Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: A meta-analysis

Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: A meta-analysis

Gynecologic Oncology 103 (2006) 1070 – 1076 www.elsevier.com/locate/ygyno Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction...

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Gynecologic Oncology 103 (2006) 1070 – 1076 www.elsevier.com/locate/ygyno

Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: A meta-analysis☆ Robert E. Bristow a,⁎, Dennis S. Chi b a

The Kelly Gynecologic Oncology Service, Departments of Gynecology and Obstetrics and Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Phipps #281, Baltimore, MD 21287, USA b Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Received 5 April 2006 Available online 27 July 2006

Abstract Objective. To determine the overall survival and relative effect of multiple prognostic variables in cohorts of patients with advanced-stage ovarian cancer treated with platinum-based neoadjuvant chemotherapy in lieu of primary cytoreductive surgery. Methods. Twenty-two cohorts of patients with Stage III and IV ovarian cancer (835 patients) were identified from articles in MEDLINE (1989– 2005). Linear regression models, with weighted correlation calculations, were used to assess the effect on median survival time of the proportion of each cohort undergoing maximum interval cytoreduction, proportion of patients with Stage IV disease, median number of pre-operative chemotherapy cycles, median age, and year of publication. Results. The mean weighted median overall survival time for all cohorts was 24.5 months. The weighted mean proportion of patients in each cohort undergoing maximal interval cytoreduction was 65.0%. Each 10% increase in maximal cytoreduction was associated with a 1.9 month increase in median survival time (p = 0.027). Median overall survival was positively correlated with platinum–taxane chemotherapy (p < 0.001) and increasing year of publication (p = 0.004) and negatively correlated with the proportion of Stage IV disease (p = 0.002). Each incremental increase in pre-operative chemotherapy cycles was associated with a decrease in median survival time of 4.1 months (p = 0.046). Conclusions. Neoadjuvant chemotherapy in lieu of primary cytoreduction is associated with inferior overall survival compared to initial surgery. Increasing percent maximal cytoreduction is positively associated with median cohort survival; however, the negative survival effect of increasing number of chemotherapy cycles prior to interval surgery suggests that definitive operative intervention should be undertaken as early in the treatment program as possible. © 2006 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Neoadjuvant chemotherapy; Interval cytoreductive surgery

Introduction Primary cytoreductive surgery for advanced ovarian cancer was first championed by Meigs in 1934 [1]. Following the landmark study by Griffiths in 1975, which quantified residual disease and conclusively demonstrated an inverse relationship between residual tumor diameter and patient survival, nearly every retrospective and prospective study has confirmed that the extent of cytoreductive surgery and the amount of residual ☆

This work supported by the Pam McDonald Drive Fore Life Ovarian Cancer Charity Golf Tournament. ⁎ Corresponding author. Fax: +1 410 614 8718. E-mail address: [email protected] (R.E. Bristow). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.06.025

disease are among the most important factors impacting the survival of women with advanced ovarian cancer [2,3]. The corollary to this principle is that even extensive surgical efforts that leave residual tumor larger than 2 cm have no meaningful impact on survival [4]. In an effort to increase the proportion of patients with advanced ovarian cancer that are ultimately left with an optimal volume of residual disease, the concept of interval cytoreduction, or a repeat attempt at debulking surgery following an initial suboptimal effort and several cycles of systemic chemotherapy, has been adopted in many centers. Notably, two of the three large randomized, prospective studies of interval cytoreduction published to date failed to demonstrate a survival advantage associated with interval surgery [5–7]. Despite these contradictory

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data, the concept of interval cytoreduction has evolved into the treatment approach now referred to as neoadjuvant chemotherapy in which the initial attempt at cytoreduction is abandoned in favor of chemotherapy in order to reduce the extent of disease or improve patient performance status [8]. Proposed advantages of neoadjuvant chemotherapy include an increased rate of optimal residual disease, less extensive surgery, reduced blood loss, lower morbidity, shortened hospital stay, improved quality of life, and acting as a mechanism to select out patients with platinum-resistant disease [9]. Furthermore, it has been suggested that neoadjuvant chemotherapy followed by interval cytoreduction does not worsen the prognosis for patients with advanced ovarian cancer [9–11]. Through a meta-analysis of the collective literature, the current study attempts to address two principal questions regarding the application of platinum-based neoadjuvant chemotherapy in lieu of primary cytoreductive surgery among cohorts of patients with advanced-stage epithelial ovarian cancer. First, what is the overall survival outcome of patients treated with this approach? Secondly, what are the clinically relevant prognostic variables within this patient population? Methods Study selection and data extraction Using the headings and keywords “ovarian carcinoma,” “ovarian cancer,” “neoadjuvant chemotherapy,” and “surgery,” a MEDLINE search for English

