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  • br The GOG and PORTEC trials

    2020-08-14


    The GOG-258 and PORTEC-3 trials examined this question from complementary angles. PORTEC-3 enrolled 660 women with high-risk stage IB-III EC, weighted heavily towards stage III, randomized to re-ceive either RT alone or RT with concurrent cisplatin followed by 4 cycles of carboplatin and paclitaxel (CRT) [1]. The addition of CT to RT was associated with a trend towards improved 5 y PFS and OS in the entire cohort. In a subset analysis limited to women with stage III disease, the 5 y PFS benefit reached statistical significance at 69% versus 58% (P = 0.03). Asking a mirror image question, GOG-258 randomized 813 women with stage III-IVA EC to 6 cycles of chemotherapy alone (carboplatin and paclitaxel) versus CRT per PORTEC (RT followed by carboplatin/paclitaxel) [2]. While the 5 y rates of vaginal and pelvic or PA recurrences were higher in the CT arm (7% vs. 3% and 19% vs. 10%, re-spectively), the rate of distant recurrences was lower in the CT arm (21% vs. 27%). There was a small, but non-significant numerical advantage in PFS favoring the CRT arm (HR 0.9), but no difference in OS. Exploratory subset analyses did not identify subgroups that derived benefit from CRT. Consistent with these data, subset analyses presented in this man-uscript show no statistical difference in OS between women treated with RT before CT compared to either CT alone as was seen in GOG-258 (Fig. 2D), or RT alone, as was seen in PORTEC-3 (Fig. 2E).
    An increase in distant failures and worse survival among women who receive RT before CT may potentially be due to delayed 387334-31-8 of CT or delivery of a fewer number of total CT cycles due to either trial design (6 vs. 4 planned cycles) or tolerability (inability to complete CT after RT). Importantly, 25% and 29% of women enrolled in the CRT arms of GOG-258 and PORTEC-3, respectively, did not receive full CT, defined as 4 cycles of carboplatin and paclitaxel following RT [1,2].
    Fig. 1. Unadjusted survival curves for all women who received adjuvant chemotherapy or radiotherapy. Unadjusted overall survival curves based on Kaplan-Meier estimates for women who received radiotherapy alone (light gray, dotted), chemotherapy alone (medium gray, dashed), radiotherapy before chemotherapy (dark gray, large dashed), or radiotherapy after chemotherapy (black, solid). RT: radiotherapy; CT: chemotherapy; Mo: months; No: number.
    Fig. 2. Adjusted survival curves for pairs of matched cohorts of women who received adjuvant radiotherapy and/or chemotherapy. Overall survival curves based on Kaplan-Meier estimates for matched cohorts of women who received A) radiotherapy after chemotherapy (black) versus radiotherapy before chemotherapy (gray); B) radiotherapy after chemotherapy (black) versus chemotherapy alone (gray); C) radiotherapy after chemotherapy (black) versus radiotherapy alone (gray); D) radiotherapy before chemotherapy (black) versus chemotherapy alone (gray); E) radiotherapy before chemotherapy (black) versus radiotherapy alone (gray); or F) chemotherapy alone (black) versus radiotherapy alone (gray). RT: radiotherapy; CT: chemotherapy; TR: Time Ratio; 95% CI: 95% Confidence Interval; P: P-value; Mo: months; No: number.
    Table 2
    Kaplan-Meier estimates of overall survival and multivariable parametric accelerated failure time models of propensity score-matched cohorts of patients who received adjuvant radiother-apy and chemotherapy.
    Variable Univariate analysis of propensity score-matched cohorts
    Multivariable AFT model
    Adjuvant therapy
    Age
    Tumor stage
    Nodal stage
    Nodal surgery
    Grade
    LVSI
    Omentectomy
    Cytology
    Margin status
    Race
    Hispanic
    Insurance status
    Comorbidity score
    Prior cancer
    Income quartile
    Education quartile
    Treatment facility
    Year diagnosed
    Variable Univariate analysis of propensity score-matched cohorts
    Multivariable AFT model
    Accelerated failure time (AFT) models for the matched cohorts were covariate-adjusted and inverse probability-weighted using propensity-weighted matched cohorts. Significance de-termined by Log-Rank test (univariate analyses) or Wald test (multivariable analyses). OS: overall survival; mo: months; y: years; N: number; RMST: restricted mean survival time; TR (95% CI): time ratio (95% confidence interval); P: P-value; RT: radiotherapy; CT: chemotherapy; LND: lymph node dissection; PA: para-aortic; LVSI: lymphovascular space invasion; Gov: other government agency; ref.: reference level.
    Although the NCDB does not provide the number of CT cycles planned and/or received, the number of CT cycles received prior to RT was esti-mated by calculating the number of days between CT and RT start dates. Furthermore, as it was not possible to determine which women may have received adjuvant therapy using a “sandwich” approach, we considered all patients who started RT ≥ 62 d following the start of CT as one group. These analyses therefore do not clarify which regimen, if either, may be associated with longer survival. Employment of a “sand-wich” regimen may enable a greater number of patients to complete at least 3 or 4 cycles of multi-agent CT as well as RT, thereby deriving the greatest benefit from both complementary therapy techniques. While a small number of retrospective and prospective cohort studies have utilized a sandwich approach with acceptable outcomes and toxicity profiles, the significant heterogeneity across studies and limited sample of patients renders further analysis difficult [19–24].