br of concordant neoadjuvant therapy to
of concordant neoadjuvant therapy to include Prostaglandin J2 therapy at a dose of 4500-5400 cGy.3 Additionally only chemoradiation or chemotherapy alone was considered guideline-concordant, as radiation alone is not considered adequate neoadjuvant treatment.
Standard descriptive statistics were applied to evaluate the distribution of categorical and continuous variables. The correlation between clinical and pathologic staging was
estimated using Spearman’s rank-order correlation. The primary outcome of interest was overall survival which was evaluated using the Kaplan-Meier method and log-rank test. The association between the receipt of guideline-concordant care and overall risk of death was evaluated using multivariable Cox regression. Model covariates were selected in a non-parsimonious fashion and included age, sex, race, insurance, education level, income level, rurality, Charlson-Deyo comorbidity score, travel distance, facility type, United States region, tumor grade, tumor histology, and hospital volume. A sub-analysis was performed to better delineate the effect of a disease response in Stage IIIA patients who received guideline-concordant care by categorizing patients as having received guideline -concordant care with a disease response, guideline-concordant care without a disease response, non-guideline concordant care. Our cohort included 11.9% of patients with at least one missing covariate data
point. Missing data were imputed using multivariate imputation by chained equations (MICE).12 Analyses were conducted using both case-complete and imputed approaches without notable differences. Imputed results are reported. All statistical analyses were conducted using Stata/MP 15.1 for Mac (StataCorp, College State, TX).
(60.3%), and Stage IIA (56.5%),. The overall Spearman’s rank correlation coefficient was 0.69 for clinical and pathologic stages (p<0.001). Primary tumor staging correlation ranged from 71.2 to 84.5%. Discordance among lower stages was due to primary tumor upstaging or discovery of positive nodes. Discordance in higher stages was due to inaccurate clinical nodal staging.
The overall primary tumor downstaging rate was 32.4%. For T1 tumors, there was a 1.6% rate of pathologic complete response following neoadjuvant therapy (Table 1). The spearman’s rank correlation coefficient was 0.73 for primary tumor staging. Positive clinical nodal staging had a positive predictive value of 78.2% and negative clinical nodal staging had a negative predictive value of 88.1%. Downstaging was observed in 17.3% of node-positive patients after neoadjuvant therapy (Table 2). Within patients with N2 disease, downstaging to N1 was observed in 1.8% and downstaging to N0 was observed in 12.0%. Overall, the nodal staging spearman’s rank correlation coefficient was 0.56.
In patients who received neoadjuvant therapy, any pathologic response was predictive of a significantly decreased risk of death (0.82, 95%CI 0.75-0.92). This held true across all stages (Supplementary Table 1). Compared to accurately staged patients, patients who were understaged had increased risk of death (1.63, 95%CI 1.58-1.69), while those who were overstaged had lower risk of death (0.72, 95%CI 0.68-0.76). (Supplementary Table 1)
Medicaid/uninsured insurance, rurality, longer travel distance, Charlson-Deyo>1, high grade, positive margins, and positive lymph nodes. (Supplementary Table 2) Guideline concordance for Stage IA and IB patients was high (97.4% and 97.9% respectively). Stage IIA (49.2%), IIB (47.5%), and IIIA patients (32.2%) had lower rates. Using more stringent criteria for neoadjuvant therapy, guideline concordance was much lower for Stage IIIA due to inadequate radiotherapy doses (Stage IA 97.7%, Stage IB 99.1%, Stage IIA 50.5%, Stage IIB 49.6%, Stage IIIA 18.7%). The sensitivity analysis using more stringent guideline criteria did not change the survival analyses, thus the more broad definition of neoadjuvant therapy was used. Patients who received guideline-concordant care were more likely to have negative margins (87.5% vs.
In patients with Stage IIIA disease, patients who responded to neoadjuvant therapy had higher unadjusted five-year OS (54.7% vs 45.5% no disease response vs 49.6% guideline discordant, Figure 2). After adjustment, patients who received neoadjuvant therapy without response had a significantly higher risk of death than those who did not receive neoadjuvant therapy (HR 1.22, 95%CI 1.11-1.34). However, there was no difference in risk of death between those who received neoadjuvant therapy with a disease response and those who did not receive neoadjuvant therapy. (HR 0.94, 95%CI 0.85-1.04). Directly comparing patients who responded and who did not respond to neoadjuvant therapy, lack of response was associated with increased risk of death (HR 1.29, 95%CI 1.15-1.45).