Delaying the primary surgical effort for advanced ovarian cancer: A systematic review of neoadjuvant chemotherapy and interval cytoreduction

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1 Gynecologic Oncology 104 (2007) Review Delaying the primary surgical effort for advanced ovarian cancer: A systematic review of neoadjuvant and interval cytoreduction Robert E. Bristow a,, Eric L. Eisenhauer b, Antonio Santillan 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 7 September 2006 Available online 12 December 2006 Abstract Objective. To summarize the existing data on interval cytoreductive surgery and neoadjuvant as alternative treatment strategies for patients with advanced-stage ovarian cancer. Methods. All investigational studies with evaluable survival data on interval cytoreductive surgery and neoadjuvant for ovarian cancer reported in the English language literature between 1989 and 2006 were systematically reviewed. Results. Three randomized trials and six non-randomized studies of interval cytoreduction following suboptimal initial surgery were identified. Twenty-six studies, including a total of 1336 patients, reporting on neoadjuvant administered in lieu of primary cytoreductive surgery were analyzed according to the survival outcome achieved, the degree of surgical effort or success, and the particular selection criteria employed to justify deferring an attempt at primary cytoreductive surgery. Conclusions. Interval surgery following a concerted but suboptimal attempt at up-front cytoreduction does not appear to have an appreciable impact on survival outcome. Maximal primary cytoreductive surgery remains the standard of care for the majority of women with suspected advanced ovarian cancer. Neoadjuvant represents a viable alternative management strategy for the limited number of patients felt to be optimally unresectable by an experienced ovarian cancer surgical team; however, currently available data suggest that the survival outcome achievable with initial is inferior to successful up-front cytoreductive surgery. Additional research is needed to devise universal selection criteria for neoadjuvant, determine the most efficacious treatment program, and characterize the appropriate proportion of patients in which an attempt at primary surgery should be abandoned in favor of initial Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Neoadjuvant ; Interval cytoreduction Contents Introduction Interval surgical cytoreduction Neoadjuvant Category I studies: Survival after neoadjuvant is inferior to survival after primary cytoreductive surgery Category II studies: No significant difference in survival outcome between neoadjuvant and a less than maximal primary cytoreductive surgical effort Category III studies: Neoadjuvant inclusion criteria with limited validation in predicting surgical outcome The challenge of predicting surgical outcome Conclusions References Corresponding author. Fax: address: rbristo@jhmi.edu (R.E. Bristow) /$ - see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.ygyno

2 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) Introduction Following the landmark publication by Griffiths more than 30 years ago, nearly every retrospective and prospective study has confirmed that the extent of cytoreductive surgery and the amount of residual disease are among the most important factors impacting the survival of women with advanced ovarian cancer [1,2]. The corollary to this principle, however, is that even extensive surgical efforts that leave residual tumor larger than 1 cm to 2 cm have no meaningful impact on survival [3]. Inan 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 following an initial suboptimal effort and several cycles of systemic, has been adopted in many centers. Despite contradictory data on survival outcome, the concept of interval cytoreduction has evolved into the treatment approach now referred to as neoadjuvant in which the initial attempt at cytoreduction is abandoned in favor of in order to reduce the extent of disease or improve patient performance status [7]. In favorable candidates, surgical cytoreduction is then attempted for the first time after some number of cycles of induction. Proposed advantages of neoadjuvant have included a reduced risk of peri-operative morbidity, a higher rate of optimal resection, and the contention that survival is not compromised by deferring the initial attempt at surgical debulking [8,9]. From an investigational standpoint, identification of appropriate indications and development of efficacious treatment protocols are the most pressing needs. Although many clinicians have already embraced this alternative treatment strategy, the precise role of neoadjuvant in the management of advanced-stage epithelial ovarian cancer has yet to be determined. The objectives of the current review are to summarize the existing data on interval debulking surgery as the basis for deferring an initial attempt at primary cytoreductive surgery and present a systematic review of all investigational studies on neoadjuvant for ovarian cancer reported in the English language literature between 1989 and Interval surgical cytoreduction For the purposes of this review, interval cytoreduction was defined as a surgical procedure with debulking intent that was preceded by during the primary treatment of advanced epithelial ovarian cancer after an initial (up-front) attempt at surgical cytoreduction had failed to achieve an optimal volume of residual disease [7]. In the 6 non-randomized studies of interval cytoreduction following an initial suboptimal surgical effort, the feasibility of obtaining an optimal resection (as defined by the authors) after induction has ranged from 24.1% to 77.3% (Table 1) [10 15]. Despite successful interval resection in a significant proportion of patients, these reports have consistently reported survival outcomes comparable to patients undergoing a suboptimal up-front resection without interval surgery [11,14,15]. For example, Redman et al. found no significant difference in overall survival between 36 patients initially left with bulky residual disease and submitted to interval debulking after 3 cycles of platinum-based and 125 control patients with residual disease >2 cm and treated with alone, leading the authors to conclude that interval surgery has only minimal impact on survival [14]. To date, there have been three prospective, randomized studies examining the utility of interval cytoreductive surgery in patients with advanced ovarian cancer left with bulky residual disease following an initial attempt