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language articles published between January 1, 1989 and September 30, 2005 was conducted. Publications were selected for initial review if the research subjects were predominantly (>90%) patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV epithelial ovarian cancer who underwent neoadjuvant chemotherapy that included cisplatin or carboplatin prior to an attempt at cytoreductive surgery. For the purposes of this study, neoadjuvant chemotherapy for advanced ovarian cancer was defined as a treatment program designed to avoid a nonuseful surgical procedure in patients considered optimally unresectable and consisted of the administration of chemotherapy, in lieu of primary cytoreductive surgery, following the histologic verification of ovarian cancer by biopsies only; after several cycles of systemic therapy, surgical cytoreduction was attempted during interval laparotomy [8]. Maximal interval cytoreduction was considered to have occurred if residual disease measured ≤2 cm in largest diameter. Articles were excluded that did not include the median survival time of individual patient cohorts, the definition of maximal cytoreduction surgery, the proportion of patients with stage IV disease, the median or mean number of pre-operative chemotherapy cycles administered prior to attempted cytoreductive surgery, or the proportion of patients receiving a taxane as part of the initial chemotherapy regimen. The bibliography of each selected article was reviewed for other potentially relevant citations. In the case of studies whose results were published more that once, data from the most recent article were used for statistical analysis. The formal published versions of all eligible studies were reviewed for content and screened according to the aforementioned inclusion criteria. The following information was recorded for each eligible cohort study: study design (nonrandomized pilot, phase II, case–control, retrospective review), year of publication of the study, number of patients, median patient age, percentage of patients with stage IV disease, specified definition of maximal interval cytoreductive surgery and the percentage of patients achieving it, chemotherapy agents administered and the median or mean number of cycles received prior to attempted interval cytoreductive surgery, and reported median survival times. We did not attempt to analyze either platinum or total drug dose intensity or cumulative dose received prior to interval cytoreductive

Table 1 Study characteristics Author [reference]

Year of publication

n

Median age

Percent Stage IV

Residual tumor criteria

Number chemotherapy cycles

Percent taxane use

Percent maximum interval cytoreduction

Median overall survival (months)

Donadio [12] a Tummarello [13] b Jacob [14] c Lim [15]a Vergote [16]b Schwartz [17]b Lu [18]b Ansquer [19]b Kuhn [20] d Vrscaj [21] e Ushijima [22]b Shibata [23]e Shibata[23]e Chan [24]a Fanfani [25]b Morice [26]b Morice [27]e Mazzeo [28]b Loizzi [29]e Avril [30]a Hegazy [31]d Le [32]b

1989 1990 1991 1993 1998 1999 2001 2001 2001 2002 2002 2003 2003 2003 2003 2003 2003 2003 2005 2005 2005 2005

24 24 22 30 75 59 45 54 31 20 65 13 10 17 73 48 34 45 25 33 27 61

54 57 58.5 56 64 67 58.5 63 61 65 60.3 53.6 60 57 60 57 59 68 64 60 58.7 63

29.2 70.8 18.2 33.3 41.3 64.4 53.3 14.8 0.0 15.0 21.5 23.1 20.0 76.5 0.0 17.2 11.8 20.0 23.3 30.3 59.3 3.3

>2 cm >2 cm >2 cm >2 cm >1.5 cm <1 cm >2 cm >2 cm >2 cm >1 cm >1 cm >2 cm >2 cm >2 cm >2 cm >2 cm >2 cm >2 cm >1 cm >1 cm >1 cm >2 cm

4.1 6 2.8 3 3 5 3 4 3 4 3.8 6 6 3 3 3 3 4 4 3 3 3

0.0 0.0 0.0 0.0 20.0 8.5 68.9 57.4 100.0 0.0 21.5 0.0 0.0 100.0 54.8 100.0 94.0 77.7 60.0 69.7 0.0 100.0

53.3 41.7 77.3 30.0 36.0 67.8 75.6 72.2 83.9 60.0 41.5 100.0 0.0 58.8 71.2 100.0 94.1 68.9 76.0 66.7 48.1 80.0

18.9 16 16 10.2 24 12.8 18 22 42 24.7 21 23 11.2 22.9 27 28 26 29 32 26.8 25 41.7

a b c d e

Phase I study. Retrospective analysis. Retrospective matched control study. Phase II study. Retrospective case–control study.

