Neoadjuvant chemotherapy for newly diagnosed, advanced ... · Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian ... Neoadjuvant chemotherapy for newly diagnosed, advanced

Gynecologic Oncology xxx (2016) xxx–xxx

YGYNO-976328; No. of pages: 13; 4C:

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Gynecologic Oncology

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Practice Guidelines

Neoadjuvant chemotherapy for newly diagnosed, advanced ovariancancer: Society of Gynecologic Oncology and American Society of ClinicalOncology Clinical Practice Guideline☆

Alexi A. Wright a,1, Kari Bohlke b, Deborah K. Armstrong c, Michael A. Bookman d, William A. Cliby e,Robert L. Coleman f, Don S. Dizon g, Joseph J. Kash h, Larissa A. Meyer i, Kathleen N. Moore j,Alexander B. Olawaiye k, Jessica Oldham l, Ritu Salani m, Dee Sparacio n, William P. Tew o,Ignace Vergote p, Mitchell I. Edelson q,⁎,1a Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United Statesb American Society of Clinical Oncology, Alexandria, VA, United Statesc Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United Statesd US Oncology Research and Arizona Oncology, Tucson, AZ, United Statese Mayo Clinic, Rochester, MN, United Statesf University of Texas, M.D. Anderson Cancer Center, Houston, TX, United Statesg Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, United Statesh Edward Cancer Center, Naperville, IL, United Statesi The University of Texas MD Anderson Cancer Center, Houston, TX, United Statesj Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, United Statesk University of Pittsburgh Medical Center, Pittsburgh, PA, United Statesl Society of Gynecologic Oncology, Chicago, IL, United Statesm The Ohio State University, Columbus, OH, United Statesn Hightstown, New Jersey, United Stateso Memorial Sloan Kettering Cancer Center, New York, NY, United Statesp Leuven Cancer Institute, Leuven, European Union, Belgiumq Hanjani Institute for Gynecologic Oncology, Abington Hospital, Jefferson Health, Abington, PA, United States

H I G H L I G H T S

• Women with high perioperative risks or low likelihood of achieving cytoreduction b1 cm (ideally no visible disease) should receive NACT.• NACT is non-inferior to PCS for progression-free and overall survival and has lower peri- and postoperative morbidity and mortality.• However, primary cytoreductive surgery may offer superior survival in selected patients.

☆ Editor's note: This joint American Society of Clinicalcomprehensive review and analyses of the relevant literaOncology. Additional information, including a Data Suppleinformation at www.cancer.net, is available at www.ascauthor contributions are found at the end of this article.⁎ Corresponding author at: Hanjani Institute for Gynec

E-mail address: [email protected] (M.I. E1 AAW and MIE were Expert Panel Co-chairs.

Please cite this article as: A.A. Wright, et al.,Oncology and American Society of Cli..., Gyn

http://dx.doi.org/10.1016/j.ygyno.2016.05.0220090-8258/© 2016 Society of Gynecologic Oncology and A

a b s t r a c t
a r t i c l e i n f o
Article history:Received 26 April 2016Received in revised form 18 May 2016Accepted 18 May 2016Available online xxxx

Purpose. To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and intervalcytoreduction among women with stage IIIC or IV epithelial ovarian cancer.

Methods. The Society of Gynecologic Oncology and the American Society of Clinical Oncology convenedan Expert Panel and conducted a systematic review of the literature.

Results. Four phase III clinical trials form the primary evidence base for the recommendations. The pub-lished studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvantchemotherapy and interval cytoreduction are non-inferior to primary cytoreduction and adjuvant

Keywords:Neoadjuvant

Oncology (ASCO) and Society of Gynecologic Oncology (SGO) Clinical Practice Guideline provides recommendations withture for each recommendation. The guideline is being published simultaneously in Journal of Clinical Oncology and Gynecologicment with additional evidence tables, a Methodology Supplement, slide sets, clinical tools and resources, and links to patiento.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki. Authors' disclosures of potential conflicts of interest and

ologic Oncology, 1200 Old York Rd, Abington, PA 19001, United States.delson).

Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologicecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.022

merican Society of Clinical Oncology. Published by Elsevier Inc. All rights reserved.

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chemotherapy with respect to overall and progression-free survival and are associated with less perioper-ative morbidity and mortality.

Recommendations. All women with suspected stage IIIC or IV invasive epithelial ovarian cancer shouldbe evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluationshould include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high peri-operative risk profile or a low likelihood of achieving cytoreduction to b1 cm of residual disease (ideally tono visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primarycytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemother-apy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a highlikelihood of achieving cytoreduction to b1 cm (ideally to no visible disease) with acceptable morbidity. Be-fore neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian,fallopian tube, or peritoneal cancer.Additional information is available at www.asco.org/NACT-ovarian-guideline andwww.asco.org/guidelineswiki.© 2016 Society of Gynecologic Oncology and American Society of Clinical Oncology. Published by Elsevier Inc. All

rights reserved.

ChemotherapyOvarian cancerCytoreductive surgeryGuideline

Neoadjuvant chemotherapy for newly diagnosed, advanced ovari-an cancer: Society of Gynecologic Oncology and American Socie-ty of Clinical Oncology Clinical Practice GuidelineGuideline questionTo provide guidance to clinicians and patients regarding the use ofneoadjuvant chemotherapy (NACT) and interval cytoreductionamong women with advanced epithelial ovarian cancer.Target populationWomenwith newly diagnosed or suspected stage IIIC or IV epithe-lial ovarian cancer, fallopian tube cancer, or primary peritonealcancer.Target audienceGynecologic and medical oncologists and women with advancedovarian cancer.MethodsAn Expert Panel was convened to develop clinical practice guide-line recommendations based on a systematic review of the medi-cal literature.

The bottom line
1. Introduction
Nearly 75% of women with ovarian cancer are diagnosed withadvanced stage disease (International Federation of Gynecologyand Obstetrics [FIGO] IIIC or IV) at presentation. Treatment withprimary cytoreductive surgery (PCS) followed by chemotherapyhas been the standard of care for these women. Recently, howev-er, two randomized clinical trials (RCTs) compared PCS and che-motherapy to neoadjuvant chemotherapy (NACT) followed byinterval cytoreductive surgery (ICS) and adjuvant chemotherapyfor women with advanced ovarian cancer [1,2]. These trialsdemonstrated that NACT was non-inferior to PCS with respectto progression-free and overall survival and resulted in a lowerincidence of treatment-related morbidity and mortality. Howev-er, both trials have been criticized because the median overallsurvival, mean operative time, and rates of optimal cytoreductionwere lower than expected [3]. The choice between PCS and NACTremains controversial. The purpose of this guideline is to provideclinicians with information regarding the use of NACT and inter-val cytoreduction versus primary cytoreduction and chemothera-py among women with stage IIIC or IV epithelial ovarian cancer.

Key pointsRecommendation 1.1. All women with suspected stage IIIC or IVinvasive epithelial ovarian cancer should be evaluated by a gyne-cologic oncologist prior to initiation of therapy to determinewhether they are candidates for primary cytoreductive surgery(PCS). (Type: evidence based; benefits outweigh harms; Evidencequality: intermediate; Strength of recommendation: strong)Recommendation 1.2. A primary clinical evaluation should includea computed tomography (CT) scan of the abdomen and pelviswith oral and intravenous contrast and chest imaging (CT pre-ferred) to evaluate the extent of disease and the feasibility of sur-gical resection. The use of other tools to refine this assessmentmay include laparoscopic evaluation or additional radiographic im-aging (e.g., [18F]fluorodeoxyglucose positron-emission tomogra-phy [FDG-PET] scan or diffusion-weighted magnetic resonanceimaging [MRI]). (Type: informal consensus; benefits outweighharms; Evidence quality: intermediate; Strength of recommenda-tion: moderate)Recommendation 2.1. Womenwho have a high perioperative riskprofile or a low likelihood of achieving cytoreduction to b1 cm (ide-ally to no visible disease) should receive NACT. (Type: evidencebased; benefits outweigh harms; Evidence quality: intermediate;Strength of recommendation: moderate)

2. Guideline questions

This clinical practice guideline addresses the following clinicalquestions: (1) what clinical evaluations should be performed in allwomen with suspected or newly diagnosed stage IIIC or IV epithelialovarian cancer? (2) Which patient and disease factors should be uti-lized as criteria for identifying patients who are not suitable for PCS?(3) How do NACT and PCS compare with respect to progression-freesurvival, overall survival, and perioperative morbidity and mortalityin women with newly diagnosed stage IIIC or IV epithelial cancerwho are fit for primary cytoreduction and have potentially resect-able disease, and how should this information be used to select ini-tial treatment? (4) What additional clinical evaluations should beperformed in all women with suspected or newly diagnosed stageIIIC or IV epithelial ovarian cancer before NACT is delivered? (5)What is the preferred chemotherapy regimen for women withstage IIIC or IV epithelial ovarian cancer who will receive NACT?(6) Among women treated with NACT, does the timing of intervalcytoreduction or the number of chemotherapy cycles after intervalcytoreduction affect the safety or efficacy of treatment? (7) Whatare the treatment options for patients with progressive disease onNACT?

Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologicecol Oncol (2016), http://dx.doi.org/10.1016/j.ygyno.2016.05.022




Recommendation2.2. Decisions thatwomenarenot eligible formedicalor surgical cancer treatment should bemade after a consultation with agynecologic oncologist and/or a medical oncologist with gynecologicexpertise. (Type: informal consensus; benefits outweigh harms; Evi-dence quality: intermediate; Strength of recommendation: moderate)Recommendation 3.1. For women who are fit for PCS, with potentiallyresectable disease, either NACT or PCS may be offered based on datafrom phase III RCTs that demonstrate that NACT is non-inferior toPCSwith respect to progression-free and overall survival. NACT is asso-ciated with less peri- and postoperative morbidity and mortalityand shorter hospitalizations, but PCS may offer superior survivalin selected patients. (Type: evidence based; benefits outweigh harms;Evidence quality: intermediate, Strength of recommendation:moderate)Recommendation 3.2. For womenwith a high likelihood of achievingcytoreduction to b1 cm (ideally to no visible disease disease) withacceptable morbidity, PCS is recommended over NACT. (Type: evi-dence based; benefits outweigh harms; Evidence quality: intermedi-ate; Strength of recommendation: moderate)Recommendation 3.3. Forwomenwhoare fit for PCS but are deemedunlikely to have cytoreduction to b1 cm (ideally to no visible diseasedisease) by a gynecologic oncologist, NACT is recommended overPCS. NACT is associated with less peri- and postoperative morbidityand mortality and shorter hospitalizations. (Type: evidence based;benefits outweigh harms;Quality of evidence: intermediate; Strengthof recommendation: moderate)Recommendation 4. Before NACT is delivered, all patients should havehistologic confirmation (core biopsy preferred) of an invasive ovarian,fallopian tube, or peritoneal cancer. In exceptional cases, when a biop-sy cannot be performed, cytologic evaluation combined with a serumCA-125 to carcinoembryonic antigen (CEA) ratio N 25 is acceptableto confirm the primary diagnosis and exclude a non-gynecologic can-cer. (Type: informal consensus; benefits outweigh harms; Evidencequality: intermediate; Strength of recommendation: moderate)Recommendation 5. For NACT, a platinum/taxane doublet is recom-mended. However, alternate regimens, containing a platinum agent,may be selected based on individual patient factors. (Type: evidence-based, benefits outweigh harms; Evidence quality: intermediate;Strength of recommendation: moderate)Recommendation 6. RCTs tested surgery following three or four cy-cles of chemotherapy in womenwho had a response to NACT or sta-ble disease. Interval cytoreductive surgery should be performed after≤4 cycles of NACT for women with a response to chemotherapy orstable disease.Alternate timing of surgery has not been prospectivelyevaluated but may be considered based on patient-centered factors.(Type: informal consensus; benefits outweigh harms; Evidence qual-ity: insufficient; Strength of recommendation: weak)Recommendation 7. Patientswith progressive disease onNACT havea poor prognosis. Options include alternative chemotherapy regi-mens, clinical trials, and/or discontinuation of active cancer therapyand initiation of end of life care. In general, there is little role for sur-gery and it is not typically advised, unless for palliation (e.g., reliefof a bowel obstruction). (Type: evidence-based; benefits outweighharms; Evidence quality: intermediate; Strength of recommendation:strong)Additional resourcesMore information, including a Data Supplement with additional evi-dence tables, a Methodology Supplement with information about ev-idence quality and strength of recommendations, slide sets, andclinical tools and resources, is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki. Patient infor-mation is available at www.cancer.net.ASCO and SGO believe that cancer clinical trials are vital to informmedical decisions and improve cancer care and that all patients shouldhave the opportunity to participate.

3A.A. Wright et al. / Gynecologic Oncology xxx (2016) xxx–xxx

Please cite this article as: A.A. Wright, et al., Neoadjuvant chemotherapy fOncology and American Society of Cli..., Gynecol Oncol (2016), http://dx.d

3. Methods

3.1. Guideline development process

The Expert Panelmet four times. The authorswere asked to considerthe available evidence, contribute to the development of the guideline,provide critical review, and finalize the guideline recommendations.Members of the Expert Panel were responsible for reviewing and ap-proving the penultimate version of guideline, whichwas then circulatedfor external review and submitted to Gynecologic Oncology and the Jour-nal of Clinical Oncology (JCO) for editorial review and consideration forpublication. The guideline was also reviewed and approved by theASCO Clinical Practice Guidelines Committee, SGO Publications, andthe SGO Clinical Practice Committees prior to publication.

The recommendationswere developedby anExpert Panelwithmul-tidisciplinary representation. Panelists were drawn from both commu-nity and academic settings, and they included gynecologic oncologists,medical oncologists, and a patient/advocacy representative. Panelistsconsidered evidence from a systematic review of phase III RCTs, meta-analyses, and multicenter cohort studies published between March 20,2005 and March 20, 2015. A list of search terms is provided in theData Supplement. Meeting abstracts were included if they provided re-sults from still-unpublished RCTs and were presented at meetings ofASCO, SGO, or the European Society for Medical Oncology (ESMO)from 2010 to 2015.

Articles were selected for inclusion in the systematic review of theevidence based on the following criteria:

• Population:Womenwith newly diagnosed stage III or stage IV epithe-lial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

• Study type: Evidence regarding the outcomes of NACT was drawnfrom published or presented phase III RCTs. Evidence regarding pre-dictive and prognostic factors in advanced ovarian cancer wasdrawn from RCTs, multicenter cohort studies, meta-analyses, andpopulation-based observational data. Inclusion of influential single-center cohort studies was made at the discretion of the panel.

Articles were excluded from the systematic review if they were edi-torials, commentaries, letters, news articles, case reports, narrative re-views, or published in a non-English language.

Ratings for the type and strength of the recommendation and thequality of the evidence are provided with each recommendation. Thebasis for these ratings is described in the Methodology Supplement(www.asco.org/NACT-ovarian-guideline), which also provides detailsregarding the literature search, data extraction processes, and other as-pects of the guideline development. Guideline staff will work with theExpert Panel co-chairs to keep abreast of the need for any substantiveupdates to the guideline. Based on formal review of the emerging liter-ature and input from the Panel, SGO and ASCO will determine the needto update the guideline.

3.2. Guideline disclaimer

The Clinical PracticeGuidelines and other guidance published hereinare provided by the American Society of Clinical Oncology, Inc. (ASCO)to assist providers in clinical decision making. The information hereinshould not be relied upon as being complete or accurate, nor should itbe considered as inclusive of all proper treatments or methods of careor as a statement of the standard of care. With the rapid developmentof scientific knowledge, new evidence may emerge between the timeinformation is developed andwhen it is published or read. The informa-tion is not continually updated and may not reflect the most recent ev-idence. The information addresses only the topics specifically identifiedtherein and is not applicable to other interventions, diseases, or stagesof diseases. This information does not mandate any particular course

or newly diagnosed, advanced ovarian cancer: Society of Gynecologicoi.org/10.1016/j.ygyno.2016.05.022





http://www.cancer.net



ofmedical care. Further, the information is not intended to substitute forthe independent professional judgment of the treating provider, as theinformation does not account for individual variation among patients.Recommendations reflect high, moderate, or low confidence that therecommendation reflects the net effect of a given course of action. Theuse of words like “must,” “must not,” “should,” and “should not” indi-cates that a course of action is recommended or not recommended foreither most or many patients, but there is latitude for the treating phy-sician to select other courses of action in individual cases. In all cases, theselected course of action should be considered by the treating providerin the context of treating the individual patient. Use of the informationis voluntary. ASCO provides this information on an “as is” basis andmakes no warranty, express or implied, regarding the information.ASCO specifically disclaims any warranties of merchantability or fitnessfor a particular use or purpose. ASCO assumes no responsibility for anyinjury or damage to persons or property arising out of or related to anyuse of this information, or for any errors or omissions.

