Gynecologic Oncology 135 (2014) 595–605

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Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Review Primary debulking surgery for advanced ovarian cancer: Are you a believer or a dissenter?

John O. Schorge a,⁎,RachelM.Clarka, Susanna I. Lee b, Richard T. Penson c a Vincent Gynecologic Oncology Service, Massachusetts General Hospital, USA b Division of Abdominal Imaging, Massachusetts General Hospital, USA c Division of Medical Gynecologic Oncology, Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, USA

HIGHLIGHTS

• The goal of primary debulking surgery should be the complete resection of all macroscopic disease. • Neoadjuvant chemotherapy has an emerging role in the treatment of selected patients. • Preoperative innovations under investigation are aimed at better triaging women to upfront surgery or chemotherapy.

article info abstract

Article history: Nothing stirs the collective soul of primary debulking surgery (PDS) advocates like hard data suggesting equiva- Received 8 September 2014 lent outcomes of neoadjuvant chemotherapy (NAC). These opposing views have even metaphorically come to Accepted 7 October 2014 blows at the highly entertaining “SGO Fight Night” that took place during the 2008 Annual Meeting on Women's Available online 12 October 2014 Cancer, replete with teams supporting each of the would-be gladiators. Decades of retrospective data supporting the clinical benefit of PDS has recently been challenged by the publication in 2010 of a randomized phase III trial Keywords: conducted in Europe supporting the clinical efficacy of NAC. Naturally, a firestorm of criticism among believers Primary debulking surgery Neoadjuvant chemotherapy ensued, yet practice patterns within the United States did slowly change, suggesting an emerging block of Advanced ovarian cancer dissenters. Another randomized phase III European trial, as presented in abstract form in 2013, showed similar findings. Few other topics within the field of gynecologic oncology have participants so entrenched in the “corners” of their existing practice patterns. This review attempts to consolidate the current evidence supporting both sides so that the patient can be declared the winner. © 2014 Elsevier Inc. All rights reserved.

Contents

Introduction...... 596 Primarydebulkingsurgery...... 596 Neoadjuvantchemotherapy(NAC)...... 598 PDSvNAC:phaseIIItrials...... 598 Specialcircumstances...... 599 Theelderly...... 599 Obesity...... 599 StageIVdisease...... 599 Clinicalinnovations...... 600 Preoperativeimaging...... 600 Minimallyinvasivesurgery...... 601 Ultra-radicalsurgery...... 602 Synopsis...... 602 Futurestrategies...... 602

⁎ Corresponding author at: Vincent Gynecologic Oncology Service, Massachusetts General Hospital, Harvard Medical School, Yawkey-9E, 55 Fruit St, Boston, MA 02114, USA. Fax: +1 617 726 6898. E-mail address: [email protected] (J.O. Schorge).

http://dx.doi.org/10.1016/j.ygyno.2014.10.007 0090-8258/© 2014 Elsevier Inc. All rights reserved. 596 J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605

Conflictofintereststatement...... 603 References...... 603

Introduction and other retrospective data rapidly accrued thereafter to establish PDS as the de facto standard of care for advanced ovarian cancer [11–13]. The consistent inability to reliably detect ovarian cancer before Removal of the uterus, ovaries and any other intra-abdominal widespread metastases has proven to be logistically problematic and a tumors as part of ovarian cancer treatment is an easy concept for source of ongoing disappointment. Unfortunately, routine screening patients and their families to understand. Often there is an unrealistic has not been shown to meaningfully improve early detection, nor assumption that taking out the offending site of origin will stop the reduce mortality in either the high-risk or general populations [1–3]. spread of cancer, and that peritoneal dissemination includes a finite The U.S. Preventative Services Task Force currently recommends against number of tumors that once removed, will not return. The actual clinical screening given the scant evidence for any benefit, but consistently ob- benefits of debulking have been harder to prove in a rigorous fashion. served harms from unnecessary interventions [4]. Symptoms of ovarian Within the broader field of oncology, this type of aggressive surgical ap- cancer tend to be vague and are often attributed to menopause, stress, proach to widely metastatic disease has some parallels, especially when or functional bowel problems. Substantial delays prior to diagnosis are complete cytoreduction can be achieved [14–17]. very common, often until an abdominal-pelvic computed tomography Several supportive, but mostly theoretical, arguments have been (CT) scan is obtained. As a result, two-thirds of women who are newly proposed to justify the biological plausibility of debulking (Table 1) diagnosed with invasive epithelial ovarian cancer still present, as they [18,19]. Disseminated ovarian cancers, like other solid tumors, are always have, with stage III–IV disease typically characterized by ascites, postulated to contain a small subpopulation of highly specialized cells carcinomatosis and omental caking. with self-renewal capacity and the potential to reconstitute the entire Advanced ovarian cancer is a heterogeneous disease requiring a cellular heterogeneity of a tumor. These ovarian cancer stem cells are disciplined sequence of treatment to consistently achieve the best out- thought to be responsible for tumor initiation, maintenance and growth. comes. No two clinical presentations are quite the same, nor would Presumably, ineffective targeting of this cell population is responsible two different clinicians necessarily be in sync on every patient. Whether for the therapeutic failures and tumor recurrences frequently observed to start with an operation, or platinum-based therapy, is not always [20,21]. The elimination of these chemo-resistant cells, removal of the obvious, no matter what the pre-existing biases. Primary debulking supportive tumor microenvironment, and potential for improved drug surgery (PDS) requires knowledge of the disease process, mastery of a delivery, are, in theory at least, other benefits of surgical cytoreduction. wide spectrum of different procedures, and the willingness to manage Additionally, removal of bulk disease should reduce the number of complex postoperative sequelae. Neoadjuvant chemotherapy (NAC) appears to involve less short-term morbidity, and has demonstrated equivalent efficacy, at least in one published phase III trial [5]. Clinical teams are charged with the challenging task of striking the perfect balance between being appropriately aggressive and trying to avoid unnecessary morbidity. The most strident advocates of either PDS or NAC will have treated selected patients with the alternative on at least some occasions. This intriguing frequency of crossover is well-known, but not often stated. Due to the complexities of providing longitudinal care for patients with ovarian cancer, better outcomes are reported when a subspecialist is involved [6,7]. Unfortunately, fewer than half of patients in the United States and Europe will have that opportunity [8]. Instead, the majority are managed by physicians not necessarily intimately familiar with the interplay between medical and surgical management. However, maximizing overall survival depends on the precise coordination of both forms of treatment at a center with expertise. PDS and NAC each have their believers and dissenters. Recently, decades of retrospective data supporting the former has collided with phase III data supporting the latter position. Apropos to the boxing analogy, we cannot retreat into our corner at this point, but must be willing to go the distance with the best currently available evidence for the benefit of all women diagnosed with advanced ovarian cancer. Furthermore, we must look for ways to improve our treatment paradigms.

Primary debulking surgery

Joe V. Meigs, a gynecologic surgeon at the Massachusetts General Hospital (Fig. 1), initially described ovarian tumor debulking in 1934 [9]. The initial intent was to enhance the effects of radiation therapy in an era before modern chemotherapeutics. However, due to limited clin- ical benefit, the concept did not really gain traction until the mid-70s when platinum drugs were emerging. Griffiths' (Fig. 2) landmark study appeared to conclusively demonstrate the inverse relationship between residual tumor diameter and patient survival [10]. Case series Fig. 1. Joe V. Meigs. J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605 597