at cytoreductive surgery (Table 1). In 1994, Redman et al. reported on 79 women with advanced ovarian cancer and residual disease >2 cm after initial surgery who were randomized to receive alone (n = 42) or in combination with interval cytoreduction (n=37) [16]. All patients received a total of 8 cycles of platinum-based. Nineteen of 37 patients (51.4%) randomized to interval surgery underwent successful cytoreduction to residual disease <1 cm. However, there was no statistically significant difference in median overall survival time for patients undergoing interval surgery (15 months) compared to patients not undergoing interval surgery (12 months). In 1995, van der Burg et al. reported results of a randomized phase III trial conducted by the European Organization for the Research and Treatment of Cancer (EORTC) to evaluate the benefit of interval surgery after suboptimal primary debulking by comparing 140 patients who received 3 cycles of cisplatin and cyclophosphamide followed by an interval attempt at cytoreduction and 3 additional cycles of to 138 similar patients receiving the same regimen without interval surgery [17]. The interval surgery group had a statistically significant advantage in median survival time (26 months) compared to patients not undergoing interval surgery (20 months). More recently, Rose et al. reported a randomized phase III trial conducted by the Gynecologic Oncology Group (GOG) of 550 patients with Stage III and Stage IV epithelial ovarian cancer left with residual disease > 1 cm following an initial attempt at primary cytoreductive surgery [18]. All patients received 3 cycles of initial with cisplatin and paclitaxel followed by response evaluation. Patients whose disease had not progressed during the treatment interval were randomly assigned to secondary surgical cytoreduction plus 3 additional cycles of or additional alone. Four hundred and forty-eight patients were randomized, with 226 assigned to secondary surgery and 222 assigned to alone. In contrast to the EORTC trial, the likelihood of progression-free survival in the group assigned to secondary surgery plus was not significantly different compared to the alone group (hazard ratio=1.07, 95% CI 0.87 to 1.31, P=0.54); there was also no significant difference in the relative risk of death for patients undergoing interval surgery (relative risk = 0.99, 95% CI 0.79 to 1.24, P=0.92).

3 482 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) Table 1 Studies of interval cytoreduction following suboptimal primary surgery Author [reference] year Treatment n FIGO stage Residual tumor criteria Platinum-based Chemotherapy cycles prior to interval surgery Proportion of optimal residual disease for treatment cohort Median overall survival (months) [significance] Non-randomized studies Wils [10]* 1986 Interval surgery 50 NR > % % NR (3-year=25%) Neijt [11]* 1987 Interval surgery 129 NR >1 cm 100% 5 to % 22.5 Lawton [12]* 1989 Interval surgery 36 III: 77.8% >2 cm 100% % NR IV: 22.2% Lawton [13] 1990 Interval surgery 108 NR Any 100% 3 to % NR Redman [14]* 1990 Interval surgery 24 III: 79.2% >2 cm 100% IV: 20.8 Jacob [15] 1991 Interval surgery 22 III: 81.8% >2 cm 100% % 16.0 IV: 18.2% Randomized studies Redman [16] 1994 Interval surgery 37 IIB: 8.1% >2 cm 100% 1 to % 15.0 III: 86.5% IV: 5.4% No interval surgery 42 IIB: 7.1% >2 cm 100% NA 0.0% 12.0 [NS] III: 71.4% IV: 21.5% van der Burg [17] 1995 Interval surgery 140 IIB: 6.0% >1 cm 100% % 26.0 III: 71.0% IV: 23.0% No interval surgery 138 IIB: 4.0% >1 cm 100% NA 0.0% 20.0 [P=0.01] III: 75.0% IV: 21.0% Rose [18] 2004 Interval surgery 216 III: 92.6% >1 cm 100% % 33.9 IV: 7.4% No interval surgery 208 III: 96.2% >1 cm 100% NA 0.0% 33.7 [NS] IV: 3.8% Legend: NR=not reported; NA=not applicable, NS=not significant, *phase I study, retrospective analysis, retrospective matched control study, phase III study. Considering the three randomized and six non-randomized studies of interval cytoreduction for ovarian cancer, the EORTC trial was the only report to demonstrate a statistically significant survival advantage, albeit relatively minor, associated with interval surgery. In spite of this observation, the above studies provide the conceptual basis for the current interest in the alternative treatment approach known as neoadjuvant. Neoadjuvant For the purposes of this review, neoadjuvant was defined as the administration of following the histologic verification of ovarian cancer by biopsies only; after a prescribed course of systemic therapy, surgical cytoreduction was attempted during interval laparotomy. Neoadjuvant has been promoted as a means of avoiding a non-useful surgical procedure in patients considered optimally unresectable after establishing a diagnosis of advanced ovarian cancer [7]. A variety of arguments have been offered as justification for this approach (Table 2) [8,9,19 28]. The reported criteria for abandoning an initial attempt at primary cytoreductive surgery in women with advanced ovarian cancer are equally diverse, with clinical and radiographic characteristics ranging from a general description of unresectable disease to specific disease locations or clinical conditions (Table 3) [29 40]. Some authors have advocated an initial assessment of disease extent via laparoscopy in order to more accurately predict surgical outcome [27,41,42]. Despite significant heterogeneity among studies, a review of the neoadjuvant literature revealed that the majority of published reports could be grouped into one of three distinct groups or categories according to the survival outcome achieved, the degree of surgical effort or success, and the particular inclusion criteria employed to select patients for neoadjuvant. For institutional case series that were reported more than once, only the most recent reports were included in this review. In all, 26 studies published in the English language literature were reviewed, encompassing a total of 1336 patients treated with neoadjuvant. The most common study design was retrospective analysis (12 reports), followed by retrospective case control (8 reports), phase I study (4 reports), and phase II study (2 reports). Collectively, these reports represent Level 3 evidence among published studies (nonrandomized clinical trial or cohort study). In evaluating these reports, it is important to note that, from the methodological standpoint of minimizing selection bias, the relevant survival comparison is between all patients treated with neoadjuvant, not just those undergoing interval surgery, and patients submitted to primary cytoreductive surgery prior to.

