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

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.

Figure 1.

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 2.

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.