survival benefit, an optimal result was initially defined as no residual tu- mors individually measuring more than 2 cm in size [26]. For purposes of uniformity, the Gynecologic Oncology Group (GOG) re-defined optimal debulking as residual implants ≤1cm[27]. For some decades, this criterion served as the benchmark of success. Patients undergoing PDS who were rendered optimal (≤1 cm residual disease), followed by intraperitoneal (IP) platinum-based chemotherapy were shown to have a median overall survival of 66 months — the longest duration ever reported in a phase III study [28]. The clinical outcomes achieved in this GOG trial still serve as the benchmark for comparisons with any other sequence of treatment. Yet one valid criticism of cytoreductive surgery is the biased, subjec- tive assessment of gross residual disease by the surgeon at the comple- tion of the operation. Due to tissue induration, inadequate exploration, radiologist over-estimation, or other factors, inaccuracies of residual tumor size are common [29,30]. Perhaps due to the inability to reliably quantify the remaining disease, a recent sub-analysis of accumulated data from several prospective GOG trials demonstrated that patients with 0.1 to 1.0 cm residual disease had only marginally improved over- all survival compared to patients with N1 cm residual disease for stage III ovarian cancer. In fact, dramatic survival benefit was only achieved with complete resection to microscopic residual disease [31].Basedon these findings and other similar reports, there is a growing consensus that optimal cytoreduction should be defined using a more stringent criterion. Thus, the current goal of PDS is to achieve complete resection with no residual disease [32]. Raising the bar for surgical success accordingly decreases the proportion of patients with advanced ovarian cancer in which this redefined optimal result can be accomplished, unless there is a change in practice. For stage IIIC disease, rates of complete resection predomi- nantly range from 15 to 30%. However, the clinical benefits appear substantial when it can be achieved (Table 2) [33–35]. Within the last decade, multiple institutions have demonstrated the ability to revise their surgical paradigm in order to safely debulk to no residual disease Fig. 2. C. Tom Griffiths. at a rate that approaches or exceeds 50% [36–38]. Broader incorporation of these types of surgical improvement programs could significantly chemotherapy-treated cancer cells that will undergo spontaneous improve outcomes. In a meta-analysis of 18 studies involving 13,257 mutations to drug-resistant phenotypes [22]. patients, Chang et al. observed that each 10% increase in the proportion PDS is a technically challenging endeavor for a number of different undergoing complete cytoreduction was associated with a 2.3-month reasons. Tumor-related sequelae such as symptomatic pleural effusions increase in cohort median survival. Additionally, for each 10% increase or hypoalbuminemia, especially when accompanied by co-existing in the proportion receiving IP chemotherapy, there was a 3.9-month health problems, often impact the ability to recover from any major increase in median cohort survival time [39]. Recently, Rosen et al. surgical procedure. Within the peritoneal cavity, anatomical landmarks reported an astonishing seven-year survival rate of 90% in women are often encased by tumor or otherwise obliterated. Routinely, radical undergoing PDS with no residual disease who subsequently received pelvic dissection, bowel resection, and aggressive upper abdominal IP treatment [40]. All attempts should be made to achieve complete surgery are necessary to achieve an optimal result [23]. Sound clinical (hereafter defined as optimal in this review) resection, as these patients, judgment is required in order to be appropriately aggressive, without when treated with adjuvant platinum-based IP chemotherapy have sur- inducing a cascade of potentially disastrous complications. Despite the vival measures that exceed any rates previously seen in this population accumulated evidence supporting the importance of PDS, it remains [41]. controversial whether the better outcome is due to the surgeon's However, despite the subjective nature of classifying residual dis- technical proficiency or some ill-defined, intrinsic feature of the cancer ease, there is evidence to support minimizing the amount of remaining that makes the tumor implants easier to remove [24,25]. While patients tumor as much as possible. Chi et al. analyzed a prospective database for definitely do appear to benefit from one maximal debulking attempt, outcomes of 465 women with stage IIIC ovarian cancer who underwent the timing of the operation and what defines success have become PDS. They observed a median overall survival of 33–34 months for increasingly controversial. those with N1 cm residual disease, 48 months with 0.6–1.0 cm residual, Proficient cytoreduction depends on numerous factors, including patient selection, tumor location, and surgeon expertise. To achieve a

Table 2 Table 1 Median overall survival of stage IIIC ovarian cancer patients undergoing primary Theoretical arguments for debulking surgery. debulking surgery (months).

Removing large necrotic masses promotes drug delivery to small tumors with good Study Residual disease blood supply Microscopic 0.1–1.0 cm N1cm Removing resistant clones decreases the likelihood of early onset drug resistance Tiny implants have a higher growth fraction that should be more chemo-sensitive Aletti [33] N84 34 25 Removing cancer in specific locations, such as tumors causing a bowel obstruction, Chang [34] 86 46 37 improves the patient's nutritional and immunologic status Chi [35] 106 59 33 598 J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605

66 months for those with ≤.5 cm, and 106 months for patients with no who performed the first surgery. In the US trial, virtually all patients gross residual disease [35]. Additionally, in a Cochrane Database review had their initial attempt by a gynecologic oncologist, unlike the of 11 retrospective studies, “near optimal” patients with b1 cm residual European study where relatively few had their first surgery performed disease collectively had better outcomes than “suboptimal” cases with by a subspecialist. Therefore, interval debulking appears to yield benefit residual disease N1cm[42]. only among the patients whose primary surgery was not performed by Occasionally, a gynecologist planning to remove an adnexal mass or a gynecologic oncologist, if the first try was not intended as a maximal a general surgeon performing abdominal surgery for presumed bowel resection of all gross disease, or if no upfront surgery was performed obstruction unexpectedly encounters widespread intra-abdominal dis- at all [55]. ease. These advanced ovarian cancer patients who are unintentionally taken for surgery typically do not get a maximal cytoreductive effort, PDS v NAC: phase III trials but are oftentimes referred postoperatively. Fortunately, upfront re- operation before the start of chemotherapy should still be feasible, In 1986, the GOG and separately a collaborative group in the and successful, in more than half of patients with incomplete primary Netherlands each opened randomized phase III trials to test the hypoth- surgery elsewhere [43]. esis that primary debulking was superior to NAC in advanced ovarian If it were possible to perform PDS and consistently achieve no resid- cancer. Both studies were closed due to poor accrual. One prevailing ual disease with limited postoperative complications, then we all would opinion at the time was that clinicians did not want to subject their be believers in this strategy. Despite attempts to develop such a model – patients to ‘substandard’ NAC treatment. Until recently, the presumed predicting successful surgery with minimal morbidity – nothing yet has benefits of primary surgical cytoreduction in advanced ovarian cancer proven reproducible in a prospectively validated manner [44,45].At had not been rigorously tested. present, the reality is that most patients will have some level of remain- The results of the randomized European Organization for Research ing tumor, and many will derive limited clinical benefit. Additionally, and Treatment of Cancer (EORTC protocol # 55971) phase III trial PDS may result in a prolonged postoperative recovery that is fraught were first presented in October 2008 and subsequently published in with complications: an observation frequently made by dissenters to September 2010. The data has fostered debate of how best to initially the upfront surgery paradigm. All too often, the initiation of chemother- treat women with advanced ovarian cancer. In the study, 670 patients apy may be delayed, or worse, postponed indefinitely. were randomized to PDS versus NAC. After three courses of platinum- based treatment, the 90% of NAC patients who demonstrated a response Neoadjuvant chemotherapy (NAC) underwent interval debulking. The authors reported a median overall survival of 29 to 30 months, regardless of the initial assigned treatment Some patients are clearly too medically ill to initially undergo any group. In the multivariate analysis, complete resection of all macroscop- type of upfront abdominal operation, whereas others have disease ic disease at debulking surgery was identified as the strongest indepen- that is too extensive to be resected even by an experienced ovarian dent prognostic factor, but the timing of surgery did not seem to matter. cancer surgical team. In these circumstances, NAC is routinely used Based on the authors' interpretation of their data, NAC and interval after the diagnosis has been confirmed. Core biopsy of the primary debulking was the preferred treatment [5]. tumor or one of the metastases is the gold standard to prove the exis- Despite these findings, the Society of Gynecologic Oncology mem- tence of a disseminated ovarian carcinoma. Cytological diagnosis by bers queried in 2010 largely remained unconvinced. Of respondents to fine needle aspiration may also be acceptable if the CA125/CEA ratio is a survey sent to the membership, most use NAC in less than 10% of N25 (as defined in trials) [46]. Following three to four courses of treat- advanced stage ovarian cancer cases [56]. In light of the phase III data, ment, the feasibility of surgery can be reassessed. In some retrospective some European gynecologic oncologists have openly questioned what series, NAC followed by interval debulking has demonstrated compara- kind of evidence would be needed to convince their US colleagues ble survival outcomes to those reported for primary surgery [47–50]. about the superiority of the NAC approach [57]. At least two criticisms Fewer radical procedures may be required, the rate of achieving mini- of the trial have been suggested as reasons why the results may not be mal residual disease may be higher, and patients may experience less applicable in the United States. First, the duration of patient survival in morbidity. Six cycles of NAC prior to surgery are another less commonly the study was shorter than expected. The median survival (29 to used option. In 82 patients treated with this extended regimen, the rate 30 months) was less than half that reported for optimally debulked of complete resection to no residual disease was 63.7%, and 23.1% were stage III patients receiving postoperative intraperitoneal chemotherapy found to have had a clinical complete response [51]. However, a meta- (66 months) [28]. Additionally, only 42% of those patients randomized analysis of 81 cohorts of 6885 patients with stage III or IV ovarian cancer to PDS had ≤1 cm of residual disease. suggested that NAC in lieu of PDS is associated with an inferior overall Since expert centers in the United States often report achieving survival [52]. Direct comparison has historically been difficult to cytoreduction to ≤1 cm of residual disease at least 75% of the time, it perform. is feasible to think that a more aggressive initial attempt might have Unfortunately, preoperative CA125 levels, imaging tests and physi- led to a better outcome for the group randomized to surgery. Chi et al. cal examinations all have limitations in consistently identifying which analyzed the outcomes of patients treated with PDS at the Memorial patients can be optimally debulked to no residual disease by a gyneco- Sloan-Kettering Cancer Center during the same time period in which logic oncologist. Invariably, the final determination cannot be made the EORTC trial was conducted, using identical inclusion criteria. Of until abdominal exploration. When it is clinically evident during surgery 316 eligible patients, 285 (90%) underwent PDS. In 203 patients (71%), that achieving b1 cm is not feasible, great discretion is required to ≤1 cm of residual disease was achieved with an overall median overall confirm the diagnosis, but not provoke unnecessary complications survival of 50 months [58]. The long-term outcomes were intriguing, that could delay subsequent therapy. but whether this was a fair comparison has been debated [59]. Two phase III trials were conducted to determine whether a second A second recently presented study is also of interest. The Medical interval debulking procedure was worthwhile after an unsuccessful ini- Research Council (MRC) CHemotherapy OR Upfront Surgery (CHORUS) tial attempt followed by a few courses of chemotherapy. A multicenter trial is a phase III, non-inferiority randomized controlled study conduct- trial conducted in Europe demonstrated a 6-month median survival ed in the United Kingdom and New Zealand. Five hundred fifty-two advantage in patients who were re-explored after three cycles of che- newly diagnosed advanced ovarian cancer patients with suspected motherapy [53]. In contrast, no survival advantage was demonstrated stages III–IV ovarian cancer were enrolled between March 2004 and when a similar study was conducted in the United States [54]. These August 2010. Women were randomized to undergo PDS followed by seemingly conflicting reports are most easily explained by clarifying 6 cycles of chemotherapy, or NAC with interval debulking surgery J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605 599 after 3 cycles, followed by completion chemotherapy. The primary out- aged ≥65 years who had PDS for stage III or IV epithelial ovarian cancer come was overall survival, with secondary outcomes of toxicity and between 1995 and 2005. The overall 30-day mortality was a sobering quality of life. Complete resection was achieved in 16% of the PDS arm 8.2%. Advancing age, increasing stage, and increasing co-morbidity versus 40% in the NAC arm. Grades 3–4 postoperative adverse events score were all associated with an increase in 30-day mortality [67]. (24% v 14%) and death (5.5% v 0.5%) within 28 days of surgery were Wright et al. analyzed the SEER-Medicare database to identify women both more common in the PDS group. Median overall survival was aged ≥65 with stages II–IV ovarian cancer who survived at least comparable between the two arms: 22.8 months for the PDS arm and 6 months from the date of diagnosis. A total of 9587 patients were iden- 24.5 months for the NAC group [60]. Peer-review of the manuscript is tified who received treatment from 1991 to 2007. Interestingly, the use eagerly awaited as it represents another meaningful contribution to of primary surgery decreased from 63.2% to 49.5% over time. In addition, the literature on this topic. overall survival with NAC did not differ from PDS in this older popula- Ultimately, a prospective phase III trial conducted within the United tion [68]. In an analysis of 28,651 women undergoing surgery for ovar- States will need to be performed to sway opinion and markedly change ian cancer from 1998 to 2007 using the Nationwide Inpatient Sample, the practice of gynecologic oncologists in this country. Unfortunately, complication rates increased with age from 17.1% in those b50 years recent attempts through the GOG or with industry support have not of age to 31.5% in those ≥80. Morbidity was observed to be greatest in yet been successful in launching. Meantime, the controversy will persist the elderly, where the effects of age and the number of radical proce- and individual patterns of care will continue. PDS is certainly the stan- dures performed had an additive effect on complication rates [69].En dard of care for patients with stage IIIA and IIIB ovarian cancer. PDS is masse, the data suggests that NAC will likely continue to have a more also favored for those with IIIC disease, in the absence of evidence for prominent role in the elderly. When complete cytoreduction is not unresectability or poor performance status. The treatment of stage IV feasible during PDS, the operation should be limited in scope to avoid is typically individualized in current patterns of practice, but NAC is a unnecessary postoperative morbidity as ultra-radical procedures can reasonable alternative [61]. be especially poorly tolerated in this population.

