Ovarian Cancer, Version

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1 1134 NCCN Ovarian Cancer, Version Clinical Practice Guidelines in Oncology Robert J. Mgan Jr, MD; Debah K. Armstrong, MD; Ronald D. Alvarez, MD; Jamie N. Bakkum-Gamez, MD; Kian Behbakht, MD; Lee-may Chen, MD; Larry Copeland, MD; Marta Ann Crispens, MD; Maria DeRosa, RN; Oliver Digo, MD, PhD; David M. Gershenson, MD; Heidi J. Gray, MD; Ardeshir Hakam, MD; Laura J. Havrilesky, MD; Carolyn Johnston, MD; Shashikant Lele, MD; Lainie Martin, MD; Ursula A. Matulonis, MD; David M. O Malley, MD; Richard T. Penson, MD, MRCP; Sanja Percac-Lima, MD, PhD; Mario Pineda, MD, PhD; Steven C. Plaxe, MD; Matthew A. Powell, MD; Elena Ratner, MD; Steven W. Remmenga, MD; Peter G. Rose, MD; Paul Sabbatini, MD; Joseph T. Santoso, MD; Theresa L. Werner, MD; Jennifer Burns; and Miranda Hughes, PhD Overview Ovarian neoplasms consist of several histopathologic entities; treatment depends on the specific tum type. 1 Epithelial ovarian cancer comprises the majity of malignant ovarian neoplasms (about 90%) 2 4 ; however, other less common pathologic subtypes may occur. The less common ovarian histopathologies (LCOHs) include carcinosarcomas (malignant mixed Müllerian tums [MMMTs] of the ovary), Abstract This selection from the NCCN Guidelines f Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algithms were added f LCOHs and current algithms were revised f the 2016 update. The new LCOHs algithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tums of the ovary), bderline epithelial tums (also known as low malignant potential tums), malignant sex cd-stromal tums, and malignant germ cell tums. J Natl Compr Canc Netw 2016;14(9): NCCN Categies of Evidence and Consensus Categy 1: Based upon high-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2A: Based upon lower-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Categy 3: Based upon any level of evidence, there is maj NCCN disagreement that the intervention is appropriate. All recommendations are categy 2A unless otherwise noted. Clinical trials: NCCN believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please Note The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) are a statement of consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk (NCCN ) makes no representation warranties of any kind regarding their content, use, application and disclaims any responsibility f their applications use in any way. The full NCCN Guidelines f Ovarian Cancer are not printed in this issue of JNCCN but can be accessed online at NCCN.g. National Comprehensive Cancer Netwk, Inc. 2016, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of NCCN. Disclosures f the NCCN Ovarian Cancer Panel At the beginning of each NCCN Guidelines panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures f panel members, staff, and NCCN itself. Individual disclosures f the NCCN Ovarian Cancer Panel members can be found on page (The most recent version of these guidelines and accompanying disclosures are available on the NCCN Web site at NCCN.g.) These guidelines are also available on the Internet. F the latest update, visit NCCN.g. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016 JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

2 Journal of the National Comprehensive Cancer Netwk NCCN Guidelines Ovarian Cancer 1135 NCCN Ovarian Cancer Panel Members *Robert J. Mgan Jr, MD/Chair City of Hope Comprehensive Cancer Center Debah K. Armstrong, MD/Vice ChairΩ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Ronald D. Alvarez, MDΩ University of Alabama at Birmingham Comprehensive Cancer Center Jamie N. Bakkum-Gamez, MDΩ Mayo Clinic Cancer Center Kian Behbakht, MDΩ University of Colado Cancer Center Lee-may Chen, MDΩ UCSF Helen Diller Family Comprehensive Cancer Center Larry Copeland, MDΩ The Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Marta Ann Crispens, MDΩ Vanderbilt-Ingram Cancer Center Maria DeRosa, RN Oliver Digo, MD, PhDΩ Stanfd Cancer Institute David M. Gershenson, MDΩ The University of Texas MD Anderson Cancer Center Heidi J. Gray, MDΩ University of Washington Medical Center/ Seattle Cancer Care Alliance Ardeshir Hakam, MD Moffitt Cancer Center Laura J. Havrilesky, MDΩ Duke Cancer Institute Carolyn Johnston, MDΩ University of Michigan Comprehensive Cancer Center Shashikant Lele, MDΩ Roswell Park Cancer Institute Lainie Martin, MD Fox Chase Cancer Center clear cell carcinomas, mucinous carcinomas, grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas, bderline epithelial tums (also known as low malignant potential tums), malignant sex cd-stromal tums, and malignant germ cell tums. Fallopian tube cancer and primary peritoneal cancer are less common neoplasms that are managed in a similar manner to epithelial ovarian cancer. However, the LCOHs may be managed differently. This selection from the NCCN Guidelines f Ovarian Cancer focuses on the LCOHs, because new algithms were added to the LCOHs f the 2016 update (see LCOH-1, page 1139). The new algithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/ endometrioid epithelial carcinomas. Other rare histologies had been previously included in the LCOH guidelines and were also revised f These other rare histologies include MMMTs, bderline epithelial tums, malignant sex cd-stromal tums, and malignant germ cell tums. The complete version of the NCCN Guidelines f Ovarian Cancer addresses all aspects of management f the different types of ovarian cancer as well as f fallopian tube cancer and primary peritoneal cancer. These NCCN Guidelines f Ovarian Cancer were iginally published 20 years ago and have been updated subsequently at least once every year. 5 A brief introduction to ovarian cancer is provided in the subsequent section. By definition, the NCCN Guidelines cannot incpate all possible clinical variations and are not intended to replace good clinical judgment individualization of treat- Text cont. on page Ursula A. Matulonis, MDΩ Dana-Farber/Brigham and Women s Cancer Center David M. O Malley, MDΩ The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Richard T. Penson, MD, MRCPΩ Massachusetts General Hospital Cancer Center Sanja Percac-Lima, MDÞ Massachusetts General Hospital Cancer Center Mario Pineda, MD, PhDΩ Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Steven C. Plaxe, MDΩ UC San Diego Moes Cancer Center Matthew A. Powell, MDΩ Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Elena Ratner, MDΩ Yale Cancer Center/Smilow Cancer Hospital Steven W. Remmenga, MDΩ Fred & Pamela Buffett Cancer Center Peter G. Rose, MDΩ Case Comprehensive Cancer Center/ University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute Paul Sabbatini, MD Þ Memial Sloan Kettering Cancer Center Joseph T. Santoso, MDΩ St. Jude Children s Research Hospital/ The University of Tennessee Health Science Center Theresa L. Werner, MD Huntsman Cancer Institute at the University of Utah NCCN Staff: Jennifer Burns and Miranda Hughes, PhD KEY: *Writing Committee member Specialties: ΩGynecology Oncology; Hematology/ Hematology Oncology; Medical Oncology; ÞInternal Medicine; Pathology; Patient Advocacy JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

