs cT3N0) (Figure 2A, Table 2). This also held true for patients with clinical N1 disease who downstaged to pT1N0 (mean survival of cT2N1 = 110.0 months, 95% CI =  99.7 to 120.4 months; mean survival of cT3N1 = 115.4 months, 95% CI =  110.1 to 120.7 months; P = .44 cT1N0 vs cT2N1, P = .22 cT1N0 vs cT3N1) (Figure 2B, Table 2). However, patients resected up front with pT2N0 disease demonstrated reduced survival compared with those downstaged to ypT2N0 from clinical T3N0 (mean survival of cT2N0 = 100.0 months, 95% CI =  97.5 to 102.5 months; mean survival of cT3N0 = 109.0 months, 95% CI =  106.7 to 111.2 months; mean survival of cT4N0 = 101.9 months, 95% CI =  92.6 to 111.2 months; P < .001 cT2N0 vs cT3N0, P = .26 cT2N0 vs cT4N0) (Figure 2C, Table 2) and clinical T3N1 disease (mean survival of cT3N1 = 112.8 months, 95% CI =  110.0 to 115.7 months; mean survival of cT4N1 = 97.7 months, 95% CI =  85.4 to 110.0 months; P < .001 cT2N0 vs cT3N1, P = .79 cT2N0 vs cT4N1) (Figure 2D, Table 2). Table 2. Three-, five-, and 10-year overall survival rates Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  * No radiation. All other values represent groups receiving neoadjuvant radiation. Kaplan-Meier curves were used to calculate three-, five-, and 10-year survival rates. OS = overall survival. Table 2. Three-, five-, and 10-year overall survival rates Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  * No radiation. All other values represent groups receiving neoadjuvant radiation. Kaplan-Meier curves were used to calculate three-, five-, and 10-year survival rates. OS = overall survival. Figure 2. View largeDownload slide Overall survival in downstaged disease. A) Kaplan-Meier survival plots generated for the following pathologic T1N0 patients: patients with clinical T1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with patients with cT2N0 (dashed, mean survival = 110.9 months, 95% CI = 104.1 to 117.6 months, P = .18 vs cT1N0) or cT3N0 disease (gray, mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12 vs cT1N0) treated with neoadjuvant radiation and downstaged to pT1N0. B) Survival plots for pathologic T1N0 patients: patients with cT1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% CI = 110.8 to 115.3 months) compared with patients downstaged from cT2N1 (dashed, mean survival = 110.0 months, 95% CI = 99.7 to 120.4 months, P = .44 vs cT1N0) or cT3N1 (gray, mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22 vs cT1N0) with neoadjuvant radiation. C) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N0 (gray, mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001 vs cT2N0) or cT4N0 (dashed, mean survival = 101.9 months, 95% CI = 92.6 to 111.2 months, P = .26 vs cT2N0) to pathologic T2N0 disease. D) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N1 (gray, mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001 vs cT2N0) or cT4N1 (dashed, mean survival = 97.7 months, 95% CI = 85.4 to 110.0 months, P = .79 vs cT2N0) to pathologic T2N0 disease. P values were calculated using the two-sided log rank test. Figure 2. View largeDownload slide Overall survival in downstaged disease. A) Kaplan-Meier survival plots generated for the following pathologic T1N0 patients: patients with clinical T1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with patients with cT2N0 (dashed, mean survival = 110.9 months, 95% CI = 104.1 to 117.6 months, P = .18 vs cT1N0) or cT3N0 disease (gray, mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12 vs cT1N0) treated with neoadjuvant radiation and downstaged to pT1N0. B) Survival plots for pathologic T1N0 patients: patients with cT1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% CI = 110.8 to 115.3 months) compared with patients downstaged from cT2N1 (dashed, mean survival = 110.0 months, 95% CI = 99.7 to 120.4 months, P = .44 vs cT1N0) or cT3N1 (gray, mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22 vs cT1N0) with neoadjuvant radiation. C) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N0 (gray, mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001 vs cT2N0) or cT4N0 (dashed, mean survival = 101.9 months, 95% CI = 92.6 to 111.2 months, P = .26 vs cT2N0) to pathologic T2N0 disease. D) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N1 (gray, mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001 vs cT2N0) or cT4N1 (dashed, mean survival = 97.7 months, 95% CI = 85.4 to 110.0 months, P = .79 vs cT2N0) to pathologic T2N0 disease. P values were calculated using the two-sided log rank test. The impact of final pathologic stage on long-term outcomes was then assessed within clinically stage-matched patients undergoing neoadjuvant radiation. In clinical T3N0 disease, Supplementary Figure 2A (available online) confirms previous observations suggesting that downstaged disease is associated with statistically significantly better outcomes compared with therapy-resistant tumors (mean survival of pT1N0 = 114.9 months, 95% CI = 110.4 to 119.3 months; mean survival of pT2N0 = 109.0 months, 95% CI =  106.7 to 111.2 months; mean survival of pT3N0 = 99.4 months, 95% CI =  97.4 to 101.4 months; mean survival of pT4N0 = 68.1 months, 95% CI =  59.8 to 76.4 months; P = .003 pT1N0 vs pT2N0, P < .001 pT2N0 vs pT3N0, P < .001 pT3N0 vs pT4N0). Similarly, pathologic stage ultimately determined long-term survival in clinical T3N1 disease with final pathologic N0 stage (mean survival of pT1N0 = 115.4 months, 95% CI =  110.1 to 120.7 months; mean survival of pT2N0 = 112.8 months, 95% CI =  110.0 to 115.7 months; mean survival of pT3N0 = 106.8 months, 95% CI =  104.2 to 109.4 months; mean survival of pT4N0 = 67.1 months, 95% CI =  58.4 to 75.9 months; P = .27 pT1N0 vs pT2N0, P < .001 pT2N0 vs pT3N0, P < .001 pT3N0 vs pT4N0) (Supplementary Figure 2B, available online) or pN1 stage (mean survival of pT1N1 = 106.8 months, 95% CI =  96.0 to 117.6 months; mean survival of pT2N1 = 106.5 months, 95% CI =  101.6 to 111.4 months; mean survival of pT3N1 = 91.6 months, 95% CI =  88.7 to 94.6 months; mean survival of pT4N1 = 67.6 months, 95% CI =  51.1 to 84.2 months; P = .28 pT1N1 vs pT2N1, P < .001 pT2N1 vs pT3N1, P = .02 pT3N1 vs pT4N1) (Supplementary Figure 2C, available online). In both instances, the degree of downstaging predicted prolonged survival. Taken together, these data demonstrate that the prognosis for stage II–III patients with rectal cancer downstaged by neoadjuvant radiation is equivalent or superior to patients undergoing up-front surgery for stage I disease. To further test if final pathologic stage is a better predictor of long-term outcomes than clinical stage in patients undergoing neoadjuvant radiation, a Cox proportional hazards model was employed. Table 3 displays a univariate analysis of overall survival to investigate the marginal impact of individual factors on patients’ survival time, confirming previously demonstrated relationships with known clinicopathologic factors. Specifically, older age (hazard ratio [HR] = 1.03, 95% CI = 1.03 to 1.04, P < .001), female sex (HR = 0.88, 95% CI =  0.84 to 0.93, P < .001), and poor tumor differentiation (HR = 1.54, 95% CI =  1.44 to 1.64, P < .001) were all statistically significantly associated with survival. No statistically significant survival difference was observed between clinical (cT2, cT1: HR = 0.87, 95% CI =  0.75 to 1.01, P = .072; cT3, cT1: HR = 1.04, 95% CI =  0.91 to 1.19, P = .58) disease pairs. Likewise, clinical N1 vs N0 disease (HR = 1.02, 95% CI =  0.97 to 1.07, P = .54) demonstrated no statistically significant difference in survival. As opposed to clinical stage, higher pathologic T stage predicted reduced survival (HR of pT2 = 1.28, 95% CI =  1.14 to 1.43, P < .001; HR of pT3 = 2.16, 95% CI =  1.94 to 2.41, P < .001; HR of pT4 = 3.37, 95% CI =  2.90 to 3.91, P < .001 vs pT1) and N stage (HR of pN1 = 1.52, 95% CI =  1.44 to 1.61, P < .001; HR of pN2 = 2.28, 95% CI =  2.12 to 2.44, P < .001 vs pN0). Multivariable analysis demonstrated no association