4 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) Table 2 Arguments offered in support of neoadjuvant for advanced ovarian cancer Rationale [references] Optimal resection (<1 cm) can only be achieved in 35% to 50% of patients [9,19,20] Easier optimal cytoreduction [9,19 22] Less extensive surgery [8,20,23] Neoadjuvant does not compromise survival [8,9,19,20,23,24] Few expert surgery centers [8] Optimal timing of initial surgical effort is debatable [8,21] Complication rate of primary cytoreduction [8,25,26] Lack of prospective quality of life data for primary cytoreduction [8,26,28] Tumor biology is a more important prognosticator than surgical outcome [8,21,27,28] Category I studies: Survival after neoadjuvant is inferior to survival after primary cytoreductive surgery Ten reports on neoadjuvant, published between 1989 and 2003, qualified as Category I studies and are characterized by: (1) a median survival time that is notably inferior compared to matched control patients from the same study undergoing primary cytoreductive surgery, or (2) a median survival time that is inferior or approximately equivalent to that of historical patients undergoing suboptimal primary surgery and comparable (Table 4) [24,27,28,43 49]. For those studies not reporting a comparison group of patients treated with up-front cytoreductive surgery, the results of GOG study protocol #111 provide a frame of reference for contemporary survival outcomes achievable in the presence of suboptimal residual disease, with median survival times of 24 months and 36 months for patients treated with cisplatin and cyclophosphamide or cisplatin and paclitaxel, respectively [50]. Collectively, the Category I studies detailed in Table 4 yielded median survival times ranging from 10.2 months to 40.0 months for patients undergoing platinum-based neoadjuvant in lieu of primary cytoreductive surgery. For example, in 2001, Ansquer et al. reported on 54 patients felt to be optimally unresectable at primary surgery [46]. Patients received a median of 4 cycles of platinum-based ; 46 of 54 patients (85.2%) underwent interval surgery, with 39 patients being left with optimal (< 2 cm) residual disease. This represented 72.2% of the entire study group and 84.8% of patients actually undergoing surgery. However, 26 of 46 interval surgery patients had disease <2 cm prior to interval cytoreduction, with just 13 of the 46 patients undergoing surgical cytoreduction to residual disease <2 cm. Therefore, only 24.1% (13 of 54 patients) of the total cohort derived a potential surgical benefit from the neoadjuvant approach. The median overall survival time for the entire group of neoadjuvant patients was 22 months. In a retrospective comparison study, Shibata et al. reported on 29 patients who were treated with 6 cycles of mostly platinum-based neoadjuvant after exploratory laparotomy only [47]. Although this study did not report the aggregate survival outcome for all neoadjuvant patients, the 13 patients (44.8%) undergoing optimal interval cytoreduction had a median overall survival time of 23.0 months, while patients left with suboptimal residual disease after interval surgery had a median survival time of just 11.0 months. In a comparative analysis with 90 patients treated with up-front cytoreductive surgery, the authors noted that the median survival of optimally debulked neoadjuvant patients was similar to patients undergoing primary debulking leaving large volume residual disease (> 5 cm). Two Category I studies in particular have been frequently cited as supporting the equivalency of neoadjuvant and primary cytoreductive surgery [24,27]. In the first, Vergote et al. compared survival outcomes of 112 patients treated with the standard treatment approach of initial surgery followed by between 1980 and 1988 versus 173 patients treated between 1989 and 1997 who were managed with selective use of neoadjuvant after diagnosis (43% of patients) or primary surgery followed by (57% of patients) [27]. The actuarial 3-year survival rate was higher for the group of patients treated during the selective neoadjuvant time period (42%) compared to the standard surgery time period (26%, P = ). However, within the selective neoadjuvant group, the actuarial 3-year survival rate for patients managed with standard initial surgery was statistically significantly superior (53%) compared to patients treated with neoadjuvant (24.8%, P =0.0025). In the second widely quoted study, Table 3 Criteria used to predict a suboptimal surgical outcome and select patients for neoadjuvant False positive rate a References Clinical characteristics Ascites >1000 cm % [29] Any 34.6% [30] 36.2% [31] 42.4% [32] Pleural effusion 57.1% [31] Serum CA125 >500 U/ml 14.3% [29] 18.2% [30] 21.8% [33] 26.7% [34] 31.6% [35] 44.7% [36] >912 U/ml 68.9% [37] >1000 U/ml 26.6% [31] Computed tomography characteristics Omental extension to spleen 25.0% [38] Diaphragm disease 35.7% [38] 50.0% [32] Parenchymal liver metastasis 20.0% [38] 37.5% [32] Peritoneal thickening 11.8% [38] 43.0% [39] Bowel mesentery 36.0% [40] 62.5% [32] a Proportion undergoing optimal cytoreduction after prediction of suboptimal resection.