Special circumstances Obesity

The elderly The epidemic of obesity taking place in the United States and throughout much of the world is increasingly going to impact the treat- Since the likelihood of a woman developing ovarian cancer increases ment of ovarian cancer. While studies exploring the association with every decade, and the population is living longer than ever before, between obesity and ovarian cancer survival have yielded conflicting it stands to reason that more and more women will be diagnosed later results [70–74], using a body mass index (BMI) of 30 kg/m2 as the tip- in life. The precise meaning of the term ‘elderly’ is somewhat fluid, occa- ping point for the definition of obesity hardly seems to reflect reality. sionally referring to those as young as 65 years of age, but in some stud- In the current vernacular, 40 is the new 30, at least as far as the aging ies defined as 75 years and older. While increasing age as a stand-alone process goes, and we should be able to comfortably extrapolate that variable should not immediately lead to a more palliative approach, it is also to BMI. Kumar et al. analyzed the Mayo experience with 620 stages a relevant factor as almost half of ovarian cancer patients diagnosed in IIIC–IV patients who underwent PDS between 2003 and 2011, divided the United States each year will be at least 65 years of age. Though the into three groups according to BMI. Women with a BMI of ≥40 were exact reasons are usually difficult to separate out and tend to be multi- found to have substantially higher rates of severe 30-day postoperative factorial, increasing age does adversely impact survival. As a group, morbidity and 90-day mortality after PDS. Although the high BMI group elderly patients with ovarian cancer are less likely to receive care with had limited numbers of patients, there did not appear to be deficits in a gynecologic oncologist, or to undergo PDS followed by adjuvant che- achieving optimal cytoreduction, nor did it impact long-term oncologic motherapy [62,63]. Some of the differences in patterns of care are likely outcomes [75]. It seems obvious enough that the likelihood of postoper- driven by medical co-morbidities, well-meaning physician bias and/or ative complications is demonstrably higher when performing PDS in the individual quality of life choices. morbidly obese population. Even though the ability to achieve complete Increasing age and co-morbid conditions are risk factors for surgical cytoreduction would seem to be in jeopardy with increasing body size, morbidity and mortality, but the interactions have not been rigorously current data do not bear this out, perhaps due to a mitigating effect of analyzed. Several studies have emphasized that elderly patients are excess body weight on tumor biology [76]. Matthews et al. observed able to tolerate an aggressive approach with relatively few complica- that survival rates were similar between obese and non-obese patients tions, when adjusted for performance status. Langstraat et al. reviewed when the amount of residual disease was the same [77]. Regardless, the Mayo experience of 280 consecutive patients ≥65 years with stage there is a price to be paid for aggressive PDS in the morbidly obese, IIIC or IV ovarian cancer treated over a 10-year period. A significant though NAC too has potential limitations in this population. number of elderly women were able to undergo PDS and adjuvant Wright et al. observed that obese patients treated with chemothera- chemotherapy. However, median overall survival still decreased with py on a GOG protocol experienced substantially less toxicity than increasing age and the impact of residual disease was greater on older normal weight women. Substandard drug dosing was thought to be patients. In addition, 37.5% of patients ≥75 years had significant periop- causative [78]. In an analysis of the Australian Ovarian Cancer Study of erative morbidity [64]. Glasgow et al. performed a retrospective cohort 333 patients, obese women were significantly more likely to have study of women ≥70 years with stage IIIC or IV disease treated at Yale, received b85% of relative dose intensity of carboplatin, leading to and observed that the 42 NAC patients had similar outcomes, but signif- worse outcomes [79]. Appropriate dosing for obese patients with ovar- icantly reduced perioperative morbidity compared to 62 women who ian cancer is a must, whether as NAC or given as postoperative adjuvant underwent PDS [65]. Worley et al. reviewed the outcome of 165 treatment. When they undergo effective and receive appropriate doses patients aged ≥70 years at their institution. Median overall survival of chemotherapy, obese patients do not have a poorer prognosis [80]. was similar between the 125 women who underwent PDS, compared to the 40 receiving NAC, but readmission rates within 30 days of surgery Stage IV disease was dramatically higher in the PDS cohort (17.6% v 2.5%) [66]. These single institution studies highlight the caution that is indicat- Roughly one-third of patients with advanced ovarian cancer will ed for elderly women, especially in the presence of other significant have stage IV disease at the time of their diagnosis [81]. This designation co-morbidities. Thrall et al. analyzed the Surveillance, Epidemiology is widely believed to be associated with a more aggressive tumor biolo- and End Results (SEER) data -base to identify a cohort of 5475 women gy having significant implications on surgical outcome and response to 600 J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605

Table 3 Success rates of primary debulking surgery in stage IV ovarian cancer.