between increasing clinical stage and worsening survival (HR of cT2 = 0.81, 95% CI =  0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI =  0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI =  0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI =  0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI =  0.86 to 1.08, P = .48 vs cN0) while further confirming this relationship between pathologic stage and long-term survival (HR of pT2 = 1.24, 95% CI =  1.10 to 1.41; HR of pT3 = 1.81, 95% CI =  1.61 to 2.05; HR of pT4 = 2.72, 95% CI =  2.28 to 3.25; P ≤ .001 vs pT1; HR of pN1 = 1.50, 95% CI =  1.41 to 1.59; HR of pN2 = 2.17, 95% CI =  2.00 to 2.35, both P < .001 vs pN0) (Table 4). Due to concern for shorter follow-up times in recently diagnosed patients, sensitivity analysis was performed in cases diagnosed before 2011, confirming similar relationships between clinical stage, pathologic stage, and survival (Supplementary Tables 1 and 2, available online). Therefore, in surgical patients undergoing neoadjuvant radiation for rectal cancer, the final pathologic stage should be the primary determinant of long-term survival, regardless of pretherapy clinical stage. Table 3. Univariate analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). Table 3. Univariate analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). Table 4. Multivariable analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). Table 4. Multivariable analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). In order to address the application of strict exclusion criteria applied to such a large data set, inverse probability weighting (IPW) was applied. Logistic regression was performed using IPW based on the probability of inclusion in the main study to an expanded cohort of patients with local excision, positive margins, metastatic disease, and adjuvant radiotherapy. Factors associated with increased odds of death within three years (Supplementary Table 3, available online) and five years (Supplementary Table 4, available online) included advanced age, male sex, poor tumor differentiation, and mucinous or signet ring histology. Pathologic staging again demonstrated greater discrimination than clinical staging. Discussion The prognosis associated with downstaging in rectal cancer after neoadjuvant therapy remains difficult to quantify. Using a large database such as the NCDB and evaluating more than 40 000 patients with rectal cancer over a 10-year time period, our study provides objective data to help answer this important clinical question. We show that patients downstaged to stage I disease with neoadjuvant radiotherapy demonstrate similar, if not better, survival than stage I patients proceeding directly to resection. In fact, all patient groups with evidence of downstaging demonstrate similar, if not better, survival than similarly pathologic staged patients having gone straight to surgery. Thus, pretherapy stage appears to have little influence on survival in patients undergoing neoadjuvant therapy. Rather, post-therapy pathologic stage (and the degree of downstaging) best predicts long-term outcomes. This represents the largest study to date analyzing survival in downstaged rectal cancer patients, demonstrating that final pathologic stage best dictates overall survival, regardless of pretherapy clinical stage. Our findings are in agreement with a smaller study conducted by Quah et al., in which the authors queried a single-institution database for stage II–III rectal cancers treated with neoadjuvant radiation and incorporated multiple calculations to assess histopathologic response to therapy (8). While our methodologies differ, the result appears to be similar: final pathologic stage after radiation is highly predictive of long-term outcomes. However, there are discordant data in the literature on this issue. A large study by Kim et al. demonstrated worse disease-free survival and distant metastasis–free survival in postneoadjuvant stage II patients compared with patients with the corresponding pathologic stage not receiving neoadjuvant chemotherapy (14,15). However, direct comparison between these investigations and our results is difficult as the NCDB records overall survival but does not include local or distant control variables. Subsequent investigations compared downstaged tumors with therapy-resistant tumors and identified survival advantages for downstaged patients (17,18). In line with these findings, we demonstrate a progressive survival benefit with increasing downstaging for pathologic stage I–III patients. Thus, the survival advantage seen is likely a reflection of inherent tumor biology and overall treatment sensitivity. Accordingly, the Neoadjuvant Rectal (NAR) Score was recently developed to quantify tumor regression. Although the NAR has yet to be formally validated as a substitute for long-term survival, it now serves as a surrogate end point for National Cancer Institute–approved phase II clinical trials (19). To our knowledge, this is the largest study of its kind to evaluate downstaged rectal cancer patients. Pathologic T1N0 patients, regardless of baseline presentation or downstaged from stage III disease, display equivalent survival patterns. In fact, pT2N0 patients having proceeded directly to surgery exhibited statistically significantly reduced survival compared with cT3N0 or cT3N1 patients who were downstaged to pT2N0 with neoadjuvant therapy. These data suggest a potential role for neoadjuvant therapy in T2N0 disease. It was particularly noteworthy that pretherapy clinical stage appeared to be inconsistent in predicting outcomes, representing a potential paradigm shift in the management of these patients. The issue is further compounded by our study showing that 40.6% of patients not receiving neoadjuvant radiation had pathologic stage II–III disease, discordant with current National Comprehensive Cancer Network (NCCN) guidelines (7). These conclusions favoring neoadjuvant therapy may be limited by confounding disparities between patients undergoing neoadjuvant radiation and those proceeding directly to surgery. However, multivariable analysis adjusting for age, sex, and pathologic tumor grade nonetheless continued to demonstrate that final pathologic stage dictated outcome in patients undergoing neoadjuvant radiation, while advanced clinical stage demonstrated no statistically significant association with survival. Men demonstrated poor long-term outcomes compared with women, a finding commonly reported in rectal cancer cohorts (20–23). The etiology of this gender disparity remains unclear. Previous investigators have claimed this to be purely an age-related effect (24). However, our data demonstrate reduced survival in men when adjusted for both age and stage, suggesting alternative reasons behind this difference. Anatomical differences may contribute, as women typically have wider pelvic dimensions, which may be further elucidated with the development of imaging-based volumetric calculators. This study has several limitations. First, the large, hospital-maintained, retrospective database affords little control over local practices. As such, chemotherapies, radiation regimens, and surgical procedures are grouped broadly, and we are unable to evaluate and adjust for specific techniques, doses, or regimens. It is worth mentioning that 29 784 (97.5%) patients undergoing neoadjuvant radiation also received chemotherapy in some form. Given this concordance and a lack of data regarding timing of systemic therapy, chemotherapy was excluded as a separate variable in this analysis. The relative impact of chemotherapy on a durable downstaging effect on survival represents an area of active investigation in our group. In addition, the absence of local recurrence and disease-free survival data in the NCDB limits our ability to understand the mode of failure in patients with poor survival. The database also fails to incorporate molecular profiling of tumors that