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surgery, because this information was inconsistently reported in the various studies.

Statistical methods Simple linear regression models were generated to examine the effect of the following on median survival time: median age of the study cohort, year of publication of the study, percentage of patients with stage IV disease, percentage of patients undergoing maximal interval cytoreductive surgery, median or mean number of pre-operative chemotherapy cycles received prior to interval surgery, and the percentage of patients receiving a taxane agent in combination with platinum chemotherapy. The regressions were weighted by the number of patients in each cohort. This tended to give more influence to the larger studies, because they necessarily contained more precise estimates of the key measures. Examination of the data revealed no nonlinear effects for the variables under study when expressed in this fashion. Given the small number of observations contained in the final data set, a multiple linear regression analysis was felt to be invalid and was not performed. All results are quoted as two-sided p values and 95% confidence intervals (CI). p < 0.05 was considered statistically significant. The analysis was carried out using the STATA statistical software package (STATA Corp., College Station, TX).

Results Study characteristics The initial MEDLINE search yielded 129 articles. The formal published reports of 50 of these studies were reviewed. Ultimately, 21 studies (22 cohorts, 835 patients) were identified as meeting all study inclusion criteria (Table 1) [12–32]. For each individual cohort, the residual tumor criteria used to select patients for neoadjuvant chemotherapy were the same as the criteria for optimal residual disease following interval cytoreductive surgery and ranged from > 1 cm to > 2 cm (Table 1). Four cohorts were extracted from nonrandomized Phase I pilot studies; 2 cohorts were from prospective, nonrandomized phase II trials; 6 cohorts were from retrospective case–control studies; and 10 were from retrospective analyses. The mean number of patients in each cohort was 38 (median = 32, range = 10–75), and the reported median survival time ranged from 10.2 to 42.0 months. For all cohorts taken together, the mean weighted median survival time was 24.5 months. Fifteen different chemotherapeutic agents (cisplatin, carboplatin, cyclophosphamide, ifosfamide, doxorubicin, farmorubicin, paxlitaxel, docetaxel, melphelan, hexamethylmelamine, irinotecan, 5-fluorouracil, bleomycin, vinorelbine, and etoposide) were used in a variety of combinations, yielding 16 distinct treatment regimens in addition to single agent cisplatin or carboplatin. Sixteen cohorts employed cisplatin; 12 cohorts administered carboplatin. Platinum dosing was reported in only 10 of 22 cohorts and ranged from 50 mg/m2 to 120 mg/m2 for cisplatin and an area under the curve (AUC) of 5–6 for carboplatin [12–15,18,20,24,25,28,30,32]. As noted above, because of the large number of individual chemotherapeutic agents and variety of combination regimens administered during the study period, coupled with inconsistent reporting of individual dosing regimens, calculations of platinum and total drug dose–intensity and cumulative dose were impractical.