5 484 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) Table 4 Category I Studies: survival after neoadjuvant is inferior to survival after primary cytoreductive surgery Author [reference] year Treatment FIGO stage n Residual tumor criteria Platinum-based Taxane Chemotherapy cycles prior to interval surgery Rate of optimal surgical resection Median overall survival (months) [significance] Donadio [43]* 1989 NACT III: 70.8% 30 >2 cm 100% 0.0% % 18.9 (responders only) IV: 29.2% Lim [44]* 1993 NACT III: 66.7% 30 >2 cm 100% 0.0% % 10.2 IV: 33.3% Surwit [45] 1996 NACT IIIC: 72.4% 29 >1 cm 100% 0.0% 2 to % 22.5 IV: 27.6% Vergote [27] 1998 NACT IIIC: 58.7% 75 >1.5 cm 92% 20.0% 3 NR NR (3-year=24.8%) IV: 41.3% PC IIIA: 8.2% 98 >1.5 cm 92% 19.0% NA 99.0% NR (3-year=53.0%) IIIB: 12.2% IIIC: 68.4% IV: 11.2% [P=0.0025] Schwartz [24] 1999 NACT III: >2 cm 100% 8.5% 5 NR 12.8 IV: 38 PC IIIC: 80.4% 206 >2 cm 100% 0.0% NA 49.0% 26.2 [NS] IV: 19.6% Ansquer [46] 2001 NACT III: 85.2% 54 >2 cm 100% 57.4% % 22.0 IV: 14.8% Shibata [47] 2003 NACT III: 82.8% 29 >2 cm 100% 0.0% % NR (optimal=23.0) IV: 17.2% (suboptimal=11.2) PC III: 86.5% 96 >2 cm 100% 0.0% NA 52.1% NR (residual 2 5 cm=28.8) IV: 13.5% (residual >5 cm=19.7) [NS] Chan [48]* 2003 NACT III: 23.5% 17 >2 cm 100% 100% % 22.9 IV: 76.5% Fanfani [49] 2003 NACT IIIC: 100% 73 >2 cm 100% 57.5% % 40.0 (responders only) PC IIIC: 100% 111 >2 cm 100% NR NA 100% >86.0 [NR] Steed [28] 2006 NACT IIIB: 16.0% 50 >2 cm 100% 98.0% 3 or % 28.8 IIIC: 52.0% IV: 32.0% PC IIIB: 15.2% 66 >2 cm 100% 94.0% NA 50.0% 44 [P=0.03] IIIC: 68.2% IV: 7.6% Legend: NACT=neoadjuvant ; PC=primary cytoreduction; NR=not reported; NA=not applicable; NS=not significant, *phase I study, retrospective analysis, retrospective case control 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 prior to consideration for surgical resection [24]. Although not statistically significant, the median survival time for neoadjuvant 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). Interestingly, the authors found no significant difference in median overall survival times between conventionally treated patients with suboptimal residual Stage IIIC disease and patients treated with neoadjuvant with disease confined to the abdominal cavity. The authors cited as justification for this approach a lower median blood loss (600 cm 3 vs 1000 cm 3 ) and shorter length of hospital stay (7 days vs 11 days) with neoadjuvant. Recently, Steed et al. retrospectively reviewed 116 consecutive patients with Stage III/IV epithelial ovarian cancer treated between 1999 and 2002 [28]. Fifty patients (43%) were selected for 3 to 4 cycles of platinum and paclitaxel neoadjuvant based on positive pleural effusion or radiographic criteria of disease within the porta hepatis, splenic hilum, peritoneal carcinomatosis, diaphragm disease > 2 cm, or bulky supra-renal adenopathy. Only 36 of the 50 neoadjuvant patients underwent interval surgery, of these, residual disease 2 cm was achieved in 26 patients, representing 52% of all patients submitted to neoadjuvant. Among the 66 control patients thought to have resectable disease and submitted to primary surgery, residual disease 2 cm was achieved in 50% of cases. The median overall survival time for all patients treated with neoadjuvant was 28.8 months, which was statistically significantly inferior to the median survival time of 44.4 months for patients treated conventionally, despite the similar rates of optimal resection. In defense of the survival outcomes for the above Category I studies, it has been argued that inherent biological factors are responsible for the development of bulky intra-abdominal disease and may characterize a more aggressive tumor type with negative prognosis even when successfully debulked [9]. Recently, Aletti and colleagues from the Mayo Clinic reported data that, at least to some extent, refute this argument [51]. In this retrospective cohort study of 194 consecutive patients with Stage IIIC ovarian cancer, the authors analyzed the effect of aggressive surgical resection on survival. Overall, 68% of