3.3. Guideline and conflicts of interest

The Expert Panel was assembled in accordance with ASCO's Conflictof Interest Policy Implementation for Clinical Practice Guidelines (“Pol-icy,” found at http://www.asco.org/rwc). Allmembers of the Panel com-pleted ASCO's disclosure form, which requires disclosure of financial

Table 1Phase III RCTs of neoadjuvant chemotherapy in stage III or IV epithelial ovarian cancer.

Author YearStudy

Enrollment criteria Primaryendpoint

Studyarm

#ofPts.

Age(years)

StageIV

Optim

Fagotti etal., 2016[34]SCORPION

Pathologically provenovarian cancer, stageIIIC\\IV. Intraoperativehigh tumor load(Fagotti's score of 8 to12) assessed by staginglaparoscopy.

Surgicalcomplications

NACTPCS

5555

5554

7%15%

2745

P =

Kehoe et al.,2015 [2]CHORUS

Stages III or IV ovariancancer based uponimaging or clinicalevidence of pelvic masswith extra-pelvicdisease; CA-125 to CEAratio N 25; if less, had toexclude gastrointestinalcarcinoma.

OS NACTPCS

274276

6566

25%25%

1212

Onda et al.,2014 [5]JCOG0602Meetingabstract

Stage III or IVbased on CT, MRI, andcytological tests.CA-125 N 200 U/ml andCEA b 20 ng/mL

OS NACTPCS

152149

6159

30%32%

3024

P b

Vergote etal., 2010EORTC55971

Biopsy-proven stageIIIC or IV. If no biopsyspecimen, fine-needleaspirate showingadenocarcinoma wasallowed under certaincircumstances.

OS NACTPCS

334336

6362

24%23%

1816

Abbreviations: # of PTS, number of patients; CA-125, cancer antigen 125; CEA, carcinoembryoa Two patients in the PCS group had grade 5 complications.


and other interests, including relationships with commercial entitiesthat are reasonably likely to experience direct regulatory or commercialimpact as a result of promulgation of the guideline. Categories for dis-closure include employment; leadership; stock or other ownership;honoraria, consulting or advisory role; speaker's bureau; researchfunding; patents, royalties, other intellectual property; expert testimo-ny; travel, accommodations, expenses; and other relationships. In ac-cordance with the Policy, the majority of the members of the Paneldid not disclose any relationships constituting a conflict under thePolicy.

4. Results

Four RCTsmet eligibility criteria and form the primary evidence basefor the guideline recommendations [1,2,4,5]. At the time that the recom-mendations were being formulated, two of these trials had been pub-lished [1,2] and two were available only as oral presentations fromnational meetings [4,5]. All four trials enrolled women with stage IIICor IV epithelial ovarian cancer, but two studies also included womenwith sub-stage IIIA and IIIb disease [2,5], and the specific requirementsregarding biopsy, imaging, serum, or staging laparoscopy findings var-ied by study (Table 1). The two published trials provided results foroverall and progression-free survival as well as perioperative morbidityand mortality. Secondary analyses of the European Organisation for

erativee (min)

Noresidualdisease

Grade 3–4 post-operativecomplications

PFS(months)

Overall survival(months)

51

0.0001

58%46%

P = 0.16

6%53%a

P = 0.0001

Not yetreported

Not yet reported

00

39%17%

P = 0.0001

14%24%

P = 0.007

12.010.7

ITTanalysis:HR = 0.91,95% CI 0.76to 1.09

24.122.6

ITT analysis:HR = 0.87, 95%CI 0.72 to 1.05

Upper bound ofone-sided 90%CI = 0.98; excludesnon-inferiorityboundary of 1.18

20

0.001

63%30%

(includesICSresults inPCS arm)

5%15%

P = 0.005

(Non-hematologicaladverse events)

Not yetreported

Not yet reported

05

51%19%

HemorrhageNACT: 4%PCS: 7%

InfectionsNACT: 2%PCS: 8%

VenousNACT: 0PCS: 3%

1212

ITTanalysis:HR = 1.01,90% CI 0.89to 1.15

3029

ITT analysis:HR = 0.98, 90%CI 0.84 to 1.13

P = 0.01 fornon-inferiority

nic antigen; HR, hazard ratio; ICS, interval cytoreductive surgery; ITT, intent-to-treat.


http://www.asco.org/rwc



Research and Treatment of Cancer (EORTC) trial explored survival bypatient subset, and evaluated quality of life. Results from the unpub-lished trials focused on perioperative outcomes.

Elements of study quality were assessed for the two published RCTswith detailed results provided in Data Supplement 1. Factors such asrandomization, intention to treat, funding sources, etc. generally indi-cated a low to intermediate potential risk of bias in each trial. Refer toMethodology Supplement for definitions of quality ratings.

Key results from each RCT are presented in Table 1. In the two pub-lished RCTs, NACT was non-inferior to PCS with respect to overall andprogression-free survival [1,2]. A secondary analysis of the EORTC

Fig. 1. Algorithm for the clinical evaluation and treatment of women with suspected stage


55971 trial suggested that outcomes by treatment arm varied by stageof disease and tumor size [6]. Specifically, patients with stage IIIC cancerand less extensive metastatic tumors (≤45 mm) had higher survivalwith PCS than with NACT, and patients with stage IV disease and largermetastatic tumors (N45 mm) had better survival with NACT than withPCS [6]. In all four RCTs, perioperative morbidity was lower with NACTthan with PCS.

Information about prognostic and predictive factors in ovarian can-cer was collected from nine multicenter or population-based cohortstudies, [7–15] three single-center cohort studies [16–18], and onemeta-analysis [19]. These studies evaluated predictors of optimal

IIIC or IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.




cytoreduction, predictors of perioperative morbidity and mortality, andprognostic factors in advanced ovarian cancer with detailed results pro-vided in Data Supplement 2.

5. Recommendations

An algorithm for the clinical evaluation and treatment of womenwith suspected stage IIIC or IV epithelial ovarian cancer, fallopian tubecancer, or primary peritoneal cancer is displayed at the end of the article( Fig. 1).

5.1. Clinical question 1

What clinical evaluations should be performed in all women withsuspected or newly diagnosed stage IIIC or IV epithelial ovarian cancer?

5.1.1. Recommendation 1.1All womenwith suspected stage IIIC or IV invasive epithelial ovarian

cancer should be evaluated by a gynecologic oncologist prior to initia-tion of therapy to determine whether they are candidates for PCS.(Type: evidence based; benefits outweigh harms; Evidence quality: in-termediate; Strength of recommendation: strong).

5.1.2. Recommendation 1.2A primary clinical evaluation should include a CT of the abdomen

and pelvis with oral and intravenous contrast and chest imaging (CTpreferred) to evaluate the extent of disease and the feasibility of surgicalresection. The use of other tools to refine this assessment may includelaparoscopic evaluation or additional radiographic imaging (e.g., FDG-PET scan or diffusion-weightedMRI). (Type: informal consensus; bene-fits outweigh harms; Evidence quality: intermediate; Strength of rec-ommendation: moderate).

5.1.2.1. Literature review and analysis. Three multicenter cohort studies[8,10,11] and one meta-analysis [19] evaluated CT findings and/orserum CA-125 predictors of suboptimal cytoreduction (residual diseaseN1 cm). The use of CT of the abdomen and pelvis and serum CA-125 aspredictors of suboptimal cytoreduction was evaluated among 350women with stage III or IV ovarian cancer diagnosed from 2001 to2012 [11]. Clinical factors that were associated with suboptimalcytoreduction were age ≥ 60, CA-125 ≥ 500 U/ml, and an American So-ciety of Anesthesiologists (ASA) Physical Status classification of 3 or 4(https://www.asahq.org/resources/clinical-information/asa-physical-status-classification-system). Radiologic predictors of suboptimalcytoreduction were retroperitoneal lymph nodes above the renalhilum (including supradiaphgragmatic) N 1 cm, diffuse small bowel ad-hesions or thickening, small bowel mesentery lesions N1 cm, root of thesuperiormesenteric artery lesions N1 cm, perisplenic lesionsN1 cm, andlesser sac lesions N1 cm.

CT and clinical predictors of suboptimal cytoreduction were alsoevaluated among115women diagnosedwith stage III or IV ovarian can-cer diagnosed between 2005 and 2008 [10]. Factors that were associat-ed with suboptimal cytoreduction were elevated preoperative bloodplatelet count (though this result was not statistically significant); dif-fuse peritoneal thickening, and ascites on at least two-thirds of CTscan slices.