3 1136 EOC/FTC/PPC* *EPITHELIAL OVARIAN CANCER/FALLOPIAN TUBE CANCER/PRIMARY PERITONEAL CANCER CLINICAL PRESENTATION WORKUP PRIMARY TREATMENT h,i,j Suspicious a /palpable pelvic mass detected on abdominal/pelvic exam and/ ascites, abdominal distention, and/ Symptoms such as bloating, pelvic abdominal pain, diffi culty eating feeling full quickly, urinary symptoms (urgency frequency b without other obvious source of malignancy Obtain family histy c,d Abdominal/pelvic exam Chest x-ray chest CT as clinically indicated Complete blood count (CBC), chemistry profile with liver function test (LFT) GI evaluation f mucinous histology Ultrasound and/ abdominal/pelvic CT/MRI as clinically indicated e,f CA-125 other tum markers as clinically indicated g Laparotomy/total abdominal hysterectomy (TAH)/bilateral salpingo-oophectomy (BSO) with comprehensive staging j unilateral salpingo-oophectomy (USO) (clinical stage 1A 1C, all grades with comprehensive staging if patient desires fertility) Cyteductive surgery j if clinical stage II, III, IV Patients with bulky stage III/ IV who are po surgical candidates due to high-risk combid conditions disease facts require evaluation by a gynecologic oncologist h f consideration of neoadjuvant chemotherapy k (categy 1)/ primary interval cyteduction h Tissue diagnosis pri to initiation of chemotherapy is required All patients with ovarian cancer, Fallopian tube cancer, primary peritoneal cancer should be referred f genetic risk evaluation c,d See Pathologic Staging (OV-3) Diagnosis by previous surgery tissue biopsy (cytopathology) Obtain family histy c Refer f genetic risk evaluation c,d Chest x-ray chest CT as clinically indicated CBC, chemistry profile with LFTs Institutional pathology review Ultrasound and/ abdominal/pelvic CT/MRI as clinically indicated e CA-125 other tum markers as clinically indicated g Consider tissue diagnosis of metastatic sites See Findings and Primary Treatment (OV-2) *Available online, in these guidelines, at NCCN.g. a Im SS, et al. Obstet Gynecol 2005;105: See Discussion. b Goff BA, Mandel L, Drescher CW, et al. Cancer 2007;109: c See NCCN Guidelines f Genetic/Familial High-Risk Assessment: Breast and Ovarian and NCCN Guidelines f Genetic/Familial High-Risk Assessment: Colectal. d Primary treatment should not be delayed f a genetic counseling referral. e Imaging perfmed with contrast unless contraindicated. f PET/CT scan MRI may be indicated f indeterminate lesions if results will alter management. g Other tum markers may include inhibin, beta-human chionic gonadotropin (β-hcg), alpha-fetoprotein, lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA). See Discussion f usefulness of diagnostic tests. h Standard recommendation includes a patient evaluation by a gynecologic oncologist pri to initiating chemotherapy. Published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage. Patients being evaluated f neoadjuvant chemotherapy should be seen by a fellowship-trained gynecologic oncologist pri to being considered a po surgical candidate. A referral to a gynecologic oncologist is also recommended f management of occult serous tubal intraepithelial carcinomas. i All women undergoing surgery f ovarian cancer should be counseled about the clinical benefi t associated with combined IV and IP chemotherapy administration pri to surgery. NCI Clinical Announcement. j See Principles of Surgery (OV-A*). k See Principles of Chemotherapy (OV-B*) and Management of Drug Reactions (OV-C*). OV-1 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