6 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) patients were left with optimal residual disease. For all patients, and after controlling for the effects of multiple factors with multivariate analysis, the amount of residual disease was the only independent predictor of survival. More specifically, the need to perform radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. In other words, this study and others recently reported have demonstrated that optimal cytoreduction, regardless of the extent of surgery, appeared to negate the effect of tumor burden [52,53]. Among the subgroup of 144 patients with carcinomatosis and the most extensive tumor burden, the performance of radical surgery and the amount of residual disease were the only independent predictors of survival [51]. Moreover, patients who were operated on by surgeons that tended to utilize radical procedures had a 5-year survival rate of 44%, which was statistically significantly better than the 5-year survival rate of 17% for patients operated on by surgeons who tended not to perform radical surgery. This study not only illustrates the potential survival impact of cytoreductive surgery in spite of an extensive disease burden, but it also highlights the importance of the individual surgeon's experience, skill, and philosophical approach to advanced ovarian cancer. Category II studies: No significant difference in survival outcome between neoadjuvant and a less than maximal primary cytoreductive surgical effort A recent questionnaire study by Chen et al. queried full members of the Society of Gynecologic Oncologists regarding surgery and for primary treatment of ovarian cancer and found that 50% of respondents agreed with a statement that neoadjuvant is equivalent to primary surgery [54]. Several studies, outlined below, have in fact described similar survival outcomes for patients treated with neoadjuvant and primary surgery, a finding that underscores the importance of carefully considering the comparative extent of the primary surgical effort. Nine neoadjuvant reports, published between 1990 and 2006, qualified as Category II studies (Table 5) [19,22,55 61]. All Category II studies provided a comparison group of patients with advanced ovarian cancer submitted to attempted primary cytoreductive surgery and reported approximately equivalent survival outcomes. However, a careful inspection of the data also suggests that the patient groups under study underwent something less than a maximal primary surgical effort characterized by: (1) a primary optimal resection rate of 33% in the comparison group, (2) the proportion of all reported advanced ovarian cancer patients initiating with optimal residual disease was 33%, or (3) the proportion of all advanced ovarian cancer patients treated with neoadjuvant was 33%. Onnis et al. reported a retrospective case series of 396 patients with Stage III and IV ovarian cancer that illustrates the limitations of the Category II studies [56]. In this study, 284 patients (71.7%) underwent primary surgery, 24 (6.1%) had palliative alone, and 88 patients (22.2%) underwent neoadjuvant followed by interval surgery. Of the 88 patients receiving neoadjuvant, optimal interval surgical resection was possible in 22.7% of cases. The overall 5-year survival rate for all neoadjuvant patients was 19.3%, which was not statistically significantly different from the 5-year survival rate of 21% for patients treated with conventional up-front cytoreductive surgery. The lack of difference in survival between patients treated with neoadjuvant and primary cytoreduction may, at least in part, be accounted for by the fact that just 15.8% of patients managed with primary cytoreductive surgery were left with residual disease < 2 cm. Considering all 396 patients with advanced ovarian cancer, only 45 of 396 (11.4%) initiated with optimal (< 2 cm) residual disease. Similarly, Vrscaj et al. described a retrospective case control study of 75 patients with advanced (Stage III/IV) epithelial ovarian cancer; 20 patients were considered unresectable and were treated with 4 cycles of platinum-based followed by interval cytoreductive surgery [57]. The median overall survival time was 24.7 months for neoadjuvant patients, which was not statistically significantly different from the median survival of 26 months for the 55 patients treated with primary cytoreductive surgery (P = 0.79). In the primary surgery group, optimal residual disease was achieved in just 21.8% of cases. So, for all 75 patients with advanced ovarian cancer eligible for study inclusion, just 12 of 75 patients (16.0%) initiated with an optimal volume of residual disease. Taken together, the above two studies demonstrate why, with optimal primary cytoreduction rates of 15.8% and 21.8%, it is not surprising that there is no significant difference in survival outcome between neoadjuvant and primary surgery that represents less than a maximal surgical effort. By the same token, the remaining Category II studies detailed in Table 5 reported that 21.1% to 33.9% of all advanced ovarian cancer patients initiated with optimal residual disease, with 45.0% to 67.4% of all patients receiving neoadjuvant, both of which are features that suggest an abbreviated