Study Residual disease

Microscopic 0.1–1.0 cm N1cm

Aletti [76] 6% 43% 51% Bristow [77] – 30% 70% Rauh-Hain [78] 8% 50% 42% Trope [79] 14% 36% 50% Winter [80] 8% 22% 70%

chemotherapy. Accordingly, the likelihood of achieving complete cytoreduction at the time of PDS is particularly dismal (Table 3) [82–86]. Furthermore, Winters et al. retrospectively reviewed 360 stage IV patients treated on phase III GOG protocols and did not observe a benefit with 0.1 to 1.0 cm residual disease versus those with 1.1 to 5.0 cm residual. They concluded that ultra-radical procedures might best be targeted to those selected patients in whom microscopic resid- ual disease is achievable [86]. Based on the available data, this would seem to apply to less than 1 in 10 patients. Van Meurs et al. used data from the EORTC 55971 trial to report that patients with stage IV disease and large (defined as N 45 mm) metastatic tumors treated with NAC had demonstrably higher survival, compared to an attempt at PDS followed by postoperative chemotherapy [87].In addition, NAC patients with stage IV disease who subsequently undergo interval debulking surgery appear to have less peri-operative morbidity, a higher likelihood of complete resection and shorter hospital stay [88]. In the EORTC trial, 10% of patients randomized to NAC never had a cytoreductive attempt [5]. Another advantage of NAC in this high-risk population appears to be the ability to better triage only responding pa- tients to interval debulking surgery. Among this subset, aggressive cytoreduction has been shown to be beneficial [89]. While historically the stage IV subcategory represented a range of clinical findings lumped together, since January 2014 these have been separated out to better reflect the disease processes [90]. It will be of Fig. 3. Ovarian carcinosarcoma with peritoneal carcinomatosis. Coronal image from an abdominal-pelvic CT with oral and intravenous contrast shows a 17-cm primary right interest to see whether having stage IVA or IVB disease will have impli- adnexal tumor (star). Bulky tumor in the lesser sac (arrow) would suggest the inability cations on the success of upfront treatment. Based on current available to perform complete cytoreductive surgery. evidence, the ability to achieve complete resection to no residual dis- ease is so limited, that upfront surgery should be limited to very select patients, while the majority should be treated with NAC. variations of image interpretation and surgical expertise across institu- tions. In a multi-institutional reciprocal validation study, high accuracy Clinical innovations rates of CT predictors could not be confirmed [93]. Suidan et al. have recently reported the results of a prospective, non-randomized two- Preoperative imaging center trial of 669 patients from 2001 to 2012 that underwent PDS for stages III–IV ovarian, fallopian tube, and peritoneal cancer. Based on The ability to reliably identify patients most likely to benefit from three clinical and six radiologic criteria (Table 4, Fig. 3), they developed PDS based on imaging findings has proven to be an immense challenge. a predictive model in which the suboptimal rate was directly propor- Bristow et al. retrospectively analyzed preoperative CT scans in a tional to the predictive value score [94]. These findings have yet to be blinded fashion and correlated them with surgical outcome to develop validated more broadly. a predictive index model [91]. In a similar study, Dowdy et al. identified The utility of preoperative whole-body (18)F-fluorodeoxyglucose only diffuse peritoneal thickening and large volume ascites as findings (FDG) PET/CT is controversial. More accurate detection of supra- associated with a low rate of optimal debulking [92]. These attempts, diaphragmatic disease via imaging might understandably dissuade and others like them, have not led to a paradigm shift, mainly due to clinicians from favoring PDS. While fusion PET/CT shows higher staging accuracy than either CT or FDG-PET alone [95–97], the impacts of these findings on rates of successful PDS have yet to be demonstrated. Table 4 Hynninen conducted a study of 41 patients undergoing preoperative Suidan et al. criteria associated with suboptimal primary cytoreductive surgery. PET/CT followed by diagnostic high dose contrast-enhanced CT scan. They observed that PET/CT was not superior to CT for the detection of Clinical Radiologic intra-abdominal disease spread, but was more effective in identifying ≥ N Age 60 years Suprarenal retroperitoneal nodes 1cm extra-abdominal metastases (Fig. 4) [98]. Fruscio et al. reviewed their CA125 ≥ 500 U/mL Diffuse small bowel adhesions/thickening ASAa 3–4 Lesion(s) N1 cm small bowel mesentery experience with 95 patients in which more than a quarter were clinical- Lesion(s) N1 cm root of superior mesenteric artery ly upstaged from stage III to stage IV by PET/CT. However, women Lesion(s) N1 cm perisplenic area upstaged to IV had a similar prognosis as stage III patients, presumably Lesion(s) N1 cm lesser sac because it was the intraperitoneal tumor load that was more likely to a American Society of Anesthesiologists Physical Status classification system. lead to death [99]. J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605 601

Minimally invasive surgery

The inherent limitations in accurately correlating imaging findings for a disease with varying levels of intraperitoneal surface implant dissemination detected at surgery has led to evolving paradigms where- in preoperative laparoscopic evaluation of disease is used to help triage patients toward PDS or NAC. In theory, this approach would avoid unnecessarily morbid, suboptimal laparotomies that unduly lengthen the time of treatment and increase overall costs. Several prospective and retrospective studies have investigated the use of laparoscopy to predict the outcome of debulking surgery. In a pilot study of patients un- dergoing laparoscopy followed by standard laparotomy, Fagotti et al. observed that optimal debulking was achievable in 87% of cases selected as being completely resectable by explorative laparoscopy [102]. With this promising preliminary data, a laparoscopy-based quantitative pre- dictive model (predictive index value [PIV]) was devised to provide an objective score of intraperitoneal disease spread (Table 5). The PIV has subsequently undergone initial testing and validation as a triage tool [103,104]. To minimize the chances of inappropriately failing to perform PDS, the best PIV cutoff was noted to be ≥8, corresponding to a positive predictive value of 100%, or a zero percent chance of complete resection among these investigators [105]. Fagotti et al. subsequently reported on 300 consecutive patients who underwent staging laparoscopy. Importantly, none had complications related to the procedure. Based on high tumor load (PIV ≥ 8), 152 (50.7%) went on to receive NAC and 57.5% had no residual disease at the time of interval debulking. Of the 148 who underwent PDS, 62.1% had complete resection. The authors concluded that this minimally invasive strategy may help to meaningfully individualize treatment, while avoiding unnecessary open surgery and its sequelae [106]. Vizzielli et al. also reported 348 consecutive advanced ovarian cancer patients who underwent preoperative laparoscopic evaluation. All study women received a PIV score and were stratified into three groups based on volume of disease. In a multivariate analysis, tumor load strat- ified by PIV was found to be independently associated with overall sur- vival, along with the amount of residual disease and performance status [107]. In a multicenter trial (Olympia-MITO 13) to prospectively evaluate the accuracy and reproducibility of staging laparoscopy at different satellite centers, 168 patients underwent PIV scoring. Following a short intensive training period, the technique was shown to be an accu- rate and reliable assessment of intraperitoneal diffusion of disease in advanced ovarian cancer patients [108]. The LapOvCa-trial is a random- ized multicenter trial including all gynecologic oncology centers in the Netherlands and their affiliated hospitals. The purpose of this ongoing study is to investigate whether laparoscopy is cost-effective in predicting which patients will benefit from PDS and which patients should be treated by NAC and interval surgery instead [109]. Fig. 4. Stage IV high grade ovarian serous carcinoma. Axial fusion images from whole Whether the PIV score will be readily adaptable to gynecologic body FDG PET-CT exam shows a hypermetabolic right adnexal primary tumor (A) and ret- oncologists in the United States remains an open question. Nick et al. roperitoneal adenopathy (B). Chest portion of the exam (C) reveals unsuspected left recently presented the triage algorithm modified from Fagotti that is supraclavicular adenopathy (arrow) that may impact primary treatment. currently under investigation at the MD Anderson Cancer Center. Of the 33 patients who underwent laparoscopy, none had an intraopera- While there is as yet no clear consensus on the criteria for resectable tive complication, and 19 (58%) who had a PIV score b8 subsequently peritoneal lesions, radiologic imaging serves as an important roadmap underwent PDS. By the use of this approach, their rate of achieving com- for treatment planning. The American College of Radiology's Appropri- plete resection improved from a historical rate of 44% to 84% [110]. ateness Criteria consensus recommendations currently rate abdomi- nal–pelvic CT as the modality of choice for pre-treatment evaluation of Table 5 ovarian cancer patients [100]. Chest CT is also indicated should the Fagotti laparoscopic predictive index value chest radiograph prove abnormal. Accurate interpretation requires (PIV) score. radiologist expertise in complex intra-abdominal anatomy, and clinical fi Omental cake dialogue with a gynecologic oncologist having familiarity with speci c Peritoneal/diaphragmatic carcinomatosis disease sites that are likely to present particular difficulties with regard Mesenteric retraction to surgical access and technique [101]. Although CT is at present the Bowel/stomach infiltration most predictive procedure, it is not in and of itself accurate enough to Spleen/liver superficial metastasis consistently guide clinical management. Each positive evaluation receives a score of 2. 602 J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605