A meta-analysis of 14 studies and 154 additional patients evaluatedpre-treatment CA-125 as a predictor of suboptimal cytoreduction [19].High CA-125 (N500 U/mL) increased the risk of suboptimalcytoreduction (odds ratio 3.69, 95% confidence interval 2.02 to 6.73)but had low sensitivity (68.9%) and specificity (63.2%) as a predictorof suboptimal cytoreduction.

Cross-validation of CT predictors of cytoreduction was performedusing three cohorts of womenwith stage III or IV ovarian cancer treatedat different institutions [8]. Predictors of suboptimal cytoreduction inthe first cohort were diaphragm disease and large bowel mesentery


implants. The accuracy of these predictors was 77% in the first cohortbut was lower in the other two cohorts (34% and 64%, respectively).The researchers concluded that the high accuracy rates of CT predictorsof suboptimal cytoreduction could not be confirmed in cross validation.

While FDG-PET has the potential to informoperability, there are lim-ited data to inform its use on a routine basis. In one prospective evalua-tion, compared to CT alone, FDG-PET was significantly better at thedetection of carcinomatosis involving the subdiaphragmatic and smallbowel peritoneal surfaces but ultimately did not correlate with the ex-tent of surgery required [17].Whole-bodyMRI with diffusion-weightedsequence (WB-DWI/MRI) has also been studied in a small group of pa-tients with suspected ovarian cancer for assessing surgical resection.Compared to CT and FDG-PET/CT, WB-DWI/MRI had higher accuracyin detecting peritoneal staging aswell as high accuracy in detecting dis-tant metastases [18].

The safety and findings of staging laparoscopy have been evaluatedin both a single-institution study and a multicenter study of womenwith advanced ovarian cancer [9,16]. Both studies demonstrated thatstaging laparoscopy is both feasible and safe, and provides a reliable as-sessment of the extent of the disease burden.

5.1.2.2. Clinical interpretation. The initial evaluation of a woman withpresumed stage IIIC/IV ovarian carcinoma should focus on whethershe is a candidate to undergo PCS with acceptable risks and associatedmorbidity. A gynecologic oncologist has specialized in the surgical andmedicalmanagement of gynecologicmalignancies and is trained to per-form the surgery needed tomanage women with ovarian cancer and tounderstand the risks and complications associated with such therapeu-tic procedures. Studies have shown that women with ovarian cancerwho are treated by a gynecologic oncologist are more likely to undergoproper staging, cytoreductive surgery, and receive adjuvant chemother-apy, comparedwith gynecologists and general surgeons, and have supe-rior survival [20–22]. The complex surgery needed to achieve resectionof all visible disease completely or at least to b1 cm is more likely tooccur when the surgery is performed at hospitals with specialists whoperform these procedures frequently [23–26]. Given that residualtumor still serves as the most important predictor of overall survival,the initial decision about surgery requires the input of a gynecologiconcologist.


Which patient and disease factors should be utilized as criteria foridentifying patients who are not suitable for PCS?

5.2.1. Recommendation 2.1Women who have a high perioperative risk profile or a low likeli-

hood of achieving cytoreduction to b1 cm (ideally to no visible disease)should receive NACT. (Type: evidence based; benefits outweigh harms;Evidence quality: intermediate; Strength of recommendation:moderate).

5.2.2. Recommendation 2.2Decisions that women are not eligible for medical or surgical cancer

treatment should be made after a consultation with a gynecologic on-cologist and/or a medical oncologist with gynecologic expertise.(Type: informal consensus; benefits outweigh harms; Evidence quality:intermediate; Strength of recommendation: moderate).

5.2.2.1. Literature review and analysis. Population-based or multicentercohort studies evaluated risk factors for high perioperative morbidityand mortality or for poor overall survival after primary cytoreduction.Using SEER-Medicare data, Thrall et al. analyzed data from more than5000 women age 65 years or older who had undergone cytoreductivesurgery for advanced ovarian cancer [12]. Overall 30-day mortalitywas 8%. Among women with elective admissions and no NACT, 30-day


https://www.asahq.org/resources/clinical-information/asa-physical-status-classification-system

https://www.asahq.org/resources/clinical-information/asa-physical-status-classification-system



mortality varied by age, cancer stage, and comorbidity. Older women(age ≥ 75 years) who had stage III disease and a modified Charlson co-morbidity score of ≥1 or stage IV disease had higher 30-day mortality.These patients accounted for 26% of patients and roughly half of thedeaths, with a thirty-day mortality of 13%. A low-risk group consistedof younger patients (age 65 to 74 years) with either stage III or stageIV disease and a comorbidity score of ≤1. These patients accounted for49% of the patient population and had a 30-day mortality of 4%. The au-thors noted that these results require confirmation from prospectiveinvestigation.

Wright, et al. examined perioperative morbidity and mortalityamong more than 28,000 women diagnosed with ovarian cancer whounderwent surgery between 1998 and 2007 using the Nationwide Inpa-tient Sample [14]. Overall, perioperative morbidity was 17% amongwomen under the age of 50 years, but it rose to 30% among womenage 70 to 79 years and 32% amongwomen age 80 years or older. Inmul-tivariablemodels, rates of surgical site complications,medical complica-tions, infectious complications, and death increased with age, thenumber of radical procedures, and the Charlson comorbidity index.

Patient and tumor factors also contributed to 30-day morbidity inanother study, which examined 564 women who underwent surgeryfor stage III or stage IV cancer from 1994 to 2003 [7]. In a multivariateanalysis, factors that were associated with an increased risk of 30-daymorbidity included: increasing age, an ASA score of 3 or 4, low albumin(b 3.5 g/dl), a higher surgical complexity score, and stage IV disease.Older age and an ASA score of 3 or 4 were also associated with higher3-month mortality.

General prognostic factors in advanced ovarian cancerwere evaluat-ed in a study of 1895 women with stage III ovarian cancer treated withprimary cytoreduction and chemotherapy [13]. Independent predictorsof mortality were older age, worse Gynecologic Oncology Group (GOG)performance status, residual disease, and histology (compared with se-rous tumors,mortalitywas lowerwith endometrioid tumors and higherwith clear cell and mucinous tumors).

5.2.2.2. Clinical interpretation. Factors that have been studied and shownto increase the risk of morbidity associated with cytoreductive surgeryinclude advanced age or frailty, multiple chronic conditions, poor nutri-tional status, low albumin, and newly diagnosed venous thromboembo-lism (Table 2). Recent studies have focused on using tools to assess thepatient's functional age and frailty status, which can better predict therisk of morbidity [27,28]. Additionally a surgical risk calculator basedon the American College of Surgeons NSQIP database has been devel-oped in order to predict surgical complications (http://www.riskcalculator.facs.org/). However, a recent study in a gynecologic on-cology population demonstrated that the calculator was able to predictthe risk of death and cardiac complications, but was not accurate forother surgical complications [29]. The SGO/ASCO Panel looks forwardto reviewing validated and tested, user-friendly risk predictiontools when they are available, but at present, none can be fullyrecommended.

After assessing the patient's status to undergo cytoreductive surgery,an assessment of resectability of the cancer to b1 cm (ideally to no vis-ible disease) must be performed. Baseline imagingwith a CT scan of theabdomen and pelvis and chest imaging (CT preferred) serves as the

Table 2Risk factors for perioperative morbidity or mortality [7,12,14,55].

• Advanced age or frailty• Multiple chronic conditions• Poor nutritional status or low albumin• Ascites• Newly diagnosed venous thromboembolism• Body mass index• Stage• Performance status


standard initial assessment of disease distribution and the initial evalu-ation of feasibility of resection. Women who have evidence of diseasethat has spread to the lungs ormediastinum, unresectable parenchymallivermetastasis, bulky periportal lymph nodes,mesenteric retraction, ornon-resectable extra abdominal lymph nodes are best treated with ini-tial NACT. While the goal for primary surgery should be resection to novisible disease, maximal cytoreduction to b1 cm still provides benefit[30], including the option of receiving intraperitoneal and intravenous(IP/IV) chemotherapy, which has a demonstrated survival benefit com-pared with intravenous (IV) chemotherapy [31]. Women with a lowlikelihood of achieving cytoreduction to b1 cm (ideally to no visible dis-ease), due to disease distribution, should receive NACT.