effort at primary surgical cytoreduction [19,22,58 61]. Category III studies: Neoadjuvant inclusion criteria with limited validation in predicting surgical outcome Seven neoadjuvant reports, published between 2001 and 2006, qualified as Category III studies (Table 6) [20,21,25,26,62 64]. These studies are characterized by non-specific or liberal selection criteria for neoadjuvant with limited external validity for predicting a suboptimal primary surgical effort. Although these reports tended to have the most favorable survival rates, the generous nature of their inclusion criteria for neoadjuvant raises questions about the survival outcome that could had been achieved in these patients had they been submitted to a maximal attempt at up-front cytoreductive surgery. In one representative report, Kuhn et al. described a nonrandomized phase II study of 31 patients with Stage IIIC ovarian cancer and large volume (>500 cm 3 ) ascites, as measured by sonography, who underwent diagnostic laparoscopy to confirm

7 486 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) Table 5 Category II studies: no significant difference in survival outcome between neoadjuvant and a less than maximal primary cytoreductive surgical effort Author [reference] year Tummarello [55]* 1990 Onnis [56] 1996 Vrscaj [57] 2002 Ushijima [58]* 2002 Morice [59]* 2003 Loizzi [22] 2005 Hegazy [60] 2005 Lee [19] 2006 Everett [61]* 2006 Treatment FIGO stage n Residual tumor criteria Platinumbased Taxane Chemotherapy cycles prior to interval surgery Rate of optimal surgical resection Median overall survival (months) [significance] Optimal disease at start of Proportion neoadjuvant NACT III: 29.2% 24 >2 cm 41.70% 0.0% % 16.0 NR NR IV: 70.8% PC III: 56.3% 16 >2 cm 31.30% 0.0% NA 0.0% 20.0 [NS] IV: 43.7% NACT III: 71.6% 88 <2 cm 59.10% 0.0% NR 22.7% NR 11.4% 28.3% IV: 28.4% (5-year=19.3%) PC III: 93.7% 284 <2 cm NR 0.0% NA 15.8% NR IV: 6.3% (5-year=21.0%) [NS] NACT IIIC: 85.0% 20 >1 cm 100% 0.0% 3 to % % 26.7% IV: 15.0% PC IIIC: 87.3% 55 >1 cm 100% 0.0% NA 21.8% 26.0 [NS] IV: 12.7% NACT IIIC: 78.5% 65 >1 cm 100% 21.5% % % IV: 21.5% PC IIIC: 77.8% 63 >1 cm 100% NR NA 0.0% 23.0 [NS] IV: 22.2% NACT IIIC: 82.8% 58 >2 cm 100% 100% % % 67.4% IV: 17.2% (optimal only) PC IIIC: 82.1% 28 >2 cm 100% 100% NA 100% 45.5 [NS] IV: 17.9% NACT IIIC: 76.7% 30 >1 cm 100% 60.0% % % NR IV: 23.3% (responders only) PC IIIC: 76.7% 30 >1 cm 1005 NR NA 60.0% 40.0 [NS] IV: 23.3% NACT IIIC: 40.7% 27 >1 cm 100% 0.0% % % 45.8% IV: 59.3% PC IIIC: 43.8% 32 >1 cm 100% 0.0% NA 62.5% 28.0 [NS] IV: 56.2% NACT IIIC: 88.9% 18 >2 cm 100% 100% % % 45.0% IV: 11.1% PC IIIC: 90.9% 22 >2 cm 100% 100% NA 45.5% 55 [NS] IV: 9.1% NACT IIIA: 6.1% 98 >1 cm 100% 94.0% % % 49.0% IIIB: 17.3% IIIC: 50.0% IV: 26.5% PC IIIA: 4.9% 102 >1 cm 100% 94.0% NA 53.9% 42 [NS] IIIB: 19.6% IIIC: 67.6% IV: 7.8% Legend: NACT=neoadjuvant ; PC=primary cytoreduction; NR=not reported; NA=not applicable; NS=not significant, *retrospective analysis, retrospective case control study, phase II study. the diagnosis and then 3 cycles of neoadjuvant with carboplatin and paclitaxel [25]. Twenty-six patients completed interval surgery with residual disease <2 cm (83.9%). The median overall survival time for all patients was 40 months. For comparison, the authors identified a control group of 32 patients with Stage IIIC ovarian cancer and large volume (>500 cm 3 ) ascites who did not agree to participate or were not psychologically suited to participate in the study protocol. For the control group, 64% achieved residual disease <2 cm and the median overall survival time was 23 months, which was statistically inferior to the neoadjuvant group (P = 0.007). The superior survival outcome of the neoadjuvant group may be accounted for, at least partially, by the use of ascites volume as the only selection criteria. For instance, Brockbank et al. and others have reported that the false positive rate for ascites as a predictor of suboptimal resection ranges from 34.6% to 42.4% [30 32]. Consequently, there may have been an undocumented and unexpectedly high number of good prognosis (i.e. optimally resectable) patients in this group. In addition, the survival outcome for the group of conventionally treated patients is surprisingly poor compared to contemporary median survival times of 36 months and 50 months for patients receiving platinum and paclitaxel after suboptimal and optimal primary cytoreduction, respectively [50,65]. This discrepancy with the published literature generates uncertainty regarding the comparable clinical characteristics of the primary cytoreduction control group and/or the intensity of the primary treatment approach.