might offer insights into inherent radiation or chemotherapy resistance or other prognostic markers that drive some of these observed differences. Further, our definition of downstaging assumes a high degree of accuracy in clinical staging. At this time, the NCDB does not distinguish patients staged with endoscopic ultrasound vs magnetic resonance imaging (MRI). This information could prove valuable in the future as superiority between these methods remains contentious. The timing of surgery after neoadjuvant regimens remains variable among institutions and represents a future direction, as the optimal interval between radiation and surgery remains controversial (25). Perhaps the most important limitation of our data set is the number of excluded patients due to missing data. In fact, the majority of patients were excluded from this analysis due to missing clinical staging. While the NCDB is actively working on resolving these issues, we have nonetheless captured the largest group of patients to be studied in this manner to date. In summary, we demonstrate that the final pathologic stage is the most reliable marker of overall survival after neoadjuvant therapy in rectal cancer. Downstaged patients survive equivalent, if not better, than pathologic stage–matched patients who proceeded directly to resection. These data will be invaluable for advocating consistency in guideline adherence to the use of neoadjuvant therapy and providing improved discussions with downstaged patients regarding prognosis. Additionally, these data will help direct organ-sparing approaches to the subset of downstaged patients while focusing future research efforts on patients with therapy-resistant tumors. Funding Supported in part by funds from the National Institutes of Health Division of Loan Repayment (DD), American Cancer Society, National Cancer Institute, and research support from Elekta A. B. to the Medical College of Wisconsin (WAH). This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through grant number UL1TR001436. Notes The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. 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 investigator. References 1 Siegel RL, Miller KD, Fedewa SAet al.  , Colorectal cancer statistics, 2017. CA Cancer J Clin.  2017; 67( 3): 177– 193. Google Scholar CrossRef Search ADS PubMed  2 Rahib L, Smith BD, Aizenberg Ret al.  , Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res.  2014; 74( 11): 2913– 2921. Google Scholar CrossRef Search ADS PubMed  3 Minsky BD, Mies C, Recht Aet al.  , Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer.  1988; 61( 7): 1408– 1416. Google Scholar CrossRef Search ADS PubMed  4 Gerard A, Buyse M, Nordlinger Bet al.  , Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg.  1988; 208( 5): 606– 614. Google Scholar CrossRef Search ADS PubMed  5 Bosset JF, Collette L, Calais Get al.  , Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med.  2006; 355( 11): 1114– 1123. Google Scholar CrossRef Search ADS PubMed  6 Sauer R, Becker H, Hohenberger Wet al.  , Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med.  2004; 351( 17): 1731– 1740. Google Scholar CrossRef Search ADS PubMed  7 Benson AB3rd, Venook AP, Bekaii-Saab Tet al.  , Rectal cancer, version 2.2015. J Natl Compr Canc Netw.  2015; 13( 6): 719– 728; quiz 728. Google Scholar CrossRef Search ADS PubMed  8 Quah HM, Chou JF, Gonen Met al.  , Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer.  2008; 113( 1): 57– 64. Google Scholar CrossRef Search ADS PubMed  9 Stipa F, Chessin DB, Shia Jet al.  , A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography. Ann Surg Oncol.  2006; 13( 8): 1047– 1053. Google Scholar CrossRef Search ADS PubMed  10 Kim NK, Baik SH, Seong JSet al.  , Oncologic outcomes after neoadjuvant chemoradiation followed by curative resection with tumor-specific mesorectal excision for fixed locally advanced rectal cancer: Impact of postirradiated pathologic downstaging on local recurrence and survival. Ann Surg.  2006; 244( 6): 1024– 1030. Google Scholar CrossRef Search ADS PubMed  11 Theodoropoulos G, Wise WE, Padmanabhan Aet al.  , T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum.  2002; 45( 7): 895– 903. Google Scholar CrossRef Search ADS PubMed  12 Bouzourene H, Bosman FT, Seelentag Wet al.  , Importance of tumor regression assessment in predicting the outcome in patients with locally advanced rectal carcinoma who are treated with preoperative radiotherapy. Cancer.  2002; 94( 4): 1121– 1130. Google Scholar CrossRef Search ADS PubMed  13 Park IJ, You YN, Agarwal Aet al.  , Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol.  2012; 30( 15): 1770– 1776. Google Scholar CrossRef Search ADS PubMed  14 Kim CH, Lee SY, Kim HRet al.  , Pathologic stage following preoperative chemoradiotherapy underestimates the risk of developing distant metastasis in rectal cancer: A comparison to staging without preoperative chemoradiotherapy. J Surg Oncol.  2016; 113( 6): 692– 699. Google Scholar CrossRef Search ADS PubMed  15 Fokas E, Liersch T, Fietkau Ret al.  , Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: The reverse of the Will Rogers phenomenon? Cancer.  2015; 121( 11): 1724– 1727. Google Scholar CrossRef Search ADS PubMed  16 Gao P, Song YX, Wang ZNet al.  , Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the Surveillance, Epidemiology, and End Results (SEER) database. BMC Cancer.  2013; 13: 123. Google Scholar CrossRef Search ADS PubMed  17 Rullier A, Laurent C, Capdepont Met al.  , Impact of tumor response on survival after radiochemotherapy in locally advanced rectal carcinoma. Am J Surg Pathol.  2010; 34( 4): 562– 568. Google Scholar CrossRef Search ADS PubMed  18 Mignanelli ED, de Campos-Lobato LF, Stocchi Let al.  , Downstaging after chemoradiotherapy for locally advanced rectal cancer: Is there more (tumor) than meets the eye? Dis Colon Rectum.  2010; 53( 3): 251– 256. Google Scholar CrossRef Search ADS PubMed  19 George TJJr., Allegra CJ, Yothers G. Neoadjuvant rectal (NAR) score: A new surrogate endpoint in rectal cancer clinical trials. Curr Colorectal Cancer Rep.  2015; 11( 5): 275– 280. Google Scholar CrossRef Search ADS PubMed  20 Rutter CM, Johnson EA, Feuer EJet al.  , Secular trends in colon and rectal cancer relative survival. J Natl Cancer Inst.  2013; 105( 23): 1806– 1813. Google Scholar CrossRef Search ADS PubMed  21 McArdle CS, McMillan DC, Hole DJ. Male gender adversely affects survival following surgery for colorectal cancer. Br J Surg.  2003; 90( 6): 711– 715. Google Scholar CrossRef Search ADS PubMed  22 Martling A, Granath F, Cedermark Bet al.  , Gender differences in the treatment of rectal cancer: A population based study. Eur J Surg Oncol.  2009; 35( 4): 427– 433. Google Scholar CrossRef Search ADS PubMed  23 Wichmann MW, Muller C, Hornung HMet al.  , Gender differences in long-term survival of patients with colorectal cancer. Br J Surg.  2001; 88( 8): 1092– 1098. Google Scholar CrossRef Search ADS PubMed  24 Lydrup ML, Hoglund P. Gender aspects of survival after surgical treatment for rectal cancer. Colorectal Dis.  2015; 17( 5): 390– 396. Google Scholar CrossRef Search ADS PubMed  25 de Campos-Lobato LF, Geisler DP, da Luz Moreira Aet al.  , Neoadjuvant therapy for rectal cancer: The impact of longer interval between chemoradiation and surgery. J Gastrointest Surg.  2011; 15( 3): 444– 450. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Prognostic Value of Clinical vs Pathologic Stage in Rectal Cancer Patients Receiving Neoadjuvant Therapy

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Oxford University Press
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© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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0027-8874
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1460-2105
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10.1093/jnci/djx228
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Abstract