At present there are no prospectively validated non-operative toolsto predict the likelihood of maximal cytoreduction to b1 cm or no visi-ble disease. CT imaging may underestimate the distribution of disease,and therefore may have limitations for predicting which women canachieve surgical cytoreduction to b1 cm (ideally to no visible disease).Alternative imaging modalities including WB-DWI/MRI MRI and/orpositron emission tomography have also been suggested to be usefulin evaluating the extent of disease, but they require further evaluationbefore being recommended. More recently, the use of diagnostic lapa-roscopy has been suggested as a modality to better assess tumor distri-bution andpredict surgical resection to a goal of no visible postoperativetumor or residuum. Some centers have demonstrated external validityusing laparoscopic evaluation of tumor distribution for this purpose. Ina randomized trial from the Netherlands, Buist, et al., reported that lap-aroscopywas of additive value to predict the outcome of PCS and to pre-vent futile laparotomies [32]. However, at present, the role oflaparoscopy is still undefined as there are insufficient published datato suggest that it is more accurate than clinical or radiologic studies. ACochrane review of multiple trials did not show a decrease in the ratesof women undergoing a suboptimal debulking surgerywhen laparosco-py was used in the triage of a patient with ovarian cancer; however, theauthors noted that no women (who might achieve maximalcytoreduction to b1 cm or no visible disease) were excluded from hav-ing cytoreductive surgery [33].


How do NACT and PCS compare with respect to progression-freesurvival, overall survival, and perioperative morbidity and mortality inwomen with newly diagnosed stage IIIC or IV epithelial ovarian cancerwho are fit for primary cytoreduction and have potentially resectabledisease, and how should this information be used to select initialtreatment?

5.3.1. Recommendation 3.1For women who are fit for PCS, with potentially resectable disease,

either NACT or PCS may be offered based on data from phase III RCTsthat demonstrate that NACT is non-inferior to PCS with respect to pro-gression-free and overall survival. NACT is associated with less peri-and postoperativemorbidity andmortality and shorter hospitalizations,but PCSmay offer superior survival in selected patients. (Type: evidencebased; benefits outweigh harms; Quality of evidence: intermediate;Strength of recommendation: moderate).

5.3.2. Recommendation 3.2For women with a high likelihood of achieving a cytoreduction to

b1 cm (ideally to no visible disease) with acceptable morbidity, PCS isrecommended over NACT. (Type: evidence based; benefits outweighharms; Evidence quality: intermediate; Strength of recommendation:moderate).

5.3.3. Recommendation 3.3For women who are fit for PCS but are deemed unlikely to have

cytoreduction to b1 cm (ideally to no visible disease) by a gynecologic


http://www.riskcalculator.facs.org

http://www.riskcalculator.facs.org



oncologist, NACT is recommended over PCS. NACT is associated withless peri- and post-operative morbidity and mortality and shorter hos-pitalizations. (Type: evidence based; benefits outweigh harms; Qualityof evidence: intermediate; Strength of recommendation: moderate).

5.3.3.1. Literature review and analysis. Four randomized clinical trials –EORTC 55971, CHORUS, JCOG0602, and SCORPION – have comparedNACT and interval cytoreduction with primary cytoreduction and che-motherapy amongwomenwith stage IIIC or IV epithelial ovarian cancer(CHORUS and JCOG0602 also includedwomenwith stage IIIA and stageIIIB disease).

In EORTC 55971 [1], 670 women were randomly assigned to eitherPCS followed by at least six cycles of platinum-based chemotherapy orto three cycles of neoadjuvant platinum-based chemotherapy, followedby interval cytoreduction in thosewhohad a response to chemotherapyor stable disease, followed by at least three cycles of platinum-basedchemotherapy. Among women in the primary cytoreduction arm, 94%underwent primary cytoreduction and 88% started chemotherapy.Amongwomen in the NACT arm, 98% started NACT and 88% underwentinterval cytoreduction. Residual tumor of 1 cm or less was achieved in42% of patients in the primary cytoreduction arm and in 81% of patientsin the NACT arm. In the intent-to-treat analysis, the NACT armwas non-inferior to the PCS arm with respect to the primary outcome of overallsurvival (Table 1). Perioperative morbidity and mortality were numeri-cally lower in the NACT arm. In a subset analysis, patientswith stage IIICcancer and less extensive metastatic tumors (≤45mm) had higher sur-vival with PCS than with NACT, and patients with stage IV disease andlarger metastatic tumors (N45 mm) had better survival with NACTthan with PCS [6]. Patients outside of these two subgroups had similarsurvival with either NACT or PCS.

In the CHORUS trial [2], 550 women were randomly assigned to ei-ther PCS followed by six cycles of platinum-based chemotherapy or tothree cycles of NACT, followed by interval cytoreduction, followed bythree courses of platinum-based chemotherapy. Of the 276 women inthe PCS arm, 91% underwent surgery and 77% started postoperativechemotherapy. Of the 274 women in the NACT arm, 92% receivedNACT and 79% underwent interval cytoreduction. Cytoreduction tob1 cm residual disease was achieved in 41% of patients in the PCS armand 73% of patients in the NACT arm (P = 0.0001). The NACT arm wasnon-inferior to the PCS arm with respect to the primary outcome ofoverall survival (Table 1). Postoperative mortality and serious (grade 3or 4) postoperative adverse events were less common in the NACTarm than in the PCS arm. The frequency of serious chemotherapy-relat-ed adverse events was not statistically significantly different in the twostudy arms.

The SCORPION trial examined perioperative outcomes for 55women assigned to PCS and 52 women assigned to NACT, all of whomhad a significant upper abdominal disease burden [34]. Completecytoreduction was achieved in 58% of women in the NACT arm and46% of women in the primary cytoreduction arm, with a shortermedianoperative time in the neoadjuvant arm (Table 1). The frequency ofupper abdominal procedures and major postoperative complicationswas lower in the neoadjuvant arm, as was the length of hospital stays.

Data from JCOG 0602 were presented at the 2014 ASCO AnnualMeeting [5]. Three hundred and one women were randomly assignedto either PCS followed by eight cycles of carboplatin and paclitaxel orto NACTwith four cycles of carboplatin and paclitaxel followed by inter-val cytoreduction, followed by four more cycles of paclitaxel andcarboplatin. Operative time during surgery was longer in the NACTarm than in the PCS arm, but patients in the NACT arm experiencedless blood loss and ascites during or after surgery, and were less likelyto experience a grade 3 or grade 4 non-hematological adverse eventsafter surgery (Table 1).

One significant limitation of NACT, compared with PCS, is that thereare insufficient data to support the use of IP/IV chemotherapy as adju-vant treatment after NACT. Several RCTs have demonstrated that IP/IV


chemotherapy improves survival in optimally resected, stage III ovariancancer, compared with IV chemotherapy alone [31,35,36]. In GOG 172,women who received IP/IV chemotherapy had a 16-month improve-ment in median overall survival, compared with women treated withIV chemotherapy alone [31].

5.3.3.2. Clinical interpretation. To date, the EORTC and CHORUS studiesare the only published randomized phase III trials to compare NACTand PCS. In both studies themedian progression-free and overall surviv-al were similar among womenwho received NACT followed by intervalcytoreductive surgery (ICS) and those who underwent PCS followed bychemotherapy. However, critics of these trials have noted that both hada shorter median overall survival than what has been reported in previ-ous studies. Prior phase III clinical trials have reported median overallsurvival times of 45–66 months in women who undergo PCS withb1 cm of residual disease, while the median overall survival was only32months and 44months in patients with b1 cm residual and no resid-ual disease, respectively, after PCS in the EORTC study. Additionally,some have argued that the “surgical effort” in both EORTC and CHORUSmay be lower than the standard of care since the median operativetimes and rates of upper abdominal surgeries were lower than expectedin clinical practice and much lower than what was reported in theSCORPION and JCOG0602 trials.

Alternatively, the lower median overall survival reported in theEORTC and CHORUS trials may reflect the population of patients whowere willing to be randomized to a trial comparing PCS and NACT andwho had clear evidence of advanced stage disease based on imagingonly. The short survival results may reflect the trial participants, ratherthan differences in treatment, which included a population of patientswho were older, with a poorer performance status, and had higherstage tumors comparedwith other trials. Observational studies examin-ingwomen N65 years of age in the SEER-Medicare database hadmediansurvivals that were similar to the EORTC and CHORUS trial participants[37,38]. In addition, nearly 25% of the patients enrolled in the CHORUStrial received single agent carboplatin instead of a platinum-based dou-blet in both the PCS and neoadjuvant arms. Together, these results sug-gest that PCS and NACT have similar results in this patient population,but it remains to be seen whether these results apply to populationsof patients who are younger, have better performance statuses, orhave less bulky disease in light of the data from an exploratory subsetanalysis of EORTC, which showed that patients with less extensive tu-mors (≤ 45mm) had better survival with PCS compared with NACT [6].