Maximal interval cytoreductive surgery Maximal interval cytoreductive surgery was defined according to the largest diameter of residual disease, with the following distribution among study cohorts: ≤2 cm in 68.2%, ≤1.5 cm in 4.5%, and ≤ 1 cm in 27.3%. The weighted mean percentage of maximal interval cytoreductive surgery for all cohorts was 65.0%, with a range from 0%–100%. Simple linear regression analysis of percent maximal interval cytoreductive surgery versus median survival time for the 22 patient cohorts is shown in Fig. 1. The regression line was computed weighted by the number of observations in each study, and the effects of other variables were ignored. Each 10% increase in the proportion of patients in each cohort undergoing maximal interval cytoreductive surgery was associated with a 1.9 month increase in median survival time (95%CI = 0.23 months–3.50 months, p = 0.027). The estimated median survival times for cohorts undergoing 0% and 100% maximal interval cytoreductive surgery were 12.5 months and 31.0 months, respectively. A total of 22 cohorts were used to evaluate the effect of residual disease criteria on median survival time. Fifteen cohorts utilized an optimal residual disease criteria of < 2 cm, 1 cohort utilized < 1.5 cm, and 6 cohorts utilized < 1.0 cm. There was no statistically significant association between residual disease criteria and median survival. Number of pre-operative chemotherapy cycles Nineteen cohorts reported the median number of preoperative chemotherapy cycles received prior to attempted interval cytoreductive surgery (range 3–6 cycles), while 3 cohorts reported mean values (range 2.8–4.1 cycles). Simple linear regression analysis of the number of the number of pre-operative chemotherapy cycles versus median survival time for the 22 patient cohorts is shown in Fig. 2. The regression line was computed weighted by the number of observations in each study, and the effects of other variables were ignored. There is a statistically significant association

Fig. 1. Simple linear regression analysis: median cohort survival time plotted against percent maximum interval cytoreductive surgery. Circle size is proportional to the number of subjects in each study and does not reflect the degree of statistical variation between studies.

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between the median/mean number of pre-operative chemotherapy cycles and survival. Each incremental chemotherapy cycle was associated with a 4.1 month decrease in median survival time (95%CI = 8.1 to − 0.1 months, p = 0.046). Percent taxane use Fourteen cohorts utilized a taxane (13 paclitaxel, 1 docetaxel) [16–20,24–30,32]. The weighted mean percentage of patients receiving a taxane per cohort was 47.7%, with a range from 0% to 100%. Simple linear regression analysis revealed a significant relationship between the percentage of patients receiving a taxane and median survival time. Each 10% increase in the proportion of patients receiving a taxane was associated with a 1.6 month increase in median survival time (95% CI = 0.87 months–2.25 months, p < 0.0005) (Fig. 3). Percent Stage IV disease The weighted mean percentage of patients with Stage IV disease per cohort was 27.4%, with a range from 0%–70.8%. Simple linear regression analysis revealed a significant relationship between percent Stage IV disease and median survival time. Each 10% increase in the proportion of patients with stage IV disease was associated with an estimated 2.3 month decrease in median survival time (95%CI = − 3.70 months to − 1.00 months, p = 0.002). Year of publication and median cohort age Sixteen of the 22 cohorts (72.7%) were published between 2001 and 2005. Simple linear regression analysis revealed a statistically significant association between year of publication and median survival time. Each one year increment in the year of publication was associated with an estimated 1.1 month increase in median survival time (95%CI = 0.40 months to 1.85 months, p = 0.004).

Fig. 2. Simple linear regression analysis: median cohort survival time plotted against the median (n = 19) and mean (n = 3) number of cycles of neoadjuvant chemotherapy prior to surgery. Circle size is proportional to the number of subjects in each study and does not reflect the degree of statistical variation between studies.

Fig. 3. Simple linear regression analysis: median cohort survival time plotted against the percentage of patients in each cohort receiving a taxane agent in addition to platinum chemotherapy. Circle size is proportional to the number of subjects in each study and does not reflect the degree of statistical variation between studies.

The mean weighted median age for all 22 cohorts was 61.1 years (range = 53.6 years–68.0 years). Simple linear regression analysis revealed no statistically significant relationship between median cohort age and median survival time (p = 0.448). Discussion To clarify the relative contributions of surgery, chemotherapy, and other clinical variables to the overall survival of patients with advanced ovarian cancer, several investigators have utilized the technique of meta-analysis, whereby multiple individual studies are evaluated collectively to provide a more expansive database [33–37]. With the standard treatment approach of cytoreductive surgery followed by chemotherapy, these reports have convincingly shown that the dominant factors influencing survival are the proportion of patients achieving optimal residual disease and the inclusion of a platinum agent in the treatment program. Limitations of the standard treatment strategy include the fact that cytoreductive surgery that does not achieve a minimal volume of residual disease (< 2 cm) has no appreciable effect on survival and that, although there is wide variation, the proportion of patients left with suboptimal residual disease may be substantial [4,38,39]. Consequently, the administration of neoadjuvant chemotherapy, in lieu of primary cytoreductive surgery, has been adopted by many clinicians in order to avoid a potentially nonuseful surgical procedure for patients considered optimally unresectable [8–10]. The current study is the first to apply the technique of meta-analysis to the published literature on platinum-based neoadjuvant chemotherapy for advanced ovarian cancer. Despite variable indications and recommended therapeutic regimens, neoadjuvant chemotherapy for ovarian cancer has achieved relatively broad implementation, with a number of centers utilizing this alternative treatment strategy in 22% to 43% of patients with advanced disease [16,17,40,41]. A recent questionnaire study by Chen et al. highlights the principal