Abstract Background Neoadjuvant chemoradiation is currently standard of care in stage II–III rectal cancer, resulting in tumor downstaging for patients with treatment-responsive disease. However, the prognosis of the downstaged patient remains controversial. This work critically analyzes the relative contribution of pre- and post-therapy staging to the anticipated survival of downstaged patients. Methods The National Cancer Database (NCDB) was queried for patients with rectal cancer treated with transabdominal resection between 2004 and 2014. Stage II–III patients downstaged with neoadjuvant radiation were compared with stage I patients treated with definitive resection alone. Patients with positive surgical margins were excluded. Overall survival was evaluated using both Kaplan-Meier analyses and Cox proportional hazards models. All statistical tests were two-sided. Results A total of 44 320 patients were eligible for analysis. Survival was equivalent for patients presenting with cT1N0 disease undergoing resection (mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with those downstaged to pT1N0 from both cT3N0 (mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12) and cT3N1 disease (mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22). Survival statistically significantly improved in patients downstaged to pT2N0 from cT3N0 disease (mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001) and cT3N1 (mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001), compared with cT2N0 patients undergoing resection alone (mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months). Multiple survival analysis confirmed that final pathologic stage dictated long-term outcomes in patients undergoing neoadjuvant radiation (hazard ratio [HR] of pT2 = 1.24, 95% CI = 1.10 to 1.41; HR of pT3 = 1.81, 95% CI = 1.61 to 2.05; HR of pT4 = 2.72, 95% CI = 2.28 to 3.25, all P ≤ .001 vs pT1; HR of pN1 = 1.50, 95% CI = 1.41 to 1.59; HR of pN2 = 2.17, 95% CI = 2.00 to 2.35, both P < .001 vs pN0); while clinical stage at presentation had little to no predictive value (HR of cT2 = 0.81, 95% CI = 0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI = 0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI = 0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI = 0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI = 0.86 to 1.08, P = .48 vs cN0). Conclusions Survival in patients with rectal cancer undergoing neoadjuvant radiation is driven by post-therapy pathologic stage, regardless of pretherapy clinical stage. These data will further inform prognostic discussions with patients. Colorectal cancer is the third most common malignancy in the United States, with an anticipated 135 000 cases diagnosed in 2017 (1). Incidence and mortality rates continue to decline in both colon and rectal cancer, largely due to improvements in both early screening and multidisciplinary treatment modalities (2). Prior to the use of multimodality therapy, local recurrence was especially common in rectal cancer, resulting in poor long-term outcomes (3). The introduction of neoadjuvant radiotherapy has decreased local recurrence rates by approximately 50% to 60% (4), with chemotherapy further improving both progression-free and overall survival (5). The current standard of care for most patients with stage II and III rectal cancer is neoadjuvant chemotherapy with radiation, followed by complete surgical resection (6,7). As neoadjuvant chemoradiation regimens continue to improve, the patient population clinically benefitting from tumor downstaging prior to surgery is growing. It has been demonstrated that downstaged tumors are associated with improved survival compared with therapy-resistant tumors (8–13). However, estimates of overall survival in downstaged patients continue to vary, as recent studies have provided conflicting evidence (8,14,15). Specifically, it remains unclear whether long-term outcomes are tied more closely to baseline or postoperative disease stage. To address this gap in prognostic knowledge, we aimed to examine the prognostic utility of pathologic stage as compared with clinical stage in patients downstaged with neoadjuvant therapy. This work queries a large national database for patients with rectal cancer who underwent transabdominal resection over a 10-year time period. Methods Patients A retrospective review of the National Cancer Database (NCDB) was performed. The NCDB is a hospital-based national registry of cancer patients and a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data files used are compliant with the United States Health Insurance Portability and Accountability Act (HIPAA) and de-identified. The participant user file analyzed in this study included all patients diagnosed with rectal cancer from 2004 through 2014. Patient characteristics examined included age at diagnosis, sex, tumor grade, margin status, receipt of chemotherapy, receipt of neoadjuvant radiation, and clinical (c) and pathologic (p) TNM stage. Patients with incomplete data were excluded, with the exception of tumor grade, as this information was unavailable in over 2500 cases. High tumor grade was defined as poor differentiation. Margin status postresection was defined as positive or negative. Clinical and pathologic TNM staging was performed according to American Joint Committee on Cancer (AJCC) guidelines, with 54% and 46% of patients classified according to the 6th edition and 7th editions, respectively. Importantly, T stage according to depth of invasion and N stage according to nodal metastasis were largely unchanged between the AJCC editions for rectal cancer (16), and the data were therefore combined for the purposes of this manuscript. In total, 243 466 patients with rectal cancer diagnosed between 2004 and 2014 were eligible for analysis from the NCDB. Inclusion criteria for this analysis consisted of histologically proven rectal adenocarcinoma in patients undergoing curative-attempt surgical resection. Patients with metastatic disease were excluded. Patients who underwent local excision and those with positive surgical margins were excluded because these patients have higher rates of local recurrence. Finally, as adjuvant radiation was uncommon (10.9%) and the reasons for adjuvant radiation were unknown, these patients were also excluded. In addition, while the vast majority of patients undergoing neoadjuvant radiation received chemotherapy (97.5%), the timing of chemotherapy was unknown. Chemotherapy was therefore excluded as a separate variable in this analysis. A detailed inclusion diagram is shown in Figure 1. Figure 1. View largeDownload slide Inclusion algorithm for National Cancer Database analysis (NCDB). All patients diagnosed with rectal cancer between 2004 and 2014 were initially included in the study, representing data obtained directly from the NCDB. Diagnosis was narrowed to adenocarcinoma, excluding neuroendocrine and other uncommon rectal tumors. Stage IV patients, defined by either clinical or pathologic M1 stage, were excluded. Patients who had positive surgical margins or who did not proceed to definitive transabdominal resection were then excluded, including nonoperative patients and those undergoing local excision. Patients with missing data were excluded, most of whom had incomplete clinical staging. Finally, patients undergoing adjuvant radiation were excluded, as the primary purpose was to compare patients who downstaged with neoadjuvant therapy with patients presenting with stage I disease undergoing surgery without neoadjuvant radiation. Figure 1. View largeDownload slide Inclusion algorithm for National Cancer Database analysis (NCDB). All patients diagnosed with rectal cancer between 2004 and 2014 were initially included in the study, representing data obtained directly from the NCDB. Diagnosis was narrowed to adenocarcinoma, excluding neuroendocrine and other uncommon rectal tumors. Stage IV patients, defined by either clinical or pathologic M1 stage, were excluded. Patients