The extent of residual disease after PCS is a significant prognosticpredictor in ovarian cancer reviews [30,39]. A recent meta-analysis ofstudies evaluating survival among patients undergoing PCS for ad-vanced ovarian cancer demonstrated a significant survival advantageassociated with patients who had no gross visible disease after surgery;each 10% increase in cytoreduction to no visible disease was associatedwith a 2.3month increase in median survival [39]. It is unclear whetherthe extent of residual disease reflects tumor biology, surgical aggres-siveness, or both, but PCS to b1 cm (ideally no visible disease) remainsone of the most significant predictors of survival. Therefore, PCS is rec-ommended for those patients with a high likelihood of achieving acytoreduction to b1 cm (ideally no visible disease) with acceptablemorbidity.


What additional clinical evaluations should be performed in allwomen with suspected or newly diagnosed stage IIIC or IV epithelialovarian cancer before NACT is delivered?

5.4.1. Recommendation 4Before NACT is delivered, all patients should have histologic confir-

mation (core biopsy preferred) of an invasive ovarian, fallopian tube,or peritoneal cancer. In exceptional cases, when a biopsy cannot be




performed, cytologic evaluation combined with a serum CA-125 tocarcinoembryonic antigen (CEA) ratio N 25 is acceptable to confirmthe primary diagnosis and exclude cancers that are not ovarian,fallopian tube, or primary peritoneal carcinomas (Type: informal con-sensus; benefits outweigh harms; Evidence quality: intermediate;Strength of recommendation: moderate).

5.4.1.1. Literature review and analysis. The frequency of other non-ovari-an cancers was described in both the EORTC and CHORUS trials. In theEORTC trial, eligible patients had to have either biopsy-proven stageIIIC or IV invasive epithelial ovarian cancer, primary peritoneal cancer,or fallopian tube cancer, or fine needle aspirate showing adenocarcino-ma in a patient with a pelvic mass, metastases outside the pelvis of atleast 2 cm in diameter, regional lymph node metastasis, or proof ofstage IV disease, and a CA-125 to CEA ratio of N25 [1]. If the CA-125 toCEA ratio was 25 or lower, patients had to have a barium enema or co-lonoscopy, gastroscopy or radiologic examination of the stomach, andmammography to exclude presence of an alternate primary tumor.Using these criteria, the incidence of other malignancies was 3%, with18 of 670 randomized patients having a change in diagnosis aftercytoreductive surgery.

In the CHORUS trial, participants had clinical or radiographic evi-dence of a pelvic mass with extrapelvic disease compatible with FIGO1988 stage III or IV ovarian, fallopian tube, or primary peritoneal cancer,and a CA-125 to CEA ratio N 25 [2]. If the CA-125 to CEA ratio was b25, agastrointestinal carcinoma had to be excluded. For women assigned toNACT, the diagnosis was confirmed by laparoscopy, biopsy, or cytology.Among the 474 study participants who had surgery, 3% were found tohave a non-ovarian cancer.

5.4.1.2. Clinical interpretation. A central tenet of oncology is that pathol-ogy should be obtained before treatment is initiated to confirm that amalignancy is present, to identify the site of origin, and to plan optimaltreatment since malignancies are treated differently based upon theirsite of origin. Thus, all patients must have a histologic or cytologic eval-uation (core biopsy preferred) to confirm the primary diagnosis of aninvasive ovarian, fallopian tube, or primary peritoneal cancer and ex-clude other primaries before receiving chemotherapy. In addition, dataon inherited mutations (e.g., germline BRCA), cell surface proteins(e.g., PD-L1), and the tumor microenvironment are beginning to be uti-lized for treatment selection and clinical trial enrollment [e.g.,poly(ADP-ribose) polymerase (PARP) inhibitors, immunotherapy]. Thepanel expects that this information will become increasingly importantwith time, and thus recommends obtaining a core biopsy prior to treat-ment to perform immunohistochemistry to verify the diagnosis and siteof origin since cytology may be insufficient to distinguish between bor-derline and invasive cancer cells and tumor cells may be too necrotic toidentify after exposure to chemotherapy.


What is the preferred chemotherapy regimen for womenwith stageIIIC or IV epithelial ovarian cancer who will receive NACT?

5.5.1. Recommendation 5For NACT, a platinum/taxane doublet is recommended. However, al-

ternate regimens, containing a platinum agent, may be selected basedon individual patient factors. (Type: evidence based; benefits outweighharms; Evidence quality: intermediate; Strength of recommendation:moderate).

5.5.1.1. Literature review and analysis. Since the publication of GOG 111,GOG 158, and AGO-OVAR3 [40–42], the standard of care for first-linetreatment of advanced ovarian cancer has been six cycles of carboplatinand paclitaxel. In the EORTC trial, 83% of patients received treatmentwith a combination of carboplatin and paclitaxel delivered every three


weeks. However, only 76% of CHORUS participants received bothcarboplatin and paclitaxel; nearly 24% were treated with single-agentcarboplatin. Alternate regimens were used rarely in both trials: 6.3% ofparticipants in EORTC and 1% in CHORUS received another chemother-apy combination. Information on the use of specific chemotherapy reg-imens in the JCOG0602 or SCORPION trials is limited.

5.5.1.2. Clinical interpretation. Treatment of advanced ovarian cancer hasevolved over the past decade. Several large phase III studies have dem-onstrated improved survivalwith alternate treatment strategies, includ-ing IP/IV chemotherapy [31], dose-dense paclitaxel [43], and theaddition of bevacizumab for patients with inoperable or suboptimallycytoreduced disease [44]. To date, randomized trials of NACT have test-ed an every three-week regimen of intravenous carboplatin and pacli-taxel. At some institutions, clinicians have replaced the 3-weekadministration of paclitaxel with the “dose-dense” weekly approach inlight of the superior survival demonstrated in JGOG 3016 [43]. Similarly,in GOG 262, which compared carboplatin and weekly paclitaxel tocarboplatin and paclitaxel every 3 weeks (with administration ofbevacizumab at the discretion of the treating physician, but deliveredto 84% of patients), patients who received weekly paclitaxel had a sim-ilar progression-free survival to those who received carboplatin andpaclitaxel with bevacizumab every 3 weeks in the intent-to-treat anal-ysis [45]. In the 112-patient cohort in whom bevacizumab was notused, patients receiving weekly paclitaxel (n = 55) had a significantlylonger median PFS (14.2 months vs 10.3 months, HR 0.62 95% CI:0.40–0.95). In the MITO-7 trial, however, weekly administration oflower doses of carboplatin and paclitaxel was not superior to everythree weeks administration of carboplatin and paclitaxel [46]. Thus,the use ofweekly paclitaxel for NACT should be formally tested in futureclinical trials.

At many institutions, patients who receive NACT are not treatedwith IP/IV chemotherapy after ICS. At present, data on the use of IP/IVchemotherapy after NACT and ICS is limited. A phase II Southwest On-cology Group Study examined the use of IP/IV chemotherapy afterNACT and ICS in a group of patients with bulky stage III/IV (pleural effu-sion only) ovarian cancer for whom optimal cytoreduction was thoughtto be unlikely on radiographic imaging. Among 58 eligible patients, only26 patients received NACT, ICS, and post-operative IP/IV chemotherapy;in this group, the median progression free and overall survival were 29and 34 months, respectively [47]. Another ongoing multi-national ran-domized phase II study, PETROC/OV21, is comparing IP/IV carboplatinand paclitaxel versus continued treatmentwith intravenous carboplatinand paclitaxel amongwomen who received NACT and optimal ICS [48].This trial was originally designed as a phase II/III clinical trial, but waslater modified to a randomized phase II trial due to poor accrual. Never-theless, in an interim analysis, reported in abstract form, IP/IV chemo-therapy was found to be both feasible and safe to use after NACT [49].A comparison of the rates of progression-free survival at 9 months(the new primary end point of the trial) showed 42.2% of women ran-domized to receive IV chemotherapy had progressive disease, com-pared with 23.3% of those who received IP/IV chemotherapy. Whilethese studies suggest that it is feasible and safe to use IP/IV chemother-apy after optimal ICS, there are insufficient data about the efficacy of thisapproach to make a formal recommendation either for or against theuse of IP/IV chemotherapy after NACT at this time.


Among women treated with NACT, does the timing of ICS or thenumber of chemotherapy cycles after ICS affect the safety or efficacyof treatment?