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assumption underlying this divergence from standard management guidelines. These authors queried full members of the Society of Gynecologic Oncologists regarding surgery and chemotherapy for primary ovarian cancer treatment and found that 50% of respondents agreed with a statement that neoadjuvant chemotherapy is equivalent to primary surgery [42]. Within the published literature, two studies in particular have been frequently cited as supporting the equivalency of neoadjuvant chemotherapy and primary cytoreductive surgery [16,17]. Vergote et al. compared survival outcomes of 112 patients treated with the standard treatment approach of initial surgery followed by chemotherapy between 1980 and 1988 versus 173 patients treated between 1989 and 1997 who were managed with a selective use of neoadjuvant chemotherapy after diagnosis (43% of patients) or primary surgery followed by chemotherapy (57% of patients) [16]. The actuarial crude 3-year survival rate was higher for the group of patients treated during the selective neoadjuvant chemotherapy time period (42%) compared to the standard surgery time period (26%, p = 0.0001). However, within the selective neoadjuvant chemotherapy group, the crude 3-year survival rate for patients managed with standard initial surgery was statistically superior (53%) compared to patients treated with neoadjuvant chemotherapy (24.8%, p = 0.0025). In another study, Schwartz et al. reported on 59 consecutive patients who were medically compromised or had surgically unresectable disease and were treated with platinum based neoadjuvant chemotherapy prior to consideration for surgical resection [17]. Although not statistically significant, the median survival time for neoadjuvant chemotherapy patients was reduced by more than 50% (12.8 months) compared to a control group of 206 patients treated with primary surgery (26.2 months). The first objective of the current report was to characterize the collective survival outcome of patients treated with neoadjuvant chemotherapy in these and other studies. The current meta-analysis of the published literature indicates that the median survival of patients treated with neoadjuvant chemotherapy in lieu of primary surgery ranges from 10–42 months, with a weighted average median survival time of 24.5 months. It is noteworthy that this survival outcome is equivalent to that reported in a large cooperative group trial of patients with advanced-stage ovarian cancer and suboptimal residual disease following primary surgery (> 1 cm) treated with 6 cycles of cisplatin and cyclophosphamide chemotherapy, Gynecologic Oncology Group protocol #111, in which the median survival time was 24 months [43]. Clearly, it can be argued that patients selected for neoadjuvant chemotherapy have an intrinsically worse prognosis on the basis of disease extent or a poor performance status [17]. This argument is mitigated, at least in part, by several recent studies indicating that the requirement to perform radical surgical procedures to achieve optimal residual disease at primary cytoreductive surgery is not associated with a significantly worse prognosis when other factors are taken into consideration [44,45]. The intrinsically worse prognosis argument notwithstanding, the current data suggests that when surgery is abandoned in favor of initial chemotherapy, the survival outcome approximates that of suboptimal primary surgery.