4 NCCN Clinical Practice Guidelines in Oncology 1137 EOC/FTC/PPC* DIAGNOSIS BY PREVIOUS SURGERY FINDINGS l *EPITHELIAL OVARIAN CANCER/FALLOPIAN TUBE CANCER/PRIMARY PERITONEAL CANCER PRIMARY TREATMENT h Adequate previous surgery and staging Suspected stage IA IB/grade 1 l Surgical staging j Incomplete previous surgery j and/ staging: 1. Uterus intact 2. Adnexa intact 3. Omentum not removed 4. Documentation of staging incomplete 5. Residual disease, potentially resectable 6. Occult invasive carcinoma found at time of risk reduction surgery 7. Incomplete lymph node dissection Suspected stage IA IB/grade 2 l Suspected stage IA IB, grade 3 clear cell stage IC l If observation considered Suspect residual disease Suspect no residual disease Suspect residual disease Suspect no residual disease Surgical staging j Completion surgery/surgical staging j Completion surgery/surgical staging j chemotherapy k f 6 cycles Completion surgery/surgical staging j Completion surgery/surgical staging j chemotherapy k f 6 cycles See Pathologic Staging (OV-3) Suspect potentially resectable residual disease Tum reductive surgery j Stage II, III, IV Suspect unresectable residual disease Chemotherapy k f a total of 6 cycles Evaluate f interval debulking surgery pri to fourth cycle of chemotherapy h,m *Available online, in these guidelines, at NCCN.g. h Standard recommendation includes a patient evaluation by a gynecologic oncologist pri to initiating chemotherapy. Published data demonstrate that primary assessment and debulking by a gynecologic oncologist results in a survival advantage. Patients being evaluated f neoadjuvant chemotherapy should be seen by a fellowship-trained gynecologic oncologist pri to being considered a po nonsurgical candidate. A referral to a gynecologic oncologist is also recommended f management of occult serous tubal intraepithelial carcinomas. j See Principles of Surgery (OV-A*). k See Principles of Chemotherapy (OV-B*) and Management of Drug Reactions (OV-C*). l Pathologists recommend that serous ovarian cancer is either low-grade (most grade 1 serous tums) high-grade (most grade 2 3 serous tums). See FIGO Guidelines (ST-5*). m Completion surgery after 3 cycles is preferred; however, surgery may be perfmed after 4 6 cycles based on the clinical judgment of the gynecologic oncologist. OV-2 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

5 1138 EOC/FTC/PPC* *EPITHELIAL OVARIAN CANCER/FALLOPIAN TUBE CANCER/PRIMARY PERITONEAL CANCER PATHOLOGIC STAGING l,n PRIMARY CHEMOTHERAPY/PRIMARY ADJUVANT THERAPY o Less common histology (ie, carcinosarcoma, clear cell, mucinous, grade 1 [low grade] serous, bderline epithelial, malignant sex cd-stromal/germ cell tums) n See LCOH-1 Grade 1 l (low grade) serous/endometrioid See LCOH-5 Stage IA IB Stage lc (Grade 1, 2, 3) Grade 2 l serous/endometrioid Grade 3 l high-grade Observe Intravenous (IV) taxane/carboplatin k x 3 6 cycles o,p IV taxane/carboplatin k x 3 6 cycles o,p Consider symptom management and best supptive care. See NCCN Guidelines f Palliative Care. Refer f palliative care assessment, if appropriate. See Moniting/ Follow-Up (OV-5*) Stage II Stage III Stage IV Chemotherapy (See Primary Regimens (OV-B, 3 of 7) o Intraperitoneal (IP) chemotherapy i,k in <1 cm optimally debulked stage II and stage III patients (categy 1 f stage III) IV taxane/carboplatin k f a total of 6 cycles (categy 1) o Completion surgery as indicated by tum response and potential resectability in selected patients j Consider symptom management and best supptive care. See NCCN Guidelines f Palliative Care. Refer f palliative care assessment, if appropriate. See Secondary Adjuvant Therapy (OV-4*) *Available online, in these guidelines, at NCCN.g. i All women undergoing surgery f ovarian cancer should be counseled about the clinical benefi t associated with combined IV and IP chemotherapy administration pri to surgery. See NCI Clinical Announcement. j See Principles of Surgery (OV-A*). k See Principles of Chemotherapy (OV-B*) and Management of Drug Reactions (OV-C*). l Pathologists recommend that serous ovarian cancer is either low-grade (most grade 1 serous tums) high-grade (most grade 2 3 serous tums). See FIGO Guidelines (ST-5*). n See WHO Histologic Classifi cation (OV-D*). o Patients receiving primary chemotherapy will be monited as follows: 1. Pelvic exams at least every 2 3 cycles 2. Interim CBC with platelets as indicated 3. Chemistry profi les if indicated 4. CA-125 levels other tum markers as clinically indicated pri to each cycle of chemotherapy 5.Chest/abdominal/pelvic CT, MRI, PET-CT, PET as indicated. p Data suggests select patients with serous histology may benefit from 6 cycles. See Discussion. OV-3 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