who had positive surgical margins or who did not proceed to definitive transabdominal resection were then excluded, including nonoperative patients and those undergoing local excision. Patients with missing data were excluded, most of whom had incomplete clinical staging. Finally, patients undergoing adjuvant radiation were excluded, as the primary purpose was to compare patients who downstaged with neoadjuvant therapy with patients presenting with stage I disease undergoing surgery without neoadjuvant radiation. Statistical Analysis All statistical analyses were performed using IBM SPSS Statistics version 24. A P value of less than .05 was considered statistically significant. Categorical variables were compared using the exact chi-square test, and continuous variables were compared using the two independent samples t test. Survival curves were estimated using Kaplan-Meier methodology and compared between two groups using the log-rank test. Univariate analysis of overall survival was performed using a Cox proportional hazards regression model. The proportional hazards assumption was validated graphically using model checking (log minus log) plots for each variable. All variables that were statistically significant on univariate analysis (P < .05) were included in a multivariable Cox proportional hazards regression model. To adjust for selection bias, inverse probability weighting was performed based on the predicted probability of inclusion in the main study population for an expanded population including subjects with local excision, positive margins, metastatic disease, and adjuvant radiotherapy. Weights were applied to logistic regression analyses to predict three-year and five-year mortality using covariates included in the original analysis. All statistical tests were two-sided unless otherwise indicated. Results Patient Population A total of 44 320 patients were included in the final analysis: 13 736 patients undergoing surgical resection up front and 30 584 patients who received neoadjuvant radiation prior to surgical resection. Baseline characteristics of each group are detailed in Table 1. Patients who underwent neoadjuvant radiation tended to be younger and female. Neoadjuvant radiation was used most commonly in clinical stage II–III disease, while those patients who did not undergo radiation were largely clinical stage I, consistent with National Comprehensive Cancer Network (NCCN) guidelines (7). Importantly, of the 13 736 patients who did not undergo radiation, 3872 were pT1N0 and 4287 were pT2N0, accounting for only 59.4% of this cohort. Thus, 40.6% of the patients who underwent surgery without radiation had pathologic stage II–III disease, discordant with NCCN guidelines. Table 1. Patient demographics and clinicopathologic data Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  * P values were calculated using two-sided independent samples t tests for continuous variables and the exact chi-square test for categorical variables. † Tumor grade was unavailable for 4208 tumors (9.5%). Table 1. Patient demographics and clinicopathologic data Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  Parameter  No radiation, No. (%)  Neoadjuvant radiation, No. (%)  P*  Age, mean (SD)  66.0 (13.3)  60.0 (12.3)  <.001  Female sex  5787 (42.1)  11 388 (37.2)  <.001  Poor tumor differentiation†  1454 (11.2)  3553 (13.1)  <.001  Histology         Adenocarcinoma  13 140 (95.7)  28 470 (93.1)     Mucinous adenocarcinoma  555 (4.0)  1949 (6.4)  <.001   Signet ring cell carcinoma  41 (0.3)  165 (0.5)    Clinical T stage         T1  4647 (33.8)  974 (3.2)  <.001   T2  4840 (35.2)  3167 (10.4)   T3  3972 (28.9)  24 396 (79.8)   T4  277 (2.0)  2047 (6.7)  Clinical N stage         N0  11 910 (86.7)  15 713 (51.4)  <.001   N1  1409 (10.3)  12 712 (41.6)   N2  417 (3.0)  2159 (7.1)  Pathologic T stage         T1  4130 (30.1)  2620 (8.6)  <.001   T2  4981 (36.3)  10 785 (35.3)   T3  4329 (31.5)  16 147 (52.8)   T4  296 (2.2)  1032 (3.4)  Pathologic N stage         N0  10 901 (79.4)  20 307 (66.4)  <.001   N1  1961 (14.3)  7363 (24.1)   N2  874 (6.4)  2914 (9.5)  * P values were calculated using two-sided independent samples t tests for continuous variables and the exact chi-square test for categorical variables. † Tumor grade was unavailable for 4208 tumors (9.5%). Clinical and Pathologic Staging Concordance We first sought to evaluate the accuracy of clinical staging in this group of patients. As such, the concordance between clinical and pathologic staging was assessed in patients undergoing surgery up front. In the absence of neoadjuvant radiation, clinical T staging was found to be approximately 70% to 80% accurate when compared with postoperative pathologic T stage (Supplementary Figure 1A, available online). In contrast, clinical T stage predicted pathologic T stage only 30% to 65% of the time in patients undergoing neoadjuvant radiation. This disparity suggests a downstaging effect (Supplementary Figure 1B, available online). Clinical N staging proved to be 87.8% and 89.4% accurate for N0 and N2 disease, respectively, but relatively poor at predicting N1 disease (60.3%) (Supplementary Figure 1C, available online). Clinical N stage was a poor indicator of pathologic N stage in patients undergoing neoadjuvant radiation, again suggesting a downstaging effect (Supplementary Figure 1D, available online). Outcomes While it has been previously demonstrated that patients responding to neoadjuvant radiation fare better than nonresponders, it remains unclear whether patients survive in a manner that most closely associates with either their pre- or postneoadjuvant therapy stage. To assess this, we compared outcomes of patients resected without neoadjuvant therapy (ie, pStageX) with those downstaged with neoadjuvant radiation to a similar stage (ie, ypStageX). All patients with final pT1N0 disease demonstrated similar overall survival, regardless of their clinical stage prior to therapy (mean survival of cT1N0 = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months; mean survival of cT2N0 = 110.9 months, 95% CI = 104.1 to 117.6 months; mean survival of cT3N0 = 114.9 months, 95% CI = 110.4 to 119.3 months; P = .18 cT1N0 vs cT2N0, P = .12 cT1N0 vs cT3N0) (Figure 2A, Table 2). This also held true for patients with clinical N1 disease who downstaged to pT1N0 (mean survival of cT2N1 = 110.0 months, 95% CI =  99.7 to 120.4 months; mean survival of cT3N1 = 115.4 months, 95% CI =  110.1 to 120.7 months; P = .44 cT1N0 vs cT2N1, P = .22 cT1N0 vs cT3N1) (Figure 2B, Table 2). However, patients resected up front with pT2N0 disease demonstrated reduced survival compared with those downstaged to ypT2N0 from clinical T3N0 (mean survival of cT2N0 = 100.0 months, 95% CI =  97.5 to 102.5 months; mean survival of cT3N0 = 109.0 months, 95% CI =  106.7 to 111.2 months; mean survival of cT4N0 = 101.9 months, 95% CI =  92.6 to 111.2 months; P < .001 cT2N0 vs cT3N0, P = .26 cT2N0 vs cT4N0) (Figure 2C, Table 2) and clinical T3N1 disease (mean survival of cT3N1 = 112.8 months, 95% CI =  110.0 to 115.7 months; mean survival of cT4N1 = 97.7 months, 95% CI =  85.4 to 110.0 months; P < .001 cT2N0 vs cT3N1, P = .79 cT2N0 vs cT4N1) (Figure 2D, Table 2). Table 2. Three-, five-, and 10-year overall survival rates Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  * No radiation. All other values represent groups receiving neoadjuvant radiation. Kaplan-Meier curves were used to calculate three-, five-, and 10-year survival rates. OS = overall survival. Table 2. Three-, five-, and 10-year overall survival rates Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  Pathologic stage  cT1N0  cT2N0  cT3N0  cT3N1  3-y OS, %           pT1N0  90.7*  95.8  92.1  92.9   pT2N0    86.3*  90.7  91.8  5-y OS, %           pT1N0  84.3*  89.5  87.1  84.5   pT2N0    75.2*  81.7  84.3  10-y OS, %           pT1N0  65.4*  69.6  69.3  68.3   pT2N0    50.7*  57.5  60.2  * No radiation. All other values represent groups receiving