5.6.1. Recommendation 6RCTs tested surgery following three or four cycles of chemotherapy

in women who had a response to NACT or stable disease. ICS should




beperformed after ≤4 cycles of NACT forwomenwith a response to che-motherapy or stable disease. Alternate timing of surgery has not beenprospectively evaluated but may be considered based on patient-cen-tered factors. (Type: informal consensus; benefits outweigh harms; Ev-idence quality: insufficient; Strength of recommendation: weak).

5.6.1.1. Literature review and analysis. RCTs have not addressed whetherthe timing of ICS or the number of chemotherapy cycles after ICS affectthe safety or efficacy of treatment. In both the EORTC and CHORUS stud-ies, patients received three cycles of NACT before ICS and three cyclesthereafter. In the JCOG0602 study, ICS followed four cycles ofcarboplatin and paclitaxel, but survival data from this trial are not ex-pected until 2017.

Rates of cytoreduction to b1 cm (and no visible disease) are higheramong patients treated with NACT, compared with PCS, but haveless prognostic significance [1]. Böhm S, et al., have developed andvalidated the three-tier “Chemotherapy Response Score” as a simple,prognostically significant, and reproducible system for grading the re-sponse toNACTusing ICS specimens [15]. This three-tier scoring system,whichuses pathologists' ratings of themost viable residual disease pres-ent in the omentum at ICS (where lower scores indicate poor responseto NACT and higher scores indicate good response), predicted PFS andsensitivity to first-line platinum in analyses that adjusted for age,stage, and debulking status.

5.6.1.2. Clinical interpretation. Patients' responses to NACT should be reg-ularlymonitoredwith clinical assessments and routinemeasurement ofCA125 each cycle and radiographic imaging should be performed early(preferentially after 3 cycles of chemotherapy) to assess clinical re-sponse. To date, phase III studies have only tested surgery after≤4 cycles of chemotherapy, and alternate timing has not been prospec-tively evaluated. Future studies should validate the Chemotherapy Re-sponse Score in prospective RCTs, and explore whether it can be usedto risk-stratify patients for additional treatment.


What are the treatment options for patientswith progressivediseaseon NACT?

5.7.1. Recommendation 7Patients with progressive disease on NACT have a poor prognosis.

Options include alternative chemotherapy regimens, clinical trials,and/or discontinuation of active cancer therapy and initiation of endof life care. In general, there is little role for surgery and it is not typicallyadvised, unless for palliation (e.g., relief of a bowel obstruction). (Type:evidence based; benefits outweigh harms; Evidence quality: intermedi-ate; Strength of recommendation: strong).

5.7.1.1. Literature review and analysis. Women who develop progressivedisease during first-line treatment with chemotherapy (i.e. platinum-refractory disease) have a poor prognosiswith amedian overall survivalof b1 year, and often shorter [50]. RCTs have not compared treatmentoptions for women who develop progressive disease during NACT.However, if treatment with further chemotherapy is appropriate, thenuse of agents that do not have cross-resistance to carboplatin orpaclitaxel (e.g., gemcitabine, pegylated liposomal doxorubicin, orbevacizumab) would be recommended.

5.7.1.2. Clinical interpretation. Patients who develop progressive diseaseduring NACT should avoid ICS unless they have a demonstrated re-sponse to an alternate chemotherapy. It is very unlikely that an optimalsurgical cytoreduction can be achieved in patients with primary plati-num-refractory disease, and the survival benefit of a potentially morbidsurgery is uncertain in this context. Instead, patients should be offeredopportunities to participate in clinical trials, palliative chemotherapy


with alternate agents, and/or discontinuation of active cancer therapyand initiation of end of life care.

6. Patient and clinician communication

For women with advanced ovarian cancer, decision-making regard-ing first-line treatment should be a process that is shared between clini-cians and their patients [51]. Clinicians must communicate evidence-based options for treatment, inclusive of their benefits and risks, and pa-tients must be allowed to express their goals and preferences. It's im-portant to recognize that patients are no longer reliant solely upontheir medical team for information, and often access other sources on-line, in-print, or through social media and support groups.

For patients faced with a decision between PCS and NACT, it is es-sential that providers first explain the diagnosis, including the extentof disease identified, stage, and prognostic implications of what isknown. Only by ensuring a common starting point can each discussand ultimately decide on a treatment plan. For women in whomthe choice is between NACT and PCS, sharing data about comparativemorbidity, survival, and quality of life outcomes in plain languagecan help to ensure understanding and help patients make more in-formed decisions.

7. Health disparities

Although ASCO clinical practice guidelines represent expert recom-mendations on the best practices in disease management to providethe highest level of cancer care, it is important to note that many pa-tients have limited access to medical care. Racial and ethnic disparitiesin health care contribute significantly to this problem in the UnitedStates. Patients with cancer who are members of racial/ethnic minori-ties suffer disproportionately from comorbidities, experience moresubstantial obstacles to receiving care, are more likely to be uninsured,and are at greater risk of receiving care of poor quality than otherAmericans. Many other patients lack access to care because of their geo-graphic location and distance from appropriate treatment facilities.Awareness of these disparities in access to care should be consideredin the context of this clinical practice guideline, and health care pro-viders should strive to deliver the highest level of cancer care to thesevulnerable populations.

Older women with ovarian cancer also receive less surgery andchemotherapy than younger women, suffer worse toxicity, andhave worse overall survival. Performance status alone has beenshown to be an inadequate tool to predict toxicity of older patientsfrom therapy. Use of formal geriatric assessment tools is a promisingdirection for risk-stratifying older patients on trials [52]. The GOG el-derly group recently completed two important trials: 1) the firstprospective trial of first-line chemotherapy in an older patientpopulation in the US (comparing: dose-modified carboplatin,carboplatin/paclitaxel and carboplatin/weekly paclitaxel) and 2) ageriatric preoperative assessment tool to predict surgical morbidity.Both studies included patients who received NACT. Once published,these results will further guide clinicians in the treatment of olderwomen with ovarian cancer.

8. Multiple chronic conditions

Creating evidence-based recommendations to inform treatment ofpatients with additional chronic conditions, a situation in which the pa-tient may have two or more such conditions – referred to as multiplechronic conditions (MCC) – is challenging. PatientswithMCCare a com-plex and heterogeneous population, making it difficult to account for allof the possible permutations to develop specific recommendations forcare. In addition, the best available evidence for treating index condi-tions, such as cancer, is often from clinical trials whose study selectioncriteria may exclude these patients in order to avoid potential




interaction effects or confounding of results associated with MCC. As aresult, the reliability of outcome data from these studiesmay be limited,thereby creating constraints for expert groups to make recommenda-tions for care in this heterogeneous patient population.

As many patients for whom guideline recommendations applypresent with MCC, any treatment plan needs to take into accountthe complexity and uncertainty created by the presence of MCCand highlights the importance of shared decision making regardingguideline use and implementation. Therefore, in consideration ofrecommended care for the target index condition, clinicians shouldreview all other chronic conditions present in the patient and takethose conditions into account when formulating the treatment andfollow-up plan.

9. Cost implications

Decisions between PCS and NACT should be driven by the expect-ed clinical risks and benefits rather than by cost. Nevertheless, costmay warrant consideration when the two treatment options appearsimilarly beneficial, or when cost is an important concern for the pa-tient. The comparative cost of PCS and NACT has been evaluatedusing observational data from SEER-Medicare. Among 4506 olderwomen with advanced ovarian cancer, the costs associated withPCS and NACT were similar for women with stage IIIC disease, butPCS was associated with higher costs in womenwith stage IV disease[53]. The cost of care among older women (≥age 65 years) with ad-vanced ovarian cancer has also been evaluated using a five-year Mar-kov model which assumed similar overall survival with PCS andNACT based upon the results of EORTC 55971 [54]. In this study,NACT was associated with a cost savings of $5616 compared withPCS, when costs included surgery, chemotherapy, and hospitalstays. To date, researchers have not included quality-adjusted life-years (QALY) in comparisons of the costs between PCS and NACT.Given the limitations of current data, the relative costs of the twotreatment approaches remain uncertain.

10. External review

The draft was submitted to two external reviewers with content ex-pertise in medical and gynecologic oncology. Revisions made in re-sponse to the external reviews were reviewed and approved by theExpert Panel.

11. Guideline implementation

ASCO guidelines are developed for implementation acrosshealth settings. Barriers to implementation include the need to in-crease awareness of the guideline recommendations among front-line practitioners and survivors of cancer and caregivers, and toprovide adequate services in the face of limited resources. Theguideline Bottom Line Box was designed to facilitate implementa-tion of recommendations. This guideline will be distributed widelythrough the ASCO Practice Guideline Implementation Network.ASCO guidelines are posted on the ASCO Web site and most oftenpublished in the Journal of Clinical Oncology and the Journal of On-cology Practice.

12. Future directions

There are several areas that the panel agreed required future study,including:

• Development and validation of a pre-operative risk prediction modelto identify patients who are at high-risk of morbidity from PCS.

• Optimized selection criteria to determine whether an R0 resectionis feasible with PCS based upon radiographic imaging and/or


laparoscopic findings.• Examination of the value of functional imaging (e.g., perfusion CT, dy-namic MRI, PET\\CT) in risk-stratifying patients for PCS vs. NACT.

• Prospective validation of the Chemotherapy Response Score in RCTs,and an exploration of whether it can be used to risk-stratify patientsfor future therapies after completion of adjuvant chemotherapy.

• Determination of benchmarks for clinical complete remission rate,pathologic complete remission rate, and progression-free survival inpatients treated with NACT to facilitate the design of clinical trials inthis population.

• Exploration of novel agents in the NACT setting (e.g., targeted thera-pies, immunotherapy, vaccines, and cancer stem cell directed treat-ments) with or without chemotherapy.

• Determination of whether there is a role for IP/IV chemotherapy inthe setting of NACT.

• Prospective study of weekly dose-dense paclitaxel vs every-three-week paclitaxel in the setting of NACT

• Prospective study to determine the ideal timingof ICS and the numberof cycles of chemotherapy delivered before and after surgery.

• Performance of a large, pragmatic, randomized clinical trial of PCS vs.NACT in the United States since themedian overall survival, mean op-erative time, and rates of optimal cytoreduction in existing trials werelower than expected.

• Development of an ASCO Value in Cancer Care Framework for NACT.

Conflict of interest

Alexi A. WrightNo relationship to disclose

Kari BohlkeNo relationship to disclose

Deborah K. ArmstrongConsulting or Advisory Role: Morphotek, Eisai (I), Vertex

Research Funding: Clovis Oncology, AstraZeneca, Eisai (I), Exelixis(I)

Other Relationship: US Food and Drug Administration, Eviti

Michael A. BookmanEmployment:McKessonHonoraria: Genentech/RocheConsulting or Advisory Role: Boehringer Ingelheim, Genentech/

Roche, AstraZeneca, Abbvie, Sanofi, Novartis, Immunogen, Endocyte,Gradalis, Oxigene, Vertex, Pfizer, Clovis Oncology, Tesaro

William A. ClibyResearch Funding: GamaMabs Pharma

Robert L. ColemanHonoraria: National Comprehensive Cancer Network, Clovis Oncol-

ogy, Genentech/Roche, Esperance Pharmaceuticals, Department of De-fense-Congressionally Directed Medical Research Programs

Research Funding: AstraZeneca/MedImmune, Esperance Pharma-ceuticals, OncoMed, Array BioPharma, Clovis Oncology, Amgen, Johnson& Johnson, Merrimack

Travel, Accommodations, Expenses: Millennium, Merck, Amgen,AstraZeneca/MedImmune, Array BioPharma, Merrimack, Gradalis,Bayer, Clovis Oncology

Don S. DizonConsulting or Advisory Role: UpToDate, PfizerResearch Funding: Aeterna Zentaris

Joseph J. KashSpeakers’ Bureau: Novartis



Table A1Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gy-necologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline,Expert Panel membership

Alexi A. Wright, MD, MPH,Co-Chair

Dana-Farber Cancer Institute, Harvard MedicalSchool, Boston, MA

Mitchell I. Edelson, MD,Co-Chair

Hanjani Institute for Gynecologic Oncology,Abington Hospital, Jefferson Health, Abington, PA

Deborah K. Armstrong, MD Johns Hopkins Sidney Kimmel ComprehensiveCancer Center, Baltimore, MD

Michael A. Bookman, MD US Oncology Research and Arizona Oncology,Tucson, AZ

William A. Cliby, MD Mayo Clinic, Rochester, MNRobert L. Coleman University of Texas, M.D. Anderson Cancer Center,

Houston, TXDon S. Dizon, MD Massachusetts General Hospital Cancer Center,

Harvard Medical School, Boston, MAJoseph J. Kash, MD, (PGINRepresentative)

Edward Cancer Center, Naperville, IL

Larissa A. Meyer, MD, MPH University of Texas, MD Anderson Cancer Center,Houston, TX

Kathleen N. Moore, MD Stephenson Oklahoma Cancer Center at theUniversity of Oklahoma, Oklahoma City, OK

Alexander B. Olawaiye, MD University of Pittsburgh Medical Center, Pittsburgh,PA

Ritu Salani, MD The Ohio State University, Columbus, OHDee Sparacio, (PatientRepresentative)

Hightstown, NJ

William P. Tew, MD Memorial Sloan Kettering Cancer Center, New York,NY

Ignace Vergote, MD, PhD Leuven Cancer Institute, Leuven, European Union

Appendix A


Larissa A. MeyerHonoraria: TRM OncologyResearch Funding: AstraZeneca

Kathleen N. MooreConsulting or Advisory Role: Genentech/Roche (Inst), Immunogen

(Inst), Advaxis, AstraZeneca (Inst), Amgen (Inst), Clovis Oncology(Inst), Merrimack

Alexander B. OlawaiyeConsulting or Advisory Role: Plasma Surgical

Jessica OldhamNo relationship to disclose

Ritu SalaniConsulting or Advisory Role: Clovis

Dee SparacioStock or Other Ownership: Exact Sciences (I), Putnam Global

Health Care FundSpeakers’ Bureau: WEGO Health SolutionsTravel, Accommodations, Expenses: Eye for Pharma, AstraZeneca/

MedImmune

William P. TewNo relationship to disclose

Ignace VergoteConsulting or Advisory Role: AstraZeneca (Inst), Amgen NV

(Inst), Array Biopharma (Inst), Biogen Indec (Inst), BoehringerIngelheim (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Eli Lillyand Company (Inst), Endocyte (Inst), Fresenius (Inst), GE Healthcare(Inst), Genentech (Inst), GlaxoSmithKline (Inst), Hampton MedicalConferences (Inst), Intuitive Surgical (Inst), Janssen-Cilag (Inst),MedImmune (Inst), Menarini Ricerche Spa (Inst), Merck Sharp &Dohme (Inst), Morphotek (Inst), Nektar (Inst), Novo Nordisk (Inst),Oasmia Pharmaceutical AB (Inst), PharmaMar (Inst), PhillipsGilmore Oncology (Inst), Quintiles Belgium (Inst), Roche-Hoffmann(Inst), Sanofi (Inst), Shering-Plough (Inst), Sigma-Tau Pharmaceuti-cals (Inst), Telik (Inst), TRM Oncology (Inst), Kendle Inc Research(Inst)

Research Funding: Amgen (Inst), AstraZeneca (Inst), BoehringerIngelheim (Inst), Bristol-Myers Squibb (Inst), Chugai Pharma (Inst),Eisai (Inst), Exelixis (Inst), Fresenius Biotech (Inst), GlaxoSmithKline(Inst), Proacta (Inst), Ipsen (Inst), Janssen-Cilag (Inst), Merck Sharp &Dohme (Inst), Merrimack (Inst), Morphotek (Inst), Nektar (Inst),NervianoMedical Sciences (Inst), Novartis (Inst), Pfizer (Inst), Quintiles(Inst), Roche (Inst), Sandoz (Inst), Sanofi (Inst), Schering-Plough (Inst),Vifor Pharma (Inst), Wyeth (Inst)

Travel, Accommodations, Expenses: GCI Health, Roche, OasmiaPharmaceutical AB, PharmaMar, AstraZeneca

Mitchell I. EdelsonEmployment:Merck (I)Stock or Other Ownership:Merck (I)

Acknowledgments

The authors wish to thank Jason Wright, Christina Annunziata,Neelima Denduluri, Cynthia Anderson, the ASCO Clinical PracticeGuidelines Committee, the SGO Publications Committee, and theSGO Clinical Practice Committee for their thoughtful reviews andinsightful comments on this guideline document. Dr. Tew receivedsupport through the NIH/NCI Cancer Center Support Grant P30CA008748 and Dr. Wright received support from NIH/NCI K07CA166210 award.


ASCO Staff: Kari Bohlke, ScD; SGO Staff: Jessica Oldham.PGIN, Practice Guideline Implementation Network.

Appendix B. Supplementary data

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.ygyno.2016.05.022.

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