8 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) Table 6 Category III studies: neoadjuvant inclusion criteria with limited validation in predicting surgical outcome Author [reference] year Treatment Neoadjuvant selection criteria FIGO stage n Residual tumor criteria Platinum-based Taxane Chemotherapy cycles prior to interval surgery Rate of optimal surgical resection Median overall survival (months) [significance] Lu [62]* 2001 NACT Pleural effusion, IIIC: 46.7% 45 >2 cm 100% 68.9% % 18.0 multiple metastasis, IV: 53.3% PC large metastatic IIIC: 64.6% 158 >2 cm 100% 49.4% NA 63.9% 25.0 [NS] plaques IV: 35.4% Kuhn [25] 2001 NACT Ascites >500 cm 3, IIIC: 100% 31 >2 cm 100% NR % 42.0 PC psychologically fit IIIC: 100% 32 >2 cm 100% NR NA 62.5% 23.0 [p=0.007] Morice [26] 2001 NACT Unresectable IIIC: 88.2% 34 >2 cm 100% 94.1% % 26.0 disease IV: 11.8% PC IIIC: 88.2% 34 >2 cm 100% 0.0% NA 94.1% 22.0 [NS] IV: 11.8% Mazzeo [21]* 2003 NACT Bowel-omental IIIC: 80.0% 45 >2 cm 100% 80.0% % 29.0 adhesions, large abdominal nodules, carcinomatosis IV: 20.0% Le [63]* 2005 NACT Pelviabdominal mass, metastatic disease, elevated CA 125 II: 6.6% 61 >2 cm 100% 100% % 41.7 III: 90.2% IV: 3.2% Avril [64] 2005 NACT Ascites >500 cm 3 IIIC: 69.7% 33 >1 cm 100% 69.7% % 26.8 IV: 30.3% Inciura [20] Large ascites, III: 77.5% 213 >2 cm 100% 0.0% % 25.9 large tumors IV: 22.5% PC III: 84.5% 361 >2 cm 100% 0.0% NA 67.0% 29.3 [NS] IV: 15.5% Legend: NACT=neoadjuvant ; PC=primary cytoreduction; NR=not reported; NA=not applicable; NS=not significant, *retrospective analysis, phase II study, retrospective case control, phase I study. In 2003, Morice et al. published a case control study of 34 patients with unresectable advanced ovarian cancer undergoing a median of 3 cycles of platinum-based, prior to interval cytoreduction [26]. An optimal resection (< 2 cm) was achieved in 94.1% of patients. Criteria for neoadjuvant included unresectable disease such that optimal resection was not feasible using a standard procedure (total hysterectomy and salpingo-oophorectomy, omentectomy, pelvic and para-aortic lymphadenectomy). A matched control group of 34 patients undergoing primary cytoreduction was provided for comparative purposes. Survival analysis revealed no significant difference between patients treated with neoadjuvant (median survival 26.0 months) and patients treated with primary cytoreduction (median survival 22.0 months). The authors' conclusion that neoadjuvant and primary cytoreduction are associated with equivalent survival outcomes must be tempered by the observation that 94.1% of neoadjuvant patients received platinum plus paclitaxel. While all patients undergoing primary cytoreductive surgery received platinum-based, none received paclitaxel. This fact alone suggests that patients receiving neoadjuvant would have had significantly worse survival than conventionally treated patients had similarly aggressive regimens been employed in both groups. Recently, Le et al. reported a retrospective analysis of 61 patients treated empirically with platinum and paclitaxel neoadjuvant based on essentially no selection criteria; all patients presenting with an abdominopelvic mass, metastatic disease, and an elevated serum CA125 consistent with epithelial ovarian cancer received initial [63]. All patients underwent interval surgery and 80.7% were left with residual disease <2 cm in maximal diameter, while 54.1% of patients were left with < 1 cm residual disease. Although the median overall survival time was 41.7 months, the indiscriminate use of neoadjuvant leaves open to speculation how close the median survival time would have come to the contemporary standard (median survival time = 50 months) for optimally resected Stage IIIC disease treated with platinum plus paclitaxel had they received an attempt at primary cytoreduction [65]. The remaining Category III studies shown in Table 6 similarly point out that liberal selection criteria for neoadjuvant are associated with optimal interval surgical resection rates of 62.9% to 75.6%; however, with median survival times of 18.0 to 29.0 months, the clinical outcomes have been generally disappointing [20,21,62,64]. The challenge of predicting surgical outcome A critical point in the process of defining the appropriate application of neoadjuvant for advanced ovarian cancer is the development of uniform selection criteria that can consistently identify patients with surgically unresectable

9 488 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) 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 CA125 threshold values, and radiographic imaging criteria have not demonstrated sufficient accuracy to achieve widespread applicability (Table 7) [21 23,25,46,48,49,59,62]. Radiographic criteria of unresectability have figured prominently in decisions to abandon an attempt at primary cytoreduction in favor of neoadjuvant. For example, in 1995 Nelson et al. retrospectively analyzed 51 patients undergoing primary surgery for ovarian cancer and correlated surgical outcome with the following computed tomographic features: attachment of the omentum to spleen or > 2 cm disease involving the bowel mesentery, liver surface or parenchyma, diaphragm, gall bladder fossa, supra-renal adenopathy, pericardiac adenopathy, and pulmonary or pleural nodules [40]. Using these parameters, the positive predictive value for a suboptimal surgical result was 66.7% when any of the specified radiographic features were present. These criteria have subsequently been used by multiple investigators to select patients for neoadjuvant, despite the fact that these radiographic features were associated with a false positive rate of 33% in the initial dataset [19,24,45,48]. In other words, for every three patients with advanced ovarian cancer treated with neoadjuvant according to these criteria, two patients would be correctly predicted to undergo a suboptimal resection, while one patient would in fact attain an optimal volume of residual disease if operated upon but is denied the survival benefit associated with up-front surgery. A number of predictive models have been developed that utilize radiographic findings as well as clinical characteristics, with false positive rates ranging from 5% to 37.1% [31,38,39,66]. Unfortunately, the widespread clinical utility of these models beyond the particular authors' experience is unclear. Recently, Axtell et al. presented data that highlight the difficulty in devising universally applicable selection criteria that reliably predict surgical outcome across institutions and Table 7 Reported criteria for unresectable advanced ovarian cancer requiring neoadjuvant in lieu of initial surgical cytoreduction Criteria [references] Optimal surgery not possible using a standard procedure: TAHBSO, infracolic omentectomy rectosigmoid resection, lymphadenectomy [46,59] Unresectable disease on CT scan, large ascites, large pleural effusion [22,62] Large (>500 cm 3 ) ascites [25] Dense adhesions between bowel and omentum [21] Omental disease extending to spleen [48,49] Large diaphragm disease [23,48,49,59,62] Large tumor nodules adherent to abdominal structures [21] Carcinomatosis on small and large bowel [21,49] Agglutination of bowel mesentery [49] Two or more bowel resections or bowel resection and splenopancreatectomy [23,59] Supra-renal adenopathy [23,48,59] Porta hepatis disease [48,49,59] Surface or parenchymal liver involvement [48,62] surgeons [67]. These investigators performed a reciprocal validation study of computed tomographic criteria predicting suboptimal cytoreduction for patients with advanced ovarian cancer developed independently at three different medical centers. Cross-validation analysis revealed that the apparently high accuracy rates of CT predictors in the original models could not be confirmed in the validation cohorts. In particular, 62 86% of patients predicted to be suboptimal using the reciprocal validation cohorts were actually optimally cytoreduced. The authors concluded that preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant. The above data underscore the principal obstacle to reliably predicting surgical outcome for ovarian cancer there is a high degree of variability among gynecologic oncology surgeons with respect to their willingness and/or capacity to utilize socalled aggressive or radical surgical techniques in the process of achieving minimal residual disease. Within the extensive body of literature on primary cytoreductive surgery, optimal resection rates range from 20% at less-experienced centers to over 90% at centers with extensive expertise in these often complex surgical procedures [68 71]. Until universally applicable and widely accepted selection criteria for neoadjuvant are developed, the patients' best interests are served by allowing experienced clinical programs with an optimal primary resection rate in the area of 75% or higher to make decisions regarding the timing of the initial surgical effort for patients with advanced ovarian cancer. Conclusions Although the current literature on interval cytoreduction and neoadjuvant in lieu of initial surgery for advanced ovarian cancer is heterogeneous and consists predominantly of retrospective studies, several conclusions can be drawn from the data. First, interval surgery following a concerted but suboptimal attempt at up-front cytoreduction does not appear to have an appreciable impact on survival outcome; consequently, alternative treatment strategies are needed for this subgroup of patients. Second, an attempt at maximal primary cytoreductive surgery remains the standard of care for the majority of women with suspected advanced ovarian cancer, based on the well-established relationship between minimal residual disease and prolonged survival. Neoadjuvant represents a viable alternative management strategy for the limited number of patients felt to be optimally unresectable by an experienced ovarian cancer surgeon or surgical team, although universal selection criteria and the most efficacious treatment program have yet to be determined. Currently, available data suggest that the survival outcome achievable with initial is inferior to successful up-front cytoreductive surgery. Indeed, a recent meta-analysis of neoadjuvant found that survival outcome was inversely proportional to an increasing number of preoperative cycles, with each additional cycle associated with a 4.1 month reduction in median survival time [72]. While this observation may reflect a requirement for more extensive

10 R.E. Bristow et al. / Gynecologic Oncology 104 (2007) preoperative in patients with bulkier or less chemo-responsive disease, the possibility that an increasing number of treatment cycles prior to definitive surgery might promote the development of chemo-resistant cell clones cannot be discounted. The EORTC is conducting a randomized prospective trial of neoadjuvant versus primary cytoreduction (EORTC 55971) in an attempt to address this issue using more rigorous methodology [73]. Third, additional research is needed to characterize the appropriate proportion of patients in which an attempt at primary surgery should be deferred in favor of initial. If the majority of patients with advanced ovarian cancer receive care at expert centers, this number should be relatively low, certainly less than 20% and probably 10% or lower. 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