neoadjuvant radiation. Kaplan-Meier curves were used to calculate three-, five-, and 10-year survival rates. OS = overall survival. Figure 2. View largeDownload slide Overall survival in downstaged disease. A) Kaplan-Meier survival plots generated for the following pathologic T1N0 patients: patients with clinical T1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with patients with cT2N0 (dashed, mean survival = 110.9 months, 95% CI = 104.1 to 117.6 months, P = .18 vs cT1N0) or cT3N0 disease (gray, mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12 vs cT1N0) treated with neoadjuvant radiation and downstaged to pT1N0. B) Survival plots for pathologic T1N0 patients: patients with cT1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% CI = 110.8 to 115.3 months) compared with patients downstaged from cT2N1 (dashed, mean survival = 110.0 months, 95% CI = 99.7 to 120.4 months, P = .44 vs cT1N0) or cT3N1 (gray, mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22 vs cT1N0) with neoadjuvant radiation. C) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N0 (gray, mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001 vs cT2N0) or cT4N0 (dashed, mean survival = 101.9 months, 95% CI = 92.6 to 111.2 months, P = .26 vs cT2N0) to pathologic T2N0 disease. D) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N1 (gray, mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001 vs cT2N0) or cT4N1 (dashed, mean survival = 97.7 months, 95% CI = 85.4 to 110.0 months, P = .79 vs cT2N0) to pathologic T2N0 disease. P values were calculated using the two-sided log rank test. Figure 2. View largeDownload slide Overall survival in downstaged disease. A) Kaplan-Meier survival plots generated for the following pathologic T1N0 patients: patients with clinical T1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with patients with cT2N0 (dashed, mean survival = 110.9 months, 95% CI = 104.1 to 117.6 months, P = .18 vs cT1N0) or cT3N0 disease (gray, mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12 vs cT1N0) treated with neoadjuvant radiation and downstaged to pT1N0. B) Survival plots for pathologic T1N0 patients: patients with cT1N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 113.0 months, 95% CI = 110.8 to 115.3 months) compared with patients downstaged from cT2N1 (dashed, mean survival = 110.0 months, 95% CI = 99.7 to 120.4 months, P = .44 vs cT1N0) or cT3N1 (gray, mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22 vs cT1N0) with neoadjuvant radiation. C) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N0 (gray, mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001 vs cT2N0) or cT4N0 (dashed, mean survival = 101.9 months, 95% CI = 92.6 to 111.2 months, P = .26 vs cT2N0) to pathologic T2N0 disease. D) Survival plots for pathologic T2N0 patients: patients with cT2N0 disease proceeding directly to definitive transabdominal resection (black, mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months) compared with patients downstaged with neoadjuvant radiation from cT3N1 (gray, mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001 vs cT2N0) or cT4N1 (dashed, mean survival = 97.7 months, 95% CI = 85.4 to 110.0 months, P = .79 vs cT2N0) to pathologic T2N0 disease. P values were calculated using the two-sided log rank test. The impact of final pathologic stage on long-term outcomes was then assessed within clinically stage-matched patients undergoing neoadjuvant radiation. In clinical T3N0 disease, Supplementary Figure 2A (available online) confirms previous observations suggesting that downstaged disease is associated with statistically significantly better outcomes compared with therapy-resistant tumors (mean survival of pT1N0 = 114.9 months, 95% CI = 110.4 to 119.3 months; mean survival of pT2N0 = 109.0 months, 95% CI =  106.7 to 111.2 months; mean survival of pT3N0 = 99.4 months, 95% CI =  97.4 to 101.4 months; mean survival of pT4N0 = 68.1 months, 95% CI =  59.8 to 76.4 months; P = .003 pT1N0 vs pT2N0, P < .001 pT2N0 vs pT3N0, P < .001 pT3N0 vs pT4N0). Similarly, pathologic stage ultimately determined long-term survival in clinical T3N1 disease with final pathologic N0 stage (mean survival of pT1N0 = 115.4 months, 95% CI =  110.1 to 120.7 months; mean survival of pT2N0 = 112.8 months, 95% CI =  110.0 to 115.7 months; mean survival of pT3N0 = 106.8 months, 95% CI =  104.2 to 109.4 months; mean survival of pT4N0 = 67.1 months, 95% CI =  58.4 to 75.9 months; P = .27 pT1N0 vs pT2N0, P < .001 pT2N0 vs pT3N0, P < .001 pT3N0 vs pT4N0) (Supplementary Figure 2B, available online) or pN1 stage (mean survival of pT1N1 = 106.8 months, 95% CI =  96.0 to 117.6 months; mean survival of pT2N1 = 106.5 months, 95% CI =  101.6 to 111.4 months; mean survival of pT3N1 = 91.6 months, 95% CI =  88.7 to 94.6 months; mean survival of pT4N1 = 67.6 months, 95% CI =  51.1 to 84.2 months; P = .28 pT1N1 vs pT2N1, P < .001 pT2N1 vs pT3N1, P = .02 pT3N1 vs pT4N1) (Supplementary Figure 2C, available online). In both instances, the degree of downstaging predicted prolonged survival. Taken together, these data demonstrate that the prognosis for stage II–III patients with rectal cancer downstaged by neoadjuvant radiation is equivalent or superior to patients undergoing up-front surgery for stage I disease. To further test if final pathologic stage is a better predictor of long-term outcomes than clinical stage in patients undergoing neoadjuvant radiation, a Cox proportional hazards model was employed. Table 3 displays a univariate analysis of overall survival to investigate the marginal impact of individual factors on patients’ survival time, confirming previously demonstrated relationships with known clinicopathologic factors. Specifically, older age (hazard ratio [HR] = 1.03, 95% CI = 1.03 to 1.04, P < .001), female sex (HR = 0.88, 95% CI =  0.84 to 0.93, P < .001), and poor tumor differentiation (HR = 1.54, 95% CI =  1.44 to 1.64, P < .001) were all statistically significantly associated with survival. No statistically significant survival difference was observed between clinical (cT2, cT1: HR = 0.87, 95% CI =  0.75 to 1.01, P = .072; cT3, cT1: HR = 1.04, 95% CI =  0.91 to 1.19, P = .58) disease pairs. Likewise, clinical N1 vs N0 disease (HR = 1.02, 95% CI =  0.97 to 1.07, P = .54) demonstrated no statistically significant difference in survival. As opposed to clinical stage, higher pathologic T stage predicted reduced survival (HR of pT2 = 1.28, 95% CI =  1.14 to 1.43, P < .001; HR of pT3 = 2.16, 95% CI =  1.94 to 2.41, P < .001; HR of pT4 = 3.37, 95% CI =  2.90 to 3.91, P < .001 vs pT1) and N stage (HR of pN1 = 1.52, 95% CI =  1.44 to 1.61, P < .001; HR of pN2 = 2.28, 95% CI =  2.12 to 2.44, P < .001 vs pN0). Multivariable analysis demonstrated no association between increasing clinical stage and worsening survival (HR of cT2 = 0.81, 95% CI =  0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI =  0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI =  0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI =  0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI =  0.86 to 1.08, P = .48 vs cN0) while further confirming this relationship between pathologic stage and long-term survival (HR of pT2 = 1.24, 95% CI =  1.10 to 1.41; HR of pT3 = 1.81, 95% CI =  1.61 to 2.05; HR of pT4 = 2.72, 95% CI =  2.28 to 3.25; P ≤ .001 vs pT1; HR of pN1 = 1.50, 95% CI =  1.41 to 1.59; HR of pN2 = 2.17, 95% CI =  2.00 to 2.35, both P < .001 vs pN0) (Table 4). Due to concern for shorter follow-up times in recently diagnosed patients, sensitivity analysis was performed in cases diagnosed before 2011, confirming similar relationships between clinical stage, pathologic stage, and survival (Supplementary Tables 1 and 2, available online). Therefore, in surgical patients undergoing neoadjuvant radiation for rectal cancer, the final pathologic stage should be the primary determinant of long-term survival, regardless of pretherapy clinical stage. Table 3. Univariate analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). Table 3. Univariate analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.03 (1.03 to 1.04)  <.001  Female sex  0.88 (0.84 to 0.93)  <.001  Poor tumor differentiation†  1.54 (1.44 to 1.64)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  1.23 (1.13 to 1.34)  <.001   Signet ring cell carcinoma  2.89 (2.30 to 3.65)  <.001  Clinical T stage (ref. T1)       T2  0.87 (0.75 to 1.01)  .07   T3  1.04 (0.91 to 1.19)  .58   T4  1.51 (1.29 to 1.76)  <.001  Clinical N stage (ref. N0)       N1  1.02 (0.97 to 1.07)  .54   N2  1.27 (1.15 to 1.40)  <.001  Pathologic T stage (ref. T1)       T2  1.28 (1.14 to 1.43)  <.001   T3  2.16 (1.94 to 2.41)  <.001   T4  3.37 (2.90 to 3.91)  <.001  Pathologic N stage (ref. N0)       N1  1.52 (1.44 to 1.61)  <.001   N2  2.28 (2.12 to 2.44)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). Table 4. Multivariable analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). Table 4. Multivariable analysis of overall survival Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  Parameter  HR (95% CI)  P*  Age, y  1.04 (1.04 to 1.04)  <.001  Female sex  0.83 (0.79 to 0.87)  <.001  Poor tumor differentiation†  1.28 (1.19 to 1.37)  <.001  Histology (ref. adenocarcinoma)       Mucinous adenocarcinoma  0.99 (0.90 to 1.09)  .82   Signet ring cell carcinoma  2.06 (1.61 to 2.64)  <.001  Clinical T stage (ref. T1)       T2  0.81 (0.69 to 0.95)  .008   T3  0.83 (0.72 to 0.96)  .009   T4  1.02 (0.85 to 1.21)  .87  Clinical N stage (ref. N0)       N1  0.96 (0.91 to 1.02)  .19   N2  0.96 (0.86 to 1.08)  .48  Pathologic T stage (ref. T1)       T2  1.24 (1.10 to 1.41)  .001   T3  1.81 (1.61 to 2.05)  <.001   T4  2.72 (2.28 to 3.25)  <.001  Pathologic N stage (ref. N0)       N1  1.50 (1.41 to 1.59)  <.001   N2  2.17 (2.00 to 2.35)  <.001  * Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and P values. These tests were two-sided. CI = confidence interval; HR = hazard ratio. † Tumor grade was unavailable for 3481 tumors (11.4%). In order to address the application of strict exclusion criteria applied to such a large data set, inverse probability weighting (IPW) was applied. Logistic regression was performed using IPW based on the probability of inclusion in the main study to an expanded cohort of patients with local excision, positive margins, metastatic disease, and adjuvant radiotherapy. Factors associated with increased odds of death within three years (Supplementary Table 3, available online) and five years (Supplementary Table 4, available online) included advanced age, male sex, poor tumor differentiation, and mucinous or signet ring histology. Pathologic staging again demonstrated greater discrimination than clinical staging. Discussion The prognosis associated with downstaging in rectal cancer after neoadjuvant therapy remains difficult to quantify. Using a large database such as the NCDB and evaluating more than 40 000 patients with rectal cancer over a 10-year time period, our study provides objective data to help answer this important clinical question. We show that patients downstaged to stage I disease with neoadjuvant radiotherapy demonstrate similar, if not better, survival than stage I patients proceeding directly to resection. In fact, all patient groups with evidence of downstaging demonstrate similar, if not better, survival than similarly pathologic staged patients having gone straight to surgery. Thus, pretherapy stage appears to have little influence on survival in patients undergoing neoadjuvant therapy. Rather, post-therapy pathologic stage (and the degree of downstaging) best predicts long-term outcomes. This represents the largest study to date analyzing survival in downstaged rectal cancer patients, demonstrating that final pathologic stage best dictates overall survival, regardless of pretherapy clinical stage. Our findings are in agreement with a smaller study conducted by Quah et al., in which the authors queried a single-institution database for stage II–III rectal cancers treated with neoadjuvant radiation and incorporated multiple calculations to assess histopathologic response to therapy (8). While our methodologies differ, the result appears to be similar: final pathologic stage after radiation is highly predictive of long-term outcomes. However, there are discordant data in the literature on this issue. A large study by Kim et al. demonstrated worse disease-free survival and distant metastasis–free survival in postneoadjuvant stage II patients compared with patients with the corresponding pathologic stage not receiving neoadjuvant chemotherapy (14,15). However, direct comparison between these investigations and our results is difficult as the NCDB records overall survival but does not include local or distant control variables. Subsequent investigations compared downstaged tumors with therapy-resistant tumors and identified survival advantages for downstaged patients (17,18). In line with these findings, we demonstrate a progressive survival benefit with increasing downstaging for pathologic stage I–III patients. Thus, the survival advantage seen is likely a reflection of inherent tumor biology and overall treatment sensitivity. Accordingly, the Neoadjuvant Rectal (NAR) Score was recently developed to quantify tumor regression. Although the NAR has yet to be formally validated as a substitute for long-term survival, it now serves as a surrogate end point for National Cancer Institute–approved phase II clinical trials (19). To our knowledge, this is the largest study of its kind to evaluate downstaged rectal cancer patients. Pathologic T1N0 patients, regardless of baseline presentation or downstaged from stage III disease, display equivalent survival patterns. In fact, pT2N0 patients having proceeded directly to surgery exhibited statistically significantly reduced survival compared with cT3N0 or cT3N1 patients who were downstaged to pT2N0 with neoadjuvant therapy. These data suggest a potential role for neoadjuvant therapy in T2N0 disease. It was particularly noteworthy that pretherapy clinical stage appeared to be inconsistent in predicting outcomes, representing a potential paradigm shift in the management of these patients. The issue is further compounded by our study showing that 40.6% of patients not receiving neoadjuvant radiation had pathologic stage II–III disease, discordant with current National Comprehensive Cancer Network (NCCN) guidelines (7). These conclusions favoring neoadjuvant therapy may be limited by confounding disparities between patients undergoing neoadjuvant radiation and those proceeding directly to surgery. However, multivariable analysis adjusting for age, sex, and pathologic tumor grade nonetheless continued to demonstrate that final pathologic stage dictated outcome in patients undergoing neoadjuvant radiation, while advanced clinical stage demonstrated no statistically significant association with survival. Men demonstrated poor long-term outcomes compared with women, a finding commonly reported in rectal cancer cohorts (20–23). The etiology of this gender disparity remains unclear. Previous investigators have claimed this to be purely an age-related effect (24). However, our data demonstrate reduced survival in men when adjusted for both age and stage, suggesting alternative reasons behind this difference. Anatomical differences may contribute, as women typically have wider pelvic dimensions, which may be further elucidated with the development of imaging-based volumetric calculators. This study has several limitations. First, the large, hospital-maintained, retrospective database affords little control over local practices. As such, chemotherapies, radiation regimens, and surgical procedures are grouped broadly, and we are unable to evaluate and adjust for specific techniques, doses, or regimens. It is worth mentioning that 29 784 (97.5%) patients undergoing neoadjuvant radiation also received chemotherapy in some form. Given this concordance and a lack