However, more data is needed. In a Cochrane Database review of seven Table 7 studies reporting on six cohorts, laparoscopy identified a broad range Patients who appear to benefit the most from neoadjuvant chemotherapy: a proposal. (27–64%) of patients with too extensive disease to warrant laparotomy Stage IIIC disease that is too extensive to be optimally debulked based on imaging and correspondingly between 36–73% having disease suitable for PDS. or laparoscopic scoring Laparoscopy is a promising tool with minimal complications, but the Stage IV disease (likelihood of complete resection b10%) limited number of studies and unproven reproducibility at present do Performance status too poor to undergo an attempt at surgical debulking No access to an experienced ovarian cancer surgical team fi not allow rm conclusions to be drawn from this data as yet [111]. The elderly or morbidly obese when ultra-radical procedures appear necessary

Ultra-radical surgery such as elderly age, morbid obesity or stage IV disease extension can all be taken into account (Tables 6 and 7). Extensive upper abdominal disease is often the limiting factor deter- Further modification of current imaging techniques is unlikely to mining whether a patient with advanced ovarian cancer can be optimal- substantially improve the triage of patients upfront. The promising ly debulked to no residual disease. While tumor in this location is work on laparoscopic scoring needs to be replicated in the United strongly indicative of aggressive tumor biology, a surgeon's experience States with reassuring survival outcomes, otherwise it is unlikely to be and willingness to employ ultra-radical procedures is correlated with widely incorporated. Ultimately, any and all of these preoperative success in achieving complete resection [112,113]. Not every gyneco- methods to predict complete resection are still intimately tied to the logic oncologist is comfortable routinely performing liver resection, surgeon's ability to translate them into a successful outcome. While sev- splenectomy, or diaphragmatic resection, and complications may not eral institutions have demonstrated improvement in rates of achieving be trivial. However, patients referred to specialized centers where optimal debulking by incorporation of ultra-radical techniques, it is such radical procedures are commonly performed may anticipate difficult to conceive of pushing the surgical limits much beyond that. higher rates of optimal debulking and improved survival, without nec- essarily leading to increased major morbidity [114]. Several institutions incorporating ultra-radical techniques have reported survival rates to Future strategies improve accordingly [36–38]. Although it is still unclear what impact ultra-radical techniques have on quality of life and morbidity, the limit- Rather than refining subjective clinical assessments such as imaging ed available evidence suggests a measured improvement in survival or laparoscopy, it is likely that a reproducible genomics-based model [115]. One common theme for safely expanding the ability to complete- will be necessary to effectively triage patients to initial therapy. Prelim- ly resect advanced ovarian cancer is the willingness to incorporate a inary data on a signature that predicts the success of debulking has been multidisciplinary surgical team, as needed, to facilitate debulking out- proposed, but much additional work is needed before this becomes a re- side of the provider's typical comfort zone. In addition, having tertiary ality [116]. It seems feasible, at least in theory, that molecular analysis of care resources to manage the wide variety of possible postoperative a percutaneous core biopsy might ultimately be the most cost-effective complications is critically important. Complex patients warrant treat- method for determining when or if a patient should go to surgery, and ment in a specialized center. what type of targeted therapy is likely to be most efficacious. At a more basic level, just having access to subspecialty care con- Synopsis tinues to be a significant problem. It is an unfortunate reality that geographic proximity to a high-volume hospital and travel distance to Current surgical management of ovarian cancer requires excellent receive treatment are independent predictors of guideline-adherent clinical judgment and technical mastery of a wide array of procedures. care for advanced ovarian cancer. Such barriers disproportionally affect Involvement of a gynecologic oncologist to oversee patient care has racial minorities and women of low socio-economic status [117]. Net- proven to improve outcomes. Complete resection of all macroscopic works that are able to successfully integrate ovarian cancer treatment disease at PDS has been shown to be the single most important inde- across tertiary and community hospitals need to be promoted and pendent prognostic factor in advanced ovarian cancer. Therefore, expanded so that all women diagnosed can receive the same level of when deciding on PDS there should be a reasonable chance of leaving care. Management of advanced ovarian cancer consistently requires a no residual tumor or at least substantial cytoreduction to b1cmatthe complex, multidisciplinary team to achieve the best outcomes. When- time of surgery [46]. ever feasible, patients should be encouraged to seek treatment at The ability to clinically gauge those most likely to be completely these expert centers. cytoreduced and thereby effectively triage patients toward PDS or Whether you are a believer or a dissenter of PDS, we have very lim- NAC involves a complex interplay of numerous factors, including imag- ited data to interpret. Only a randomized phase III trial of PDS versus ing findings, physical examination, existing medical co-morbidities, and NAC performed in the United States with impressive rates of optimal the expertise of the surgical team. No single individual has the capacity cytoreduction will be definitive. We should embrace this challenge of to make the right call in every circumstance, and even if it were the case, constructing a well-designed definitive study and vigorously support it would not necessarily benefit patients outside of his/her purview. We those, such as Dennis Chi, who are trying to find a way to fund such a advocate a team approach to interpret available information and allow trial. It is telling that without substantial pharmaceutical industry the patient to make an informed decision toward initial therapy. To that support of an agent or device, there is an impasse in conducting a trial end, a consistent preoperative treatment planning conference is ideal, to answer this basic question. with multi-disciplinary attendance, consistent imaging review and ongo- Finally, since surgical paradigms have been shown to improve with ing reassessment of outcome measures. In this way, co-existing factors sustained effort, more transparency per provider or per institution would be helpful in measuring where there are lessons to be learned or improvements to be incorporated. Hopefully, the newly launched Table 6 SGO Clinical Outcomes Registry will provide this type of detailed data. Patients who appear to benefit the most from primary debulking surgery: a proposal. In the meantime, the gynecologic oncology community is charged Stage IIIA or IIIB disease with identifying further evidence-based refinements in the approach Stage IIIC disease with Fagotti laparoscopic score b8 to upfront treatment, continuing to train fellows in the range of proce- Stage IIIC disease with promising multidisciplinary imaging review at ‘expert’ dures that may be required for primary or interval debulking surgery, center routinely able to incorporate ultra-radical procedures as appropriate and broadening the access to subspecialty care. J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605 603

