Introduction Ovarian cancer is the leading cause
Ovarian cancer is the leading cause of death among gynecologic malignancies, chiefly due to the large proportion of cases diagnosed at advanced stage [, , ]. Optimal debulking (<1 cm residual disease) is an important predictor of survival for patients with advanced ovarian cancer, and an additional survival benefit is conferred for those with resection to no gross residual disease [, , , , , , , , , , ].
The standard treatment for advanced ovarian cancer in the U.S. has traditionally been primary debulking surgery (PDS) – which aims to remove the majority of disease upfront – followed by adjuvant chemotherapy. However, optimal debulking often requires aggressive surgery that is associated with substantial morbidity, including complications that can delay chemotherapy [11,, , ].
Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery and adjuvant chemotherapy has become an increasingly accepted alternative to PDS for advanced ovarian cancer [, , ]. NACT aims to reduce tumor burden and improve performance status preoperatively. This decreases the need for aggressive procedures, reduces post-operative complications, and increases the probability of optimal debulking [17,21,22]. However, it Conessine is unclear whether NACT provides a survival benefit.
In the U.S., the role of NACT in advanced ovarian cancer remains controversial [, , , , , , ]. Although two randomized controlled trials (RCTs) outside the U.S. observed non-inferior survival with NACT versus PDS [10,30], the generalizability of these trials to U.S. practice has been questioned due to lower median overall survival and lower rates of optimal debulking compared to U.S. populations [28,29]. A less aggressive surgical effort compared to that commonly performed in the U.S. has been postulated as the cause of the observed non-inferiority results [27,, , , , , ]. Among U.S. gynecologic oncologists surveyed in 2010, 82% did not believe there was sufficient evidence to justify NACT ; conversely, a European survey found that 70% of gynecologic oncologists believed there was sufficient evidence for use of NACT in advanced ovarian cancer .
Materials and methods We conducted a PubMed search on February 5th, 2017 using keywords selected based on prior knowledge and examination of previously-identified studies (Fig. 1). Eligible studies met the following criteria: (1) compared the effectiveness of NACT and PDS on overall survival for advanced ovarian, fallopian, or primary peritoneal cancer; (2) conducted in the U.S.; (3) published in English, and (4) published 2010 or later (reviews published in 2007 and 2011 outline evidence before 2010) [33,34]. We screened titles and abstracts identified through the electronic search for eligibility. The full text of potentially-eligible articles was then reviewed to confirm eligibility.
Results Nine observational studies met eligibility criteria for review (Table 1) [19,20,, , , , , , ]. Data from 1991  through 2013  were used to conduct these studies. Most studies included women with stage IIIC-IV ovarian cancer [19,36,37,39,41], one included only stage IV , and others included earlier stage disease [20,38,40]. Four studies included only NACT patients who received interval debulking surgery [35,37,39,41]. Three studies [20,36,40] used nationally-representative registry data, while the remaining studies used institutional medical record data. All studies compared overall survival between patients treated with NACT versus PDS using hazard ratios and/or Kaplan-Meier survival estimates, except one study  that used incidence rate ratios (Table 1). Studies used various methods to control for confounding, including multivariable adjustment [20,35,, , ], propensity score methods [19,20,36], instrumental variable analysis , stratification [19,36,37,40], and restriction . Two studies did not report any confounder control when comparing overall survival [37,38]. Though measured confounders were listed for most studies, covariates used for confounder control were unclear for some studies [20,35,39,41]. Four studies conditioned on residual disease, a variable on the causal pathway and one that is not known preoperatively when treatment decisions are being made [19,35,39,41].