of data regarding timing of systemic therapy, chemotherapy was excluded as a separate variable in this analysis. The relative impact of chemotherapy on a durable downstaging effect on survival represents an area of active investigation in our group. In addition, the absence of local recurrence and disease-free survival data in the NCDB limits our ability to understand the mode of failure in patients with poor survival. The database also fails to incorporate molecular profiling of tumors that might offer insights into inherent radiation or chemotherapy resistance or other prognostic markers that drive some of these observed differences. Further, our definition of downstaging assumes a high degree of accuracy in clinical staging. At this time, the NCDB does not distinguish patients staged with endoscopic ultrasound vs magnetic resonance imaging (MRI). This information could prove valuable in the future as superiority between these methods remains contentious. The timing of surgery after neoadjuvant regimens remains variable among institutions and represents a future direction, as the optimal interval between radiation and surgery remains controversial (25). Perhaps the most important limitation of our data set is the number of excluded patients due to missing data. In fact, the majority of patients were excluded from this analysis due to missing clinical staging. While the NCDB is actively working on resolving these issues, we have nonetheless captured the largest group of patients to be studied in this manner to date. In summary, we demonstrate that the final pathologic stage is the most reliable marker of overall survival after neoadjuvant therapy in rectal cancer. Downstaged patients survive equivalent, if not better, than pathologic stage–matched patients who proceeded directly to resection. These data will be invaluable for advocating consistency in guideline adherence to the use of neoadjuvant therapy and providing improved discussions with downstaged patients regarding prognosis. Additionally, these data will help direct organ-sparing approaches to the subset of downstaged patients while focusing future research efforts on patients with therapy-resistant tumors. Funding Supported in part by funds from the National Institutes of Health Division of Loan Repayment (DD), American Cancer Society, National Cancer Institute, and research support from Elekta A. B. to the Medical College of Wisconsin (WAH). This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through grant number UL1TR001436. Notes The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. 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 investigator. References 1 Siegel RL, Miller KD, Fedewa SAet al.  , Colorectal cancer statistics, 2017. CA Cancer J Clin.  2017; 67( 3): 177– 193. Google Scholar CrossRef Search ADS PubMed  2 Rahib L, Smith BD, Aizenberg Ret al.  , Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res.  2014; 74( 11): 2913– 2921. Google Scholar CrossRef Search ADS PubMed  3 Minsky BD, Mies C, Recht Aet al.  , Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer.  1988; 61( 7): 1408– 1416. Google Scholar CrossRef Search ADS PubMed  4 Gerard A, Buyse M, Nordlinger Bet al.  , Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg.  1988; 208( 5): 606– 614. Google Scholar CrossRef Search ADS PubMed  5 Bosset JF, Collette L, Calais Get al.  , Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med.  2006; 355( 11): 1114– 1123. Google Scholar CrossRef Search ADS PubMed  6 Sauer R, Becker H, Hohenberger Wet al.  , Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med.  2004; 351( 17): 1731– 1740. Google Scholar CrossRef Search ADS PubMed  7 Benson AB3rd, Venook AP, Bekaii-Saab Tet al.  , Rectal cancer, version 2.2015. J Natl Compr Canc Netw.  2015; 13( 6): 719– 728; quiz 728. Google Scholar CrossRef Search ADS PubMed  8 Quah HM, Chou JF, Gonen Met al.  , Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer.  2008; 113( 1): 57– 64. Google Scholar CrossRef Search ADS PubMed  9 Stipa F, Chessin DB, Shia Jet al.  , A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography. Ann Surg Oncol.  2006; 13( 8): 1047– 1053. Google Scholar CrossRef Search ADS PubMed  10 Kim NK, Baik SH, Seong JSet al.  , Oncologic outcomes after neoadjuvant chemoradiation followed by curative resection with tumor-specific mesorectal excision for fixed locally advanced rectal cancer: Impact of postirradiated pathologic downstaging on local recurrence and survival. Ann Surg.  2006; 244( 6): 1024– 1030. Google Scholar CrossRef Search ADS PubMed  11 Theodoropoulos G, Wise WE, Padmanabhan Aet al.  , T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum.  2002; 45( 7): 895– 903. Google Scholar CrossRef Search ADS PubMed  12 Bouzourene H, Bosman FT, Seelentag Wet al.  , Importance of tumor regression assessment in predicting the outcome in patients with locally advanced rectal carcinoma who are treated with preoperative radiotherapy. Cancer.  2002; 94( 4): 1121– 1130. Google Scholar CrossRef Search ADS PubMed  13 Park IJ, You YN, Agarwal Aet al.  , Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol.  2012; 30( 15): 1770– 1776. Google Scholar CrossRef Search ADS PubMed  14 Kim CH, Lee SY, Kim HRet al.  , Pathologic stage following preoperative chemoradiotherapy underestimates the risk of developing distant metastasis in rectal cancer: A comparison to staging without preoperative chemoradiotherapy. J Surg Oncol.  2016; 113( 6): 692– 699. Google Scholar CrossRef Search ADS PubMed  15 Fokas E, Liersch T, Fietkau Ret al.  , Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: The reverse of the Will Rogers phenomenon? Cancer.  2015; 121( 11): 1724– 1727. Google Scholar CrossRef Search ADS PubMed  16 Gao P, Song YX, Wang ZNet al.  , Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the Surveillance, Epidemiology, and End Results (SEER) database. BMC Cancer.  2013; 13: 123. Google Scholar CrossRef Search ADS PubMed  17 Rullier A, Laurent C, Capdepont Met al.  , Impact of tumor response on survival after radiochemotherapy in locally advanced rectal carcinoma. Am J Surg Pathol.  2010; 34( 4): 562– 568. Google Scholar CrossRef Search ADS PubMed  18 Mignanelli ED, de Campos-Lobato LF, Stocchi Let al.  , Downstaging after chemoradiotherapy for locally advanced rectal cancer: Is there more (tumor) than meets the eye? Dis Colon Rectum.  2010; 53( 3): 251– 256. Google Scholar CrossRef Search ADS PubMed  19 George TJJr., Allegra CJ, Yothers G. Neoadjuvant rectal (NAR) score: A new surrogate endpoint in rectal cancer clinical trials. Curr Colorectal Cancer Rep.  2015; 11( 5): 275– 280. Google Scholar CrossRef Search ADS PubMed  20 Rutter CM, Johnson EA, Feuer EJet al.  , Secular trends in colon and rectal cancer relative survival. J Natl Cancer Inst.  2013; 105( 23): 1806– 1813. Google Scholar CrossRef Search ADS PubMed  21 McArdle CS, McMillan DC, Hole DJ. Male gender adversely affects survival following surgery for colorectal cancer. Br J Surg.  2003; 90( 6): 711– 715. Google Scholar CrossRef Search ADS PubMed  22 Martling A, Granath F, Cedermark Bet al.  , Gender differences in the treatment of rectal cancer: A population based study. Eur J Surg Oncol.  2009; 35( 4): 427– 433. Google Scholar CrossRef Search ADS PubMed  23 Wichmann MW, Muller C, Hornung HMet al.  , Gender differences in long-term survival of patients with colorectal cancer. Br J Surg.  2001; 88( 8): 1092– 1098. Google Scholar CrossRef Search ADS PubMed  24 Lydrup ML, Hoglund P. Gender aspects of survival after surgical treatment for rectal cancer. Colorectal Dis.  2015; 17( 5): 390– 396. Google Scholar CrossRef Search ADS PubMed  25 de Campos-Lobato LF, Geisler DP, da Luz Moreira Aet al.  , Neoadjuvant therapy for rectal cancer: The impact of longer interval between chemoradiation and surgery. J Gastrointest Surg.  2011; 15( 3): 444– 450. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Nov 20, 2017

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