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    • Introduction Ovarian cancer is the leading cause

    2019-08-11

    Introduction Ovarian cancer is the leading cause of death among gynecologic malignancies, chiefly due to the large proportion of cases diagnosed at advanced stage [[1], [2], [3]]. 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 [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]]. 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,[15], [16], [17]]. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery and adjuvant chemotherapy has become an increasingly accepted alternative to PDS for advanced ovarian cancer [[18], [19], [20]]. 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 [[23], [24], [25], [26], [27], [28], [29]]. 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,[24], [25], [26], [27], [28], [29]]. Among U.S. gynecologic oncologists surveyed in 2010, 82% did not believe there was sufficient evidence to justify NACT [31]; conversely, a European survey found that 70% of gynecologic oncologists believed there was sufficient evidence for use of NACT in advanced ovarian cancer [32].
    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,[35], [36], [37], [38], [39], [40], [41]]. Data from 1991 [20] through 2013 [41] 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 [35], 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 [40] that used incidence rate ratios (Table 1). Studies used various methods to control for confounding, including multivariable adjustment [20,35,[39], [40], [41]], propensity score methods [19,20,36], instrumental variable analysis [20], stratification [19,36,37,40], and restriction [36]. 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].