For the foreseeable future, most women will continue to be diag- [24] Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with nosed with ovarian cancer after it has already spread extensively within advanced ovarian cancer: a prospective study. Gynecol Oncol 2003;90:390–6. the peritoneal cavity. The debate on efficacy of PDS versus NAC appears [25] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive to be still in the early rounds. None of us should prematurely declare our surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47: side the winner, nor throw in the towel on this metaphorical boxing 159–66. match, but instead work together to fight the common enemy. It is [26] Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual incumbent upon all of us to continue exploring ways to establish a disease on survival after primary cytoreductive surgery in patients with suboptimal – structured, consistent, transparent approach to the best initial manage- residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974 9. [27] Whitney CW, Spirtos N. Gynecologic Oncology Group surgical procedures manual. ment of this disease. Hopefully, that is something that we can all believe www.gog.org Philadelphia, PA: Gynecologic Oncology Group; 2010 [Ref Type: Elec- in, without dissent. tronic Citation]. [28] Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. Conflict of interest statement [29] Chi DS, Ramirez PT, Teitcher JB, et al. Prospective study of the correlation between postoperative computed tomography scan and primary surgeon assessment in The authors have no financial disclosures to report at this time. patients with advanced ovarian, tubal, and peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease 1 cm or less. J Clin Oncol 2007;25:4946–51. References [30] Sala E, Mannelli L, Yamamoto K, Griffin M, Griffin N, Grant L, et al. The value of post- operative/preadjuvant chemotherapy computed tomography in the management [1] Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, et al. Sensitiv- of patients with ovarian cancer. Int J Gynecol Cancer 2011;21:296–301. ity and specificity of multimodal and ultrasound screening for ovarian cancer, and [31] Winter III WE, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial stage distribution of detected cancers: results of the prevalence screen of the UK ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2007;25:3621–7. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 2009; [32] Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advanced- 10:327–40. stage ovarian cancer: redefining ‘optimal’ residual disease. Gynecol Oncol 2012; [2] Schorge JO, Modesitt SC, Coleman RL, Cohn DE, Kauff ND, Duska LR, et al. SGO 125:483–92. White Paper on ovarian cancer: etiology, screening and surveillance. Gynecol [33] Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO, et al. Aggres- Oncol 2010;119:7–17. sive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet [3] Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screen- Gynecol 2006;107:77–85. ing on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) [34] Chang SJ, Bristow RE, Ryu HS. Impact of complete cytoreduction leaving no gross Cancer Screening Randomized Controlled Trial. JAMA 2011;305:2295–303. residual disease associated with radical cytoreductive surgical procedures on [4] Moyer VA. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffir- survival in advanced ovarian cancer. Ann Surg Oncol 2012;19:4059–67. mation recommendation statement. Ann Intern Med 2012;157:900–4. [35] Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary [5] Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53. Gynecol Oncol 2006;103:559–64. [6] Earle CC, Schrag D, Neville BA, Yabroff KR, Topor M, Fahey A, et al. Effect of surgeon [36] Aletti GD, Dowdy SC, Gostout BS, et al. Quality improvement in the surgical specialty on processes of care and outcomes for ovarian cancer patients. J Natl approach to advanced ovarian cancer: the Mayo Clinic experience. J Am Coll Surg Cancer Inst 2006;98:172–80. 2009;208:614–20. [7] Engelen MJ, Kos HE, Willemse PH, et al. Surgery by consultant gynecologic oncolo- [37] Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall gists improves survival in patients with ovarian carcinoma. Cancer 2006;106: survival in advanced ovarian cancer as a result of a change in surgical paradigm. 589–98. Gynecol Oncol 2009;114:26–31. [8] Carney ME, Lancaster JM, Ford C, et al. A population-based study of patterns of care [38] Harter P, Muallem ZM, Buhrmann C, Lorenz D, Kaub C, Hils R, et al. Impact of a for ovarian cancer: who is seen by a gynecologic oncologist and who is not? structured quality management program on surgical outcome in primary advanced Gynecol Oncol 2002;84:36–42. ovarian cancer. Gynecol Oncol 2011;121:615–9. [9] Meigs JV. Tumors of the female pelvic organs. New York: Macmillen; 1934. [39] Chang SJ, Hodeib M, Chang J, Bristow RE. Survival impact of complete cytoreduction [10] Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. carcinoma. Natl Cancer Inst Monogr 1975;42:101–4. Gynecol Oncol 2013;130:493–8. [11] Griffiths CT, Parker LM, Fuller Jr AF. Role of cytoreductive surgical treatment in the [40] Rosen B, Laframboise S, Ferguson S, Dodge J, Bernardini M, Murphy J, et al. The management of advanced ovarian cancer. Cancer Treat Rep 1979;63:235–40. impacts of neoadjuvant chemotherapy and of debulking surgery on survival from [12] Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive advanced ovarian cancer. Gynecol Oncol 2014;134:462–7. surgery for epithelial ovarian cancer. Obstet Gynecol 1983;61:413–20. [41] Landrum LM, Java J, Mathews CA, Lanneau Jr GS, Copeland LJ, Armstrong DK, et al. [13] Piver MS, Lele SB, Marchetti DL, et al. The impact of aggressive debulking surgery Prognostic factors for stage III epithelial ovarian cancer treated with intraperitoneal and cisplatin-based chemotherapy on progression-free survival in stage III and IV chemotherapy: a Gynecologic Oncology Group study. Gynecol Oncol 2013;130:12–8. ovarian carcinoma. J Clin Oncol 1988;6:983–9. [42] Elattar A, Bryant A, Winter-Roach BA, Hatem M, Naik R. Optimal primary surgical [14] Blackham AU, Russell GB, Stewart JH, Votanopoulos K, Levine EA, Shen P. Metasta- treatment for advanced epithelial ovarian cancer. Cochrane Database Syst Rev tic colorectal cancer: survival comparison of hepatic resection versus cytoreductive 2011:CD007565. surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2014;21: [43] Grabowski JP, Harter P, Hils R, Lorenz D, Kaub C, Barinoff J, et al. Outcome of imme- 2667–74. diate re-operation or interval debulking after chemotherapy at a gynecologic [15] Heng DY, Wells JC, Rini BI, Beuselinck B, Lee JL, Knox JJ, et al. Cytoreductive oncology center after initially incomplete cytoreduction of advanced ovarian nephrectomy in patients with synchronous metastases from renal cell carcinoma: cancer. Gynecol Oncol 2012;126:54–7. results from the International Metastatic Renal Cell Carcinoma Database Consor- [44] Aletti GD, Santillan A, Eisenhauer EL, Hu J, Aletti G, Podratz KC, et al. A new frontier tium. Eur Urol 2014;66:704–10. for quality of care in gynecologic oncology surgery: multi-institutional assessment [16] Rudloff U, Langan RC, Mullinax JE, Beane JD, Steinberg SM, Beresnev T, et al. Impact of short-term outcomes for ovarian cancer using a risk-adjusted model. Gynecol of maximal cytoreductive surgery plus regional heated intraperitoneal chemother- Oncol 2007;107:99–106. apy (HIPEC) on outcome of patients with peritoneal carcinomatosis of gastric [45] Stashwick C, Post MD, Arruda JS, Spillman MA, Behbakht K, Davidson SA, et al. origin: results of the GYMSSA trial. J Surg Oncol 2014;110:275–84. Surgical risk score predicts suboptimal debulking or a major perioperative compli- [17] Salti GI, Ailabouni L, Undevia S. Cytoreductive surgery and hyperthermic intraper- cation in patients with advanced epithelial ovarian, fallopian tube, or primary itoneal chemotherapy for the treatment of peritoneal sarcomatosis. Ann Surg Oncol peritoneal cancer. Int J Gynecol Cancer 2011;21:1422–7. 2012;19:1410–5. [46] Vergote I, Du BA, Amant F, Heitz F, Leunen K, Harter P. Neoadjuvant chemotherapy [18] Covens AL. A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol in advanced ovarian cancer: on what do we agree and disagree? Gynecol Oncol Oncol 2000;78:269–74. 2013;128:6–11. [19] Napoletano C, Bellati F, Landi R, Pauselli S, Marchetti C, Visconti V, et al. Ovarian [47] Fago-Olsen CL, Ottesen B, Kehlet H, Antonsen SL, Christensen IJ, Markauskas A, et al. cancer cytoreduction induces changes in T cell population subsets reducing immu- Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer nosuppression. J Cell Mol Med 2010;14:2748–59. patients? A nationwide Danish study. Gynecol Oncol 2014;132:292–8. [20] Curley MD, Garrett LA, Schorge JO, Foster R, Rueda BR. Evidence for cancer stem [48] Lawton FG, Redman CW, Luesley DM, Chan KK, Blackledge G. Neoadjuvant cells contributing to the pathogenesis of ovarian cancer. Front Biosci 2011;16: (cytoreductive) chemotherapy combined with intervention debulking surgery in 368–92. advanced, unresected epithelial ovarian cancer. Obstet Gynecol 1989;73:61–5. [21] Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer [49] Schwartz PE, Chambers JT, Makuch R. Neoadjuvant chemotherapy for advanced 2005;5:275–84. ovarian cancer. Gynecol Oncol 1994;53:33–7. [22] Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of [50] Vergote IB, De WI, Decloedt J, Tjalma W, Van GM, van DP. Neoadjuvant chemother- tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727–33. apy versus primary debulking surgery in advanced ovarian cancer. Semin Oncol [23] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, et al. The addition of extensive upper 2000;27:31–6. abdominal surgery to achieve optimal cytoreduction improves survival in patients [51] da C.M. V, de Souza Fede AB, Dos Anjos CH, da Silva JR, Sanchez FB, da Silva Bessa with stages IIIC–IV epithelial ovarian cancer. Gynecol Oncol 2006;103:1083–90. LR, et al. Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in 604 J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605