The second objective of the current study was to determine which clinical and treatment-related variables influence the survival outcome of patients with advanced ovarian cancer receiving neoadjuvant chemotherapy before a deferred attempt at cytoreductive surgery. It is somewhat intuitive that an increasing proportion of patients with stage IV disease would be negatively correlated with survival, while more prevalent use of a taxane in combination with a platinum agent would be positively associated with survival outcome. The observation that more recent studies were associated with a statistically significant extension in median survival time has been previously described [46,47]. Although the observed effect may have been due to improvements in cancer care, the potential contribution of other unmeasured factors must also be considered. The current data also indicate that the proportion of patients in each cohort undergoing maximal interval cytoreduction is a significant predictor of median survival time. Each 10% increase in the proportion of patients in each cohort undergoing maximal interval cytoreductive surgery was associated with a 1.9 month increase in median survival time. This is consistent with the findings of a large meta-analysis of the effect of primary cytoreductive surgery in which each 10% increase in the proportion of patients undergoing maximal cytoreduction was associated with an increase in median cohort survival time of 1.5 months [34]. Perhaps the most interesting finding from the current study is the significant detrimental impact on median cohort survival time associated with increasing number of pre-operative chemotherapy cycles. Within the range of 3–6 median cycles of chemotherapy prior to interval surgery, each additional cycle of chemotherapy was associated with an incremental decrease in median cohort survival time of 4.1 months. Whether this observation reflects underlying tumor biology manifested as an extensive initial tumor burden, the progressive emergence of chemotherapy-resistant disease with an increasing number of treatment cycles, or represents an artifact of surgical selection criteria cannot be determined. A critical review of the data presented requires an appreciation for the methodological limitations of a meta-analysis of this nature. First, the potential for selection bias, with regard to both studies selected for our analysis and the inclusion of patients within each individual study, must be considered. In particular, the criteria for administering neoadjuvant chemotherapy varied across studies and included clinical and radiographic imaging characteristics as well as findings at diagnostic laparoscopy. A second limitation is that the large variety of different chemotherapeutic agents and administrations schedules used during the study period precluded an analysis of platinum and total drug intensity or cumulative dose. Although this omission may be a potential source of confounding, similar meta-analyses of ovarian cancer studies have not found these factors to affect survival significantly [35,37]. A third limitation of the current study is that we did not examine additional prognostic factors, such as extent of disease and performance status that might have influenced either survival or the proportion of patients undergoing maximal interval cytoreductive surgery. At least one meta-analysis has found that

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performance status, in addition to optimal surgery and the use of platinum chemotherapy, had a measurable effect on survival [33]. Lastly, the limited number of studies available for inclusion in the current analysis would have rendered any attempt to control for potential interactions between variables through a multiple linear regression model invalid. It is possible that one or more of the statistically significant variables associated with cohort survival on simple linear regression analysis could be irrelevant if interactions between variables were taken into account. Despite these limitations, the current data provide a valuable perspective on the survival outcome achievable when neoadjuvant chemotherapy is substituted for an attempt at primary cytoreductive surgery. Within the framework of this alternative treatment approach, increasing percent maximal interval cytoreduction is positively associated with median cohort survival; however, the negative survival effect of increasing number of chemotherapy cycles prior to interval surgery suggests that definitive operative intervention should be undertaken as early in the treatment program as possible. Additional research on neoadjuvant chemotherapy for advanced ovarian cancer will need to address two critically important issues. First, can uniform selection criteria be developed that can consistently identify patients with surgically unresectable disease without depriving viable surgical candidates the potential survival advantage associated with an optimal primary resection? To date, the predictive performance of clinical parameters (e.g. ascites), serum CA 125 threshold values, and radiographic imaging criteria have not demonstrated sufficient accuracy to achieve widespread applicability [40,48–54]. The second topic for future investigation is to determine what is the acceptable proportion of patients with advanced ovarian cancer that ought to forgo initial surgery in favor of neoadjuvant chemotherapy. Consecutive case series of patients with advanced-stage epithelial ovarian cancer indicate a wide variation in the proportion of patients in whom an optimal volume of residual disease is achievable with cytoreductive surgery, ranging from 20.2% to 98.8% [38,39]. However, the majority of contemporary reports from centers experienced in ovarian cancer surgery describe optimal resection rates of 75% or higher [55–58]. Workable solutions to both of these issues will need to account for the complex interaction between patient-related characteristics, tumor biology, and operative expertise, while adjusting for the fact that ovarian cancer resectability is a highly surgeon-dependent variable [45,59]. References [1] Meigs JV. Tumors of the Female Pelvic Organs. New York: MacMillan; 1934. [2] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975;42:101–4. [3] Chi DS, Liao JB, Leon LF, Venkatraman ES, Hensley ML, Bhaskaran D, et al. Identification of prognostic factors in advanced epithelial ovarian carcinoma. Gynecol Oncol 2001;82:532–7. [4] Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, et al. The effect of diameter of largest residual disease on

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