6 NCCN Clinical Practice Guidelines in Oncology 1139 LESS COMMON OVARIAN HISTOPATHOLOGIES DIAGNOSIS a,b Carcinosarcoma (malignant mixed Müllerian tum [MMMT]) See LCOH-2, below Clear cell carcinoma of the ovary See LCOH-3 Mucinous carcinoma of the ovary See LCOH-4 Surgery c and histologic diagnosis d Grade 1 (low grade) serous/endometrioid epithelial carcinoma See LCOH-5 Bderline epithelial tums (low malignant potential [LMP]) See LCOH-6 Malignant sex cd-stromal tums See LCOH-9 Malignant germ cell tums See LCOH-10 CARCINOMA (MALIGNANT MÜLLERIAN TUMORS) PATHOLOGIC DIAGNOSIS a ADJUVANT TREATMENT e MONITORING/FOLLOW-UP Carcinosarcoma (malignant mixed Müllerian tums [MMMTs]) of the ovary Complete surgical staging c Stage I-IV Treat per Epithelial Ovarian Cancer (See OV-3) Cisplatin/ifosfamide Carboplatin/ifosfamide Paclitaxel/ifosfamide (categy 2B) See Moniting/ Follow-Up (OV-5*) *Available online, in these guidelines, at NCCN.g. a See WHO Histologic Classifi cation (OV-D*). b Due to emerging therapeutics f specifi c histologies, there is value in identifying potential pathways f rare histologies and it may be useful f clinical trial recruitment. There are limited data in these histologies given their infrequency and it will be diffi cult to acquire prospective data. Individualized treatment may be the best treatment f these rare tums. c See Principles of Surgery (OV-A*). d Less common ovarian histopathologies are typically diagnosed after surgery. See Wkup (OV-1). e See Principles of Chemotherapy (OV-B*) and Management of Drug Reactions (OV-C*). LCOH-1 LCOH-2 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

7 1140 CLEAR CELL CARCINOMA OF THE OVARY PATHOLOGIC DIAGNOSIS a ADJUVANT TREATMENT MONITORING/FOLLOW-UP Stage IA-C IV taxane/carboplatin e x 3 6 cycles See Moniting/ Follow-Up (OV-5*) Clear cell carcinoma of the ovary Stage II-IV Treat per Epithelial Ovarian Cancer (See OV-3) Bderline See LCOH-6 MUCINOUS CARCINOMA OF THE OVARY PATHOLOGIC DIAGNOSIS a ADDITIONAL WORKUP ADJUVANT TREATMENT e MONITORING/ FOLLOW-UP Stage IA-IB Observe Mucinous carcinoma of the ovary If not previously done: GI evaluation f Carcinoembryonic antigen (CEA) Consider surgical staging Stage IC Observe IV taxane/carboplatin e x 3 6 cycles 5-FU + leucovin + oxaliplatin Capecitabine + oxaliplatin See Moniting/ Follow-Up (OV-5*) Stage II-IV Chemotherapy (See Primary Regimens, OV-B, 3 of 7) e 5-FU + leucovin + oxaliplatin Capecitabine + oxaliplatin Bderline See LCOH-6 *Available online, in these guidelines, at NCCN.g. a See WHO Histologic Classifi cation (OV-D*). e See Principles of Chemotherapy (OV-B*) and Management of Drug Reactions (OV-C*). f Consider molecular testing f GI malignancies. LCOH-3 LCOH-4 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

8 1141 NCCN Clinical Practice Guidelines in Oncology GRADE 1 (LOW-GRADE) SEROUS/ENDOMETROID EPITHELIAL CARCINCOMA PATHOLOGIC DIAGNOSIS a ADJUVANT TREATMENT MONITORING/FOLLOW-UP Stage IA-IB Observe Grade 1 (Low Grade) Serous/Endometrioid Epithelial Carcinoma Stage IC-II Stage III-IV Observe (categy 2B) IV taxane/carboplatin e x 3 6 cycles Hmone therapy (categy 2B) (ie, aromatase inhibits [anastrozole, letrozole], leuprolide acetate, tamoxifen) Chemotherapy (See Primary Regimens, OV-B, 3 of 7) e Hmone therapy (categy 2B) (ie, aromatase inhibits [anastrozole, letrozole], leuprolide acetate, tamoxifen) See Moniting/Follow-Up (OV-5*) Bderline See LCOH-6, below BORDERLINE EPITHELIAL TUMORS (LOW MALIGNANT POTENTIAL) PATHOLOGIC DIAGNOSIS a ADJUVANT TREATMENT g No invasive implants Observe Bderline epithelial tums (LMP) a Previous surgical staging was comprehensive c Invasive implants Observe Consider treatment as grade 1 (low-grade) serous epithelial carcinoma h (See LCOH-5, above) See Moniting/ Follow-up (LCOH-8, below) Incomplete surgical staging c See LCOH-7 *Available online, in these guidelines, at NCCN.g. a See WHO Histologic Classifi cation (OV-D*). c See Principles of Surgery (OV-A*). e See Principles of Chemotherapy (OV-B*) and Management of Drug Reactions (OV-C*). g Standard recommendation includes a patient evaluation by a gynecologic oncologist. h Chemotherapy (IV IP) has not been shown to be benefi cial in ovarian bderline epithelial tums (LMP). LCOH-5 LCOH-6 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