advanced ovarian cancer patients unsuitable for primary surgery: safety and effec- [79] Au-Yeung G, Webb PM, DeFazio A, Fereday S, Bressel M, Mileshkin L. Impact of tiveness. Gynecol Oncol 2014;132:287–91. obesity on chemotherapy dosing for women with advanced stage serous ovarian [52] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of cancer in the Australian Ovarian Cancer Study (AOCS). Gynecol Oncol 2014;133: maximal cytoreductive surgery for advanced ovarian carcinoma during the plati- 16–22. num era: a meta-analysis. J Clin Oncol 2002;20:1248–59. [80] Barrett SV, Paul J, Hay A, Vasey PA, Kaye SB, Glasspool RM. Does body mass index [53] van der Burg ME, van LM, Buyse M, et al. The effect of debulking surgery after affect progression-free or overall survival in patients with ovarian cancer? Results induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. from SCOTROC I trial. Ann Oncol 2008;19:898–902. Gynecological Cancer Cooperative Group of the European Organization for [81] Howell EA, Egorova N, Hayes MP, Wisnivesky J, Franco R, Bickell N. Racial dispar- Research and Treatment of Cancer. N Engl J Med 1995;332:629–34. ities in the treatment of advanced epithelial ovarian cancer. Obstet Gynecol [54] Rose PG, Nerenstone S, Brady MF, Clarke-Pearson D, Olt G, Rubin SC, et al. Second- 2013;122:1025–32. ary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351: [82] Aletti GD, Dowdy SC, Podratz KC, Cliby WA. Analysis of factors impacting operabil- 2489–97. ity in stage IV ovarian cancer: rationale use of a triage system. Gynecol Oncol 2007; [55] Tangjitgamol S, Manusirivithaya S, Laopaiboon M, Lumbiganon P, Bryant A. Interval 105:84–9. debulking surgery for advanced epithelial ovarian cancer. Cochrane Database Syst [83] Bristow RE, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY. Survival impact of surgi- Rev 2013;4:CD006014. cal cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol 1999;72: [56] Dewdney SB, Rimel BJ, Reinhart AJ, et al. The role of neoadjuvant chemotherapy in 278–87. the management of patients with advanced stage ovarian cancer: survey results [84] Rauh-Hain JA, Growdon WB, Rodriguez N, et al. Primary debulking surgery versus from members of the Society of Gynecologic Oncologists. Gynecol Oncol 2010; neoadjuvant chemotherapy in stage IV ovarian cancer. Gynecol Oncol 2011;120: 119:18–21. S12–3. [57] Vergote I, Amant F, Leunen K. Neoadjuvant chemotherapy in advanced ovarian [85] Trope CG, Elstrand MB, Sandstad B, Davidson B, Oksefjell H. Neoadjuvant chemo- cancer: what kind of evidence is needed to convince US gynaecological oncolo- therapy, interval debulking surgery or primary surgery in ovarian carcinoma gists? Gynecol Oncol 2010;119:1–2. FIGO stage IV? Eur J Cancer 2012;48:2146–54. [58] Chi DS, Musa F, Dao F, Zivanovic O, Sonoda Y, Leitao MM, et al. An analysis of pa- [86] Winter III WE, Maxwell GL, Tian C, et al. Tumor residual after surgical cytoreduction tients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic with primary debulking surgery (PDS) during an identical time period as the ran- Oncology Group study. J Clin Oncol 2008;26:83–9. domized EORTC–NCIC trial of PDS vs neoadjuvant chemotherapy (NACT). Gynecol [87] van Meurs HS, Tajik P, Hof MH, Vergote I, Kenter GG, Mol BW, et al. Which patients Oncol 2012;124:10–4. benefit most from primary surgery or neoadjuvant chemotherapy in stage IIIC or IV [59] Vergote I, Leunen K, Amant F. Primary surgery or neoadjuvant chemotherapy in ovarian cancer? An exploratory analysis of the European Organisation for Research ovarian cancer: what is the value of comparing apples with oranges? Gynecol and Treatment of Cancer 55971 randomised trial. Eur J Cancer 2013;49:3191–201. Oncol 2012;124:1–2. [88] Hou JY, Kelly MG, Yu H, et al. Neoadjuvant chemotherapy lessens surgical morbid- [60] Kehoe S, Hook J, Nankivell M, et al. Chemotherapy or upfront surgery for newly ity in advanced ovarian cancer and leads to improved survival in stage IV disease. diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. ASCO; Gynecol Oncol 2007;105:211–7. 6-1-2013 [Ref Type: Abstract]. [89] Rafii A, Deval B, Geay JF, Chopin N, Paoletti X, Paraiso D, et al. Treatment of FIGO [61] Morrison J, Haldar K, Kehoe S, Lawrie TA. Chemotherapy versus surgery for initial stage IV ovarian carcinoma: results of primary surgery or interval surgery after treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev neoadjuvant chemotherapy: a retrospective study. Int J Gynecol Cancer 2007;17: 2012;8:CD005343. 777–83. [62] Hightower RD, Nguyen HN, Averette HE, Hoskins W, Harrison T, Steren A. National [90] Prat J. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. survey of ovarian carcinoma. IV: patterns of care and related survival for older Int J Gynaecol Obstet 2014;124:1–5. patients. Cancer 1994;73:377–83. [91] Bristow RE, Duska LR, Lambrou NC, Fishman EK, O'Neill MJ, Trimble EL, et al. A [63] Uyar D, Frasure HE, Markman M, von Gruenigen VE. Treatment patterns by decade model for predicting surgical outcome in patients with advanced ovarian carcino- of life in elderly women (Nor =70 years of age) with ovarian cancer. Gynecol ma using computed tomography. Cancer 2000;89:1532–40. Oncol 2005;98:403–8. [92] Dowdy SC, Mullany SA, Brandt KR, Huppert BJ, Cliby WA. The utility of computed [64] Langstraat C, Aletti GD, Cliby WA. Morbidity, mortality and overall survival in el- tomography scans in predicting suboptimal cytoreductive surgery in women derly women undergoing primary surgical debulking for ovarian cancer: a delicate with advanced ovarian carcinoma. Cancer 2004;101:346–52. balance requiring individualization. Gynecol Oncol 2011;123:187–91. [93] Axtell AE, Lee MH, Bristow RE, Dowdy SC, Cliby WA, Raman S, et al. Multi- [65] Glasgow MA, Yu H, Rutherford TJ, Azodi M, Silasi DA, Santin AD, et al. Neoadjuvant institutional reciprocal validation study of computed tomography predictors of chemotherapy (NACT) is an effective way of managing elderly women with suboptimal primary cytoreduction in patients with advanced ovarian cancer. advanced stage ovarian cancer (FIGO Stage IIIC and IV). J Surg Oncol 2013;107: J Clin Oncol 2007;25:384–9. 195–200. [94] Suidan RS, Ramirez PT, Sarasohn DM, Teitcher JB, Mironov S, Iyer RB, et al. A mul- [66] Worley Jr MJ, Guseh SH, Rauh-Hain JA, Williams KA, Muto MG, Feltmate CM, et al. ticenter prospective trial evaluating the ability of preoperative computed tomogra- Does neoadjuvant chemotherapy decrease the risk of hospital readmission follow- phy scan and serum CA-125 to predict suboptimal cytoreduction at primary ing debulking surgery? Gynecol Oncol 2013;129:69–73. debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer. [67] Thrall MM, Goff BA, Symons RG, Flum DR, Gray HJ. Thirty-day mortality after pri- Gynecol Oncol 2014;134:455–61. mary cytoreductive surgery for advanced ovarian cancer in the elderly. Obstet [95] Kitajima K, Murakami K, Yamasaki E, Kaji Y, Fukasawa I, Inaba N, et al. Diagnostic Gynecol 2011;118:537–47. accuracy of integrated FDG-PET/contrast-enhanced CT in staging ovarian cancer: [68] Wright JD, Ananth CV, Tsui J, Glied SA, Burke WM, Lu YS, et al. Comparative effec- comparison with enhanced CT. Eur J Nucl Med Mol Imaging 2008;35:1912–20. tiveness of upfront treatment strategies in elderly women with ovarian cancer. [96] Pfannenberg C, Konigsrainer I, Aschoff P, Oksuz MO, Zieker D, Beckert S, et al. (18) Cancer 2014;120:1246–54. F-FDG-PET/CT to select patients with peritoneal carcinomatosis for cytoreductive [69] Wright JD, Lewin SN, Deutsch I, Burke WM, Sun X, Neugut AI, et al. Defining the surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol 2009; limits of radical cytoreductive surgery for ovarian cancer. Gynecol Oncol 2011; 16:1295–303. 123:467–73. [97] Yoshida Y, Kurokawa T, Kawahara K, Tsuchida T, Okazawa H, Fujibayashi Y, et al. [70] Backes FJ, Nagel CI, Bussewitz E, Donner J, Hade E, Salani R. The impact of body Incremental benefits of FDG positron emission tomography over CT alone for the weight on ovarian cancer outcomes. Int J Gynecol Cancer 2011;21:1601–5. preoperative staging of ovarian cancer. AJR Am J Roentgenol 2004;182:227–33. [71] Fotopoulou C, Richter R, Braicu EI, Kuhberg M, Feldheiser A, Schefold JC, et al. Im- [98] Hynninen J, Kemppainen J, Lavonius M, Virtanen J, Matomaki J, Oksa S, et al. A pro- pact of obesity on operative morbidity and clinical outcome in primary epithelial spective comparison of integrated FDG-PET/contrast-enhanced CT and contrast- ovarian cancer after optimal primary tumor debulking. Ann Surg Oncol 2011;18: enhanced CT for pretreatment imaging of advanced epithelial ovarian cancer. 2629–37. Gynecol Oncol 2013;131:389–94. [72] Kotsopoulos J, Moody JR, Fan I, Rosen B, Risch HA, McLaughlin JR, et al. Height, [99] Fruscio R, Sina F, Dolci C, Signorelli M, Crivellaro C, Dell'Anna T, et al. Preoperative weight, BMI and ovarian cancer survival. Gynecol Oncol 2012;127:83–7. 18F-FDG PET/CT in the management of advanced epithelial ovarian cancer. Gynecol [73] Protani MM, Nagle CM, Webb PM. Obesity and ovarian cancer survival: a systemat- Oncol 2013;131:689–93. ic review and meta-analysis. Cancer Prev Res (Phila) 2012;5:901–10. [100] Mitchell DG, Javitt MC, Glanc P, Bennett GL, Brown DL, Dubinsky T, et al. ACR appro- [74] Worley Jr MJ, Guseh SH, Rauh-Hain JA, Esselen KM, Muto MG, Feltmate CM, et al. priateness criteria staging and follow-up of ovarian cancer. J Am Coll Radiol 2013; What is the optimal treatment for obese patients with advanced ovarian carcinoma? 10:822–7. Am J Obstet Gynecol 2014;211:231.e1–9. [101] Nougaret S, Addley HC, Colombo PE, Fujii S, Al Sharif SS, Tirumani SH, et al. Ovarian [75] Kumar A, Bakkum-Gamez JN, Weaver AL, McGree ME, Cliby WA. Impact of obesity carcinomatosis: how the radiologist can help plan the surgical approach. Radio- on surgical and oncologic outcomes in ovarian cancer. Gynecol Oncol 2014;135: graphics 2012;32:1775–800. 19–24. [102] Fagotti A, Fanfani F, Ludovisi M, Lo VR, Bifulco G, Testa AC, et al. Role of laparoscopy [76] Pavelka JC, Brown RS, Karlan BY, Cass I, Leuchter RS, Lagasse LD, et al. Effect of to assess the chance of optimal cytoreductive surgery in advanced ovarian cancer: obesity on survival in epithelial ovarian cancer. Cancer 2006;107:1520–4. a pilot study. Gynecol Oncol 2005;96:729–35. [77] Matthews KS, Straughn Jr JM, Kemper MK, Hoskins KE, Wang W, Rocconi RP. The [103] Brun JL, Rouzier R, Uzan S, Darai E. External validation of a laparoscopic-based score effect of obesity on survival in patients with ovarian cancer. Gynecol Oncol 2009; to evaluate resectability of advanced ovarian cancers: clues for a simplified score. 112:389–93. Gynecol Oncol 2008;110:354–9. [78] Wright JD, Tian C, Mutch DG, Herzog TJ, Nagao S, Fujiwara K, et al. Carboplatin dos- [104] Fagotti A, Ferrandina G, Fanfani F, Ercoli A, Lorusso D, Rossi M, et al. A laparoscopy- ing in obese women with ovarian cancer: a Gynecologic Oncology Group study. based score to predict surgical outcome in patients with advanced ovarian carcinoma: Gynecol Oncol 2008;109:353–8. a pilot study. Ann Surg Oncol 2006;13:1156–61. J.O. Schorge et al. / Gynecologic Oncology 135 (2014) 595–605 605

