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Meta-Analysis
. 2023 Jun 1;6(6):e2318602.
doi: 10.1001/jamanetworkopen.2023.18602.

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas

Koji Matsuo  1   2 , Shinya Matsuzaki  3 , Michihide Maeda  3 , Alesandra R Rau  1 , Kosuke Yoshihara  4 , Ryo Tamura  4 , Muneaki Shimada  5 , Hiroko Machida  6 , Mikio Mikami  6 , Maximilian Klar  7 , Lynda D Roman  1   2 , Jason D Wright  8 , Anil K Sood  9 , David M Gershenson  9
Affiliations
Meta-Analysis

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas

Koji Matsuo et al. JAMA Netw Open. .

Abstract

Importance: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied.

Objective: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer.

Design, setting, and participants: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy.

Exposures: Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group).

Main outcomes and measures: Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score.

Results: A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas.

Conclusions and relevance: Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr. Matsuzaki reported receiving a research grant from Merck. Dr Shimada reported receiving fees from Chugai Pharmaceutical Co, AstraZeneca Ltd, MSD Ltd, Eisai Co Ltd, Takeda Pharmaceuticals Ltd, and Mochida Pharmaceuticals Ltd during the conduct of the study. Dr. Machida reported receiving an honorarium from AstraZeneca and a research grant from Bristol-Myers Squibb. Prof Klar reported receiving lecture fees from KLS Martin and Cooper Surgical outside the submitted work. Dr Wright reported receiving grants from Merck and personal fees from UpToDate outside the submitted work. Dr Sood reported receiving consulting fees from Merck, GSK, Kiyatec, Iylon, Onxeo, and ImmunoGen outside the submitted work; in addition, Dr Sood had a patent for EGFL6 antibody licensed to Top Alliance and is a shareholder in BioPath. Dr Gershenson reported receiving grants from Novartis outside the submitted work; receiving royalties from Elsevier for UpToDate; serving as an unpaid consultant for Genentech and as a consultant for Verastem; serving on the advisory boards of Springworks, Verastem, Aadi, and Onconova; and holding stock equity in a managed account with Bristol-Myers Squibb, Johnson & Johnson, and Procter and Gamble. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Temporal Trends
Use of neoadjuvant chemotherapy (NACT) is shown in 3-year increments during the study period for clear cell (A), low-grade serous (B), and mucinous (C) carcinomas in the main study cohort (National Cancer Database [NCDB] 2006-2017) and the second study cohort (Surveillance, Epidemiology, and End Results [SEER] 2006-2019). Error bars represent SEs. The Cochran-Armitage trend test was used to determine P for trend values. aP < .001 for trend. bP < .05 for trend. cP = .07 for trend.
Figure 2.
Figure 2.. Overall Survival in the National Cancer Database Cohort
Overall survival based on the exposure assignment (neoadjuvant chemotherapy [NACT] vs primary debulking surgery [PDS]) is shown for clear cell (A), mucinous (B), and low-grade serous (C) carcinomas. The survival curves were constructed in the inverse probability of treatment weighting cohorts in each histologic subtype. The exposure-outcome association was also found when unknown cases were excluded in the analysis. Color band widths indicate 95% CIs. Number at risk is per a propensity score–weighted model. HR indicates hazard ratio. aSmall number suppressed.
Figure 3.
Figure 3.. Subgroup Analysis of the National Cancer Database Cohort
Overall survival associated with the exposure (neoadjuvant chemotherapy [NACT] compared with primary debulking surgery [PDS]) in each histologic subtype and the hazard ratio (HR) and the corresponding 95% CIs are displayed (orange boxes indicate HR>1 with P < .05; blue boxes indicate HR<1 with P < .05). Younger and older age groups were based on the median age of patients within each histologic subtype. Comorbidity was dichotomized by Charlson-Deyo score (0 vs ≥1). Analysis was based on the inverse probability of treatment weighting model.
Figure 4.
Figure 4.. Meta-analysis of Neoadjuvant Chemotherapy (NACT) and Overall Survival
Results of a meta-analysis for the association of neoadjuvant chemotherapy (NACT) with overall survival in patients with clear cell (A), mucinous (B), and low-grade serous (C) carcinomas are shown. Results of a fixed-effects meta-analysis of studies for overall survival are ordered within stratum by year of publication and relative weight (%) of studies. No heterogeneity was noted among the studies (I2 = 0%). LGSOC indicates low-grade serous ovarian carcinoma; MOC, mucinous ovarian carcinoma; OCCC, ovarian clear cell carcinoma; and PDS, primary debulking surgery.
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