9 1142 BORDERLINE EPITHELIAL TUMORS (LOW MALIGNANT POTENTIAL) PATHOLOGIC DIAGNOSIS a ADJUVANT TREATMENT g No invasive implants Unknown Observe (categy 2B) Fertility-sparing surgery c and resection of residual disease i Bderline epithelial tum (LMP), incomplete surgical staging a Residual disease remaining after first procedure Fertility desired If no desire f fertility Invasive implants at previous surgery No invasive implants Unknown Invasive implants at previous surgery Fertility-sparing surgery c and resection of residual disease Observe (categy 3) Consider treatment as grade 1 (low-grade) serous epithelial carcinoma (See LCOH-5) Observe (categy 2B) Completion surgery c,i and resection of residual disease Completion surgery c,i and resection of residual disease Observe (categy 3) Consider treatment as grade 1 (low-grade) serous epithelial carcinoma i (See LCOH-5) See Moniting/ Follow-up (LCOH-8, below) No residual disease remaining after first procedure Observe MONITORING/FOLLOW-UP RECURRENT DISEASE RECURRENCE THERAPY Visits every 3 6 mo f up to 5 y, then annually Physical exam including pelvic exam CA-125 j other tum markers every visit if initially elevated After completion of childbearing in patients who underwent USO, consider completion surgery (categy 2B) CBC, chemistry profi le as indicated Imaging as clinically indicated: Chest/ abdominal/pelvic CT, MRI, PET-CT, PET k Ultrasound as indicated f patients with fertility-sparing surgery Clinical relapse Surgical evaluation + debulking if appropriate Noninvasive disease Invasive implants of LMP Low-grade invasive carcinoma Invasive carcinoma (high grade) Observe See grade 1 (low-grade) serous epithelial carcinoma h (LCOH-5) Treatment as epithelial ovarian cancer h (See OV-3) *Available online, in these guidelines, at NCCN.g. a See WHO Histologic Classifi cation (OV-D*). c See Principles of Surgery (OV-A*). g Standard recommendation includes a patient evaluation by a gynecologic oncologist. h Chemotherapy (IV IP) has not been shown to be benefi cial in ovarian bderline epithelial tums (LMP). i F pathologically proven LMP, lymph node evaluation may be considered on a case-by-case basis. j There are data regarding the utility of CA-125 f moniting of ovarian cancer after completion of primary therapy. See The Society of Gynecologic Oncology (SGO) position statement and Discussion. k Imaging perfmed with contrast unless contraindicated. LCOH-7 LCOH-8 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

10 NCCN Clinical Practice Guidelines in Oncology 1143 MALIGNANT SEX CORD-STROMAL TUMORS CLINICAL PRESENTATION/ DIAGNOSIS ADJUVANT TREATMENT RECURRENCE THERAPY Stage I Low risk Observe n Malignant sex cd-stromal tums a Stage IA/IC: Fertility desired Fertilitysparing surgery with complete staging c,l Stage I, high risk (eg, ruptured stage IC poly differentiated stage I) Intermediate risk (eg, heterologous elements) Observe m (categy 2B) Consider platinumbased chemotherapy n (categy 2B) See Surveillance (LCOH-12*) All others Complete staging c,l Stage II-IV Platinum-based chemotherapy n (categy 2B) RT f limited disease (categy 2B) See Surveillance (LCOH-12*) If clinical relapse: Clinical trial Consider secondary cyteductive surgery Recurrence therapy o *Available online, in these guidelines, at NCCN.g. a See WHO Histologic Classifi cation (OV-D*). c See Principles of Surgery (OV-A*). l Lymphadenectomy may be omitted. m Inhibin levels can be followed if initially elevated f granulosa cell tums (categy 2B). n Malignant germ cell regimens paclitaxel/carboplatin regimens are preferred. See Primary Chemotherapy Regimens f Malignant Germ Cell/ Sex Cd-Stromal Tums (OV-B, 4 of 7). o See Acceptable Recurrence Therapies f Malignant Germ Cell/Sex Cd- Stromal Tums (OV-B, 6 of 7). LCOH-9 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

11 1144 MALIGNANT GERM CELL TUMORS CLINICAL PRESENTATION/DIAGNOSIS ADJVUANT TREATMENT g Initial surgery p Fertility desired Fertility not desired Fertility-sparing surgery and comprehensive staging (See OV-A*) Complete staging surgery (See OV-A*) See Treatment (LCOH-11) Malignant germ cell tums Pri surgery p Incompletely staged, consider repeat imaging (CT, MRI, PET-CT) as indicated Dysgerminoma Grade 1 immature teratoma Embryonal, endodermal sinus tum (yolk sac tum), grade 2 3 immature teratoma, mixed histology Positive imaging and positive tum markers Negative imaging and positive tum markers Negative imaging and negative tum markers Positive imaging and positive tum markers Negative imaging and positive negative tum markers Fertility desired, then fertility-sparing surgery and comprehensive staging; fertility not desired, then completion staging surgery (See OV-A*) Consider observation (categy 2B) (See LCOH-12*) Fertility desired, then fertility-sparing surgery and comprehensive staging; fertility not desired, then completion staging surgery with possible tum reductive surgery (See OV-A*) Chemotherapy (See LCOH-11) See Treatment (LCOH-11) Completely staged *Available online, in these guidelines, at NCCN.g. g Standard recommendation includes a patient evaluation by a gynecologic oncologist. p Surgical principles f pediatric/young adult patients may differ from those f adult patients. See Principles of Surgery (OV-A*). LCOH-10 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

