Effect of adoption of neoadjuvant chemotherapy for advanced ovarian cancer on all cause mortality: quasi-experimental study

Abstract

Objective: To estimate the causal effect of increased use of neoadjuvant chemotherapy (NACT) on all cause mortality in advanced epithelial ovarian cancer.

Design: Quasi-experimental fuzzy regression discontinuity design and cross sectional analysis.

Setting: Cancer programs throughout the United States accredited by the Commission on Cancer.

Participants: 6034 women with a diagnosis of stage 3C or 4 epithelial ovarian cancer from regions that rapidly adopted use of NACT from 2011 to 2012 (27% increase in the New England and east south central regions) or remained unchanged (control regions, south Atlantic, west north central, and east north central regions).

Main outcome measure: All cause mortality within three years of diagnosis. Kaplan-Meier curves and proportional hazard models were estimated to compare mortality differences between rapidly adopting regions and controls.

Results: 1156 women were treated for advanced epithelial ovarian cancer during 2011 and 2012 in the two rapidly adopting regions and 4878 women in the three control regions. In the rapidly adopting regions, patients treated in 2012 compared with 2011 had a mortality hazard ratio of 0.81 (95% confidence interval 0.71 to 0.94) after adjusting for mortality time trends, whereas no difference was observed in control regions (1.02, 0.93 to 1.12). Compared with control regions, larger declines in 90 day surgical mortality (7.0% to 4.0% v 5.0% to 4.3%, P=0.01) and in the proportion of women not receiving surgery and chemotherapy (20.0% to 17.4% v 19.0 to 19.5%, P=0.04) were observed in rapidly adopting regions. Cross sectional analysis confirmed that treatment in regions with greater use of NACT was associated was lower mortality (P=0.001).

Conclusions: Adoption of NACT for advanced epithelial ovarian cancer in New England and east south central regions led to a sizable reduction in mortality within three years after diagnosis.

Fig 1

Annual frequency of neoadjuvant chemotherapy for advanced epithelial ovarian cancer (blue circles) in New England and east south central census division (A), and south Atlantic, west north central, and east north central census divisions (B). Red lines represent linear trends in use of neoadjuvant chemotherapy estimated from 2007 to 2011 and extrapolated for 2012. Shade areas are 95% prediction intervals. After adjustment for secular trends, there was a significant increase in frequency of neoadjuvant chemotherapy in 2012 in the New England and east south central division (odds ratio 1.41, 95% confidence interval 1.25 to 1.72, P<0.001). In south Atlantic, west north central, and east north central divisions, treatment in 2012 was not associated with any deviation from secular trends (odds ratio 0.98, 95% confidence interval 0.86 to 1.12; P=0.78)

Fig 2

Plots of annual mortality hazard rates from 2007 to 2012, and Kaplan-Meier survival curves for women treated in 2011 and 2012 in the New England and east south central census divisions (A and C) and control regions (B and D). While survival remained unchanged from 2011 to 2012 in control regions (log rank P=0.99), in New England and east south central regions survival improved in 2012 coincident with increased utilization of neoadjuvant chemotherapy (log rank P=0.02)

Fig 3

For each year from 2004 to 2013, the relative prevalence of neoadjuvant chemotherapy in each of nine census divisions is plotted against the relative hazard of all cause mortality. Region specific relative mortality hazard and prevalence estimates utilize the national averages in each year as referents. Predicted relative hazards estimated from an exponential proportional hazard model are displayed as the blue line. After adjusting for year of diagnosis, treatment in regions with higher use of neoadjuvant chemotherapy was associated with a significantly lower hazard of death (P=0.001)