[105] Fagotti A, Ferrandina G, Fanfani F, Garganese G, Vizzielli G, Carone V, et al. Prospec- [112] Aletti GD, Gostout BS, Podratz KC, Cliby WA. Ovarian cancer surgical resectability: tive validation of a laparoscopic predictive model for optimal cytoreduction in relative impact of disease, patient status, and surgeon. Gynecol Oncol 2006;100: advanced ovarian carcinoma. Am J Obstet Gynecol 2008;199:642–6. 33–7. [106] Fagotti A, Vizzielli G, Fanfani F, Costantini B, Ferrandina G, Gallotta V, et al. Intro- [113] McCann CK, Growdon WB, Munro EG, et al. Prognostic significance of splenectomy duction of staging laparoscopy in the management of advanced epithelial ovarian, as part of initial cytoreductive surgery in ovarian cancer. Ann Surg Oncol 2011;18: tubal and peritoneal cancer: impact on prognosis in a single institution experience. 2912–8. Gynecol Oncol 2013;131:341–6. [114] Wimberger P, Lehmann N, Kimmig R, et al. Prognostic factors for complete [107] Vizzielli G, Costantini B, Tortorella L, Petrillo M, Fanfani F, Chiantera V, et al. Influ- debulking in advanced ovarian cancer and its impact on survival. An exploratory ence of intraperitoneal dissemination assessed by laparoscopy on prognosis of analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft advanced ovarian cancer: an exploratory analysis of a single-institution experience. Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Ann Surg Oncol 2014;21:3170–7. Oncol 2007;106:69–74. [108] Fagotti A, Vizzielli G, De IP, Surico D, Buda A, Mandato VD, et al. A multicentric trial [115] Ang C, Chan KK, Bryant A, Naik R, Dickinson HO. Ultra-radical (extensive) surgery (Olympia-MITO 13) on the accuracy of laparoscopy to assess peritoneal spread in versus standard surgery for the primary cytoreduction of advanced epithelial ovar- ovarian cancer. Am J Obstet Gynecol 2013;209:462. ian cancer. Cochrane Database Syst Rev 2011:CD007697. [109] Rutten MJ, Gaarenstroom KN, Van GT, van Meurs HS, Arts HJ, Bossuyt PM, et al. [116] Riester M, Wei W, Waldron L, Culhane AC, Trippa L, Oliva E, et al. Risk prediction for Laparoscopy to predict the result of primary cytoreductive surgery in advanced late-stage ovarian cancer by meta-analysis of 1525 patient samples. J Natl Cancer ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled Inst 2014;106. study. BMC Cancer 2012;12:31. [117] Bristow RE, Chang J, Ziogas A, Anton-Culver H, Vieira VM. Spatial analysis of adher- [110] Nick AM, Ramirez PT, Rangel KM, Schmeler KM, Soliman PT, Burzawa JK, et al. ence to treatment guidelines for advanced-stage ovarian cancer and the impact of Launching personalized surgical therapy for advanced ovarian cancer. Gynecol race and socioeconomic status. Gynecol Oncol 2014;134:60–7. Oncol 2014;133:28 [Supp 1]. [111] Rutten MJ, Leeflang MM, Kenter GG, Mol BW, Buist M. Laparoscopy for diagnosing resectability of disease in patients with advanced ovarian cancer. Cochrane Data- base Syst Rev 2014;2:CD009786.