12 1145 NCCN Clinical Practice Guidelines in Oncology MALIGNANT GERM CELL TUMORS PATHOLOGIC DIAGNOSIS TREATMENT MONITORING/ FOLLOW-UP RECURRENT/ PERSISTENT DISEASE Stage I Dysgerminoma q Stage I, grade 1 Immature teratoma q Any stage Embryonal tum q Any stage Endodermal sinus tum (yolk sac tum) q Stage II-IV Dysgerminoma Stage I, grade 2 3 Stage II-IV Immature teratoma Observe See Surveillance (LCOH-12*) Chemotherapy r Imaging as clinically indicated: Chest/ abdominal/ pelvic CT, MRI, PET-CT, PET k Complete clinical response Residual tum on radiographic imaging; markers nmal s Persistently elevated markers s with definitive residual disease Observe (See LCOH-12*) Consider surgical resection Observe (See Surveillance LCOH-12*) Abnmal markers, definitive recurrent disease Necrotic tissue Benign teratoma Residual malignancy Consider additional chemotherapy o (categy 2B) High-dose chemotherapy t (categy 2B) Chest/abdominal/ pelvic CT k MRI as clinically indicated Consider additional platinum-based chemotherapy x 2 cycles o TIP (paclitaxel/ifosfamide/cisplatin) High-dose chemotherapy t (strongly recommend referral to tertiary care center f potentially curative regimen) Complete clinical response Incomplete clinical response See OV-B (6 of 7) See Surveillance (LCOH-12) *Available online, in these guidelines, at NCCN.g. k Imaging perfmed with contrast unless contraindicated. o See Acceptable Recurrence Therapies f Malignant Germ Cell/Sex Cd- Stromal Tums (OV-B, 6 of 7). q Pediatric/adolescent patients with the following clinical presentations may consider observation chemotherapy as treatment options: stage IA, IB dysgerminoma; stage IA, grade 1 immature teratoma; stage IA embryonal tums; stage IA yolk sac tums. r See Primary Chemotherapy Regimens f Malginant Germ Cell Tums (OV-B, 4 of 7). s See LCOH-1 f markers. t High-dose chemotherapy regimens vary among institutions. Some patients are potentially curable with stem cell transplantation. Patients with potentially curable recurrent germ cell disease should be referred to a tertiary care institution f stem-cell transplant consultation and potentially curative therapy. LCOH-11 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

13 1146 EOC/FTC/PPC & LCH* *EPITHELIAL OVARIAN CANCER/FALLOPIAN TUBE CANCER/PRIMARY PERITONEAL CANCER & LESS COMMON HISTOPATHOLOGIES PRINCIPLES OF SYSTEMIC THERAPY (3 of 7) Primary Chemotherapy/Primary Adjuvant Therapy Regimens a Ovarian/Fallopian Tube/Primary Peritoneal/Carcinosarcoma/Clear Cell/Mucinous/Bderline Epithelial/Grade 1 (Low-Grade) Serous/Endometrioid Stage II-IV IP/IV Regimen Paclitaxel 135 mg/m 2 IV continuous infusion over 3 24 h c Day 1; cisplatin mg/m 2 IP, Day 2 after IV paclitaxel; paclitaxel 60 mg/m 2 IP Day 8. Repeat every 3 weeks x 6 cycles. (categy 1) IV Regimens b Paclitaxel 175 mg/m 2 IV over 3 hours followed by carboplatin d AUC 5 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. (categy 1) Dose-dense paclitaxel 80 mg/m 2 IV over 1 hour Days 1, 8, and 15 followed by carboplatin d AUC 5 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. (categy 1) Paclitaxel 60 mg/m 2 IV over 1 hour followed by carboplatin AUC 2 IV over 30 minutes. Weekly f 18 weeks. e (categy 1) Docetaxel mg/m 2 IV over 1 hour followed by carboplatin d AUC 5 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. (categy 1) Bevacizumab-containing regimens per ICON-7 and GOG-218: Paclitaxel 175 mg/m 2 IV over 3 hours followed by carboplatin d AUC 5 6 IV over 1 hour, and bevacizumab 7.5 mg/kg IV over minutes Day 1. Repeat every 3 weeks x 5 6 cycles. Continue bevacizumab f up to 12 additional cycles. (categy 2B) Paclitaxel 175 mg/m 2 IV over 3 hours followed by carboplatin d AUC 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. Starting Day 1 of cycle 2, give bevacizumab 15 mg/kg IV over minutes every 3 weeks f up to 22 cycles. (categy 2B) Additional options f the following less common histopathologies: Carcinosarcoma (MMMT) Carboplatin/ifosfamide Cisplatin/ifosfamide Paclitaxel/ifosfamide (categy 2B) Mucinous tums 5-FU/leucovin/oxaliplatin Capecitabine/oxaliplatin Grade 1 (low-grade) serous/endometrioid and bderline epithelial carcinoma Hmone therapy (Aromatase inhibits [ie, anastrozole, letrozole], leuprolide acetate, tamoxifen) (categy 2B) PRINCIPLES OF SYSTEMIC THERAPY (4 of 7) Primary Chemotherapy/Primary Adjuvant Therapy Regimens a Malignant Germ Cell/Sex Cd-Stromal Tums Malignant Germ Cell Tums a BEP (bleomycin, etoposide, cisplatin) f Bleomycin 30 units per week Etoposide 100 mg/m 2 daily f days 1 5, cisplatin 20 mg/m 2 daily f days 1 5 Repeat every 21 days f 3 cycles f good risk (categy 2B), 4 cycles f po risk. Etoposide/carboplatin a F select patients with stage IB-III resected dysgerminoma f whom minimizing toxicity is critical, 3 cycles of etoposide/carboplatin can be used. Carboplatin 400 mg/m 2 on day 1 plus etoposide 120 mg/m 2 on days 1, 2, and 3 every 4 weeks f 3 cycles. Malignant Sex Cd-Stromal Tums BEP (categy 2B) f Paclitaxel/carboplatin (categy 2B) Continued on OV-B 5 of 7 (available online, in these guidelines, at NCCN.g) a See Discussion f references. b IV regimens may be considered f neoadjuvant therapy f epithelial ovarian cancer. c The published randomized trial regimen used IV continuous infusion paclitaxel over 24 h. d Due to changes in creatinine methodology, changes regarding carboplatin dosing can be considered. See FDA carboplatin dosing statement. e This regimen may be considered f elderly patients those with po perfmance status. f Recommend pulmonary function test if considering bleomycin. OV-B 3 and 4 of 7 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

14 NCCN Clinical Practice Guidelines in Oncology 1147 EOC/FTC/PPC & LCH* *EPITHELIAL OVARIAN CANCER/FALLOPIAN TUBE CANCER/PRIMARY PERITONEAL CANCER & LESS COMMON HISTOPATHOLOGIES PRINCIPLES OF SYSTEMIC THERAPY (6 of 7) Acceptable Recurrence Therapies F Malignant Germ Cell/Sex Cd-Stromal Tums Malignant Germ Cell Tums n Cytotoxic Therapy (In alphabetical der) Hmonal Therapy Targeted Therapy Potentially Curative Therapy: High-dose chemotherapy n TIP (paclitaxel, ifosfamide, cisplatin) Radiation Therapy Palliative localized radiation therapy Palliative Therapy Only: Cisplatin/etoposide Docetaxel Docetaxel/carboplatin Paclitaxel Paclitaxel/ifosfamide Paclitaxel/carboplatin Paclitaxel/gemcitabine VIP (etoposide, ifosfamide, cisplatin) VeIP (vinblastine, ifosfamide, cisplatin) VAC (vincristine, dactinomycin, cyclophosphamide) TIP S upptive care only (See NCCN Supptive Care Guidelines, available at NCCN.g) Docetaxel Paclitaxel Paclitaxel/ifosfamide Paclitaxel/carboplatin VAC S upptive care only (See NCCN Supptive Care Guidelines, available at NCCN.g) Malignant Sex Cd- Stromal Tums o Aromatase inhibits (ie, anastrozole, letrozole) Leuprolide acetate (f granulosa cell tums) Tamoxifen Bevacizumab (single agent) Palliative localized radiation therapy *Available online, in these guidelines, at NCCN.g. n High-dose chemotherapy regimens vary among institutions. Some patients are potentially curable with stem cell transplantation. Patients with potentially curable recurrent germ cell disease should be referred to a tertiary care institution f stem-cell transplant consultation and potentially curative therapy. o See WHO Histologic Classification (OV-D*). OV-B 6 of 7 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

15 1148 NCCN Clinical Practice Guidelines in Oncology Text cont. from page ments. Exceptions to the rule were discussed among the panel members while developing these NCCN Guidelines. Epidemiology Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country s fifth most common cause of cancer mtality in women. 6 However, LCOHs are rare cancers that present at an earlier age than epithelial ovarian cancer. The risk f bderline epithelial tums may be increased after ovarian stimulation f in vitro fertilization. 7,8 Family histy (primarily patients having 2 firstdegree relatives with ovarian cancer) including linkage with BRCA1 and BRCA2 genotypes (hereditary breast and ovarian cancer syndrome) families affected by Lynch syndrome (hereditary nonpolyposis colectal cancer syndrome) is associated with earlyonset disease Lynch syndrome is associated with risk f endometrioid carcinomas, clear cell carcinomas, and papillary serous carcinomas In women at high risk (with either BRCA1 BRCA2 mutations), prophylactic bilateral salpingooophectomy (BSO) is associated with a reduced risk f breast, ovarian, fallopian tube, and primary peritoneal cancers Occult ovarian cancer is sometimes found after prophylactic salpingooophectomy, thus emphasizing the need f careful pathologic review of the ovaries and tubes (see Risk-Reducing Salpingo- Oophectomy [RRSO] Protocol in the complete version of these guidelines, available at NCCN.g [OV-A]) The risks of surgery include injury to the bowel, bladder, ureter, and vessels. 32 Screening Because of the location of the ovaries and the biology of most epithelial cancers, it has been difficult to diagnose ovarian cancer at an earlier, me curable stage. However, evaluations of patients with newly diagnosed ovarian cancer have resulted in consensus guidelines f ovarian cancer symptoms, which may enable earlier identification of patients possibly at an increased risk of having early-stage ovarian cancer. 33,34 Symptoms suggestive of ovarian cancer include bloating, pelvic abdominal pain, difficulty eating feeling full quickly, and urinary symptoms (urgency frequency), especially if these symptoms are new and frequent (>12 d/mo). 33 Physicians evaluating women with this constellation of symptoms must be cognizant of the possibility that ovarian pathology may be causing these symptoms. 35 However, some evidence suggests that the screening test using these symptoms is not as sensitive specific as necessary, especially in those with early-stage disease. 32,36 38 Randomized data do not yet suppt routine screening f ovarian cancer in the general population, and routine screening is not currently recommended by any professional society. 32,35,39 46 Some physicians follow-up women with high-risk facts (eg, BRCA mutations, family histy) using cancer antigen 125 (CA 125) moniting and endovaginal ultrasound 39 ; however, prospective validation of these tests remains elusive. Staging The NCCN Guidelines f Ovarian Cancer reflect the imptance of stage and grade of disease on prognosis and treatment recommendations. Ovarian cancer is classified primarily as stages I to IV using the FIGO (International Federation of Gynecology and Obstetrics) and AJCC staging systems (see Table 1 and other staging tables in the complete version of these guidelines, available at NCCN.g [ST-1 5]). 47 Serous ovarian cancer is now often referred to as either low grade (most grade 1 serous tums) high grade (most grade 2 3 serous tums) Pathologists may use histologic grades 1, 2, 3 f endometrioid carcinomas, mucinous carcinomas, and stage IC tums. 48 Staging f the LCOHs is perfmed using the ovarian cancer staging system. 47 FIGO recently updated the staging f ovarian, fallopian tube, and peritoneal cancer; their new staging system has been approved by the AJCC (see Staging in the complete version of these guidelines [ST-1 5]). 49,50 In the new staging guidelines, old stages IC, IIIA, and IV are now subdivided, and the old stage IIC has been eliminated. These changes will be included in the next edition of the AJCC Cancer Staging Manual (8th edition), which will be published in 2016 and will be effective f all cancer cases recded on after January 1, The 2016 protocol from the College of American Pathologists (CAP) f ovarian cancer includes the LCOHs. 48,54 Recommended Wkup The LCOH algithms begin after surgery and histologic diagnosis of a suspicious pelvic mass (see LCOH-1; JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

16 NCCN Clinical Practice Guidelines in Oncology 1149 page 1139). The recommended wkup f the LCOHs is similar to the wkup f epithelial ovarian cancer (see OV-1; page 1136). The NCCN Guidelines f Epithelial Ovarian Cancer begin with the management of an undiagnosed pelvic mass a pri diagnosis of a malignant epithelial ovarian tum. Many patients with this diagnosis come to NCCN Member Institutions after having had previous surgery. The NCCN Guidelines recommend symptom management and best supptive care f all patients; patients should be referred f palliative care assessment if appropriate (see the NCCN Guidelines f Palliative Care, available at NCCN.g). Undiagnosed Pelvic Mass: The primary wkup should include an ultrasound and/ abdominal/pelvic CT/MRI scan (after an abdominal/pelvic examination) and appropriate labaty studies f a patient with a suspicious pelvic mass (detected on abdominal/ pelvic examination) and/ ascites, abdominal distention, and/ symptoms (ie, bloating, pelvic abdominal pain, difficulty eating feeling full quickly, urinary symptoms) without other obvious sources of malignancy (see LCOH-1; page 1139). 33,55 62 Tum markers (including CA 125, inhibin, alpha fetoprotein [AFP], and beta-human chionic gonadotropin [beta-hcg]) can be measured if clinically indicated to assess f LCOH and pregnancy (see Less Common Ovarian Histopathologies, page 1150, and LCOH-1, page 1139) F example, AFP levels should be considered to assess f germ cell tums in women younger than 35 years with a pelvic mass Ultrasound is typically used f initial evaluation; however, CT is useful to assess f metastases. 57 MRI may be useful f determining malignant potential if ultrasound is not reliable. 61,62 CT/MRI imaging should be perfmed with contrast unless contraindicated. FDG-PET/CT scan may be useful f indeterminate lesions Most ovarian cancers, including the LCOHs, are diagnosed after pathologic analysis of a biopsy surgical specimen, which may occur preoperatively, intraoperatively, postoperatively. If possible, fineneedle aspiration (FNA) should be avoided f diagnosing ovarian cancer in patients with presumed early-stage disease to prevent rupturing the cyst and spilling malignant cells into the peritoneal cavity; however, FNA may be necessary in patients with bulky disease who are not surgical candidates. 69,70 Other cancers that should be ruled out include bowel, uterine, and pancreatic cancers and lymphoma. 71,72 Benign ovarian and nonovarian conditions also need to be ruled out (eg, serous cystadenoma), 73 as do metastases to the ovaries (see Mucinous Carcinomas, page 1152). It has been suggested that specific biomarkers (serum HE4 and CA 125) along with an algithm (Risk of Ovarian Malignancy Algithm [ROMA]) may be useful f determining whether a pelvic mass is malignant benign. 74,75 The FDA has approved the use of HE4 and CA 125 f estimating the risk f ovarian cancer in women with a pelvic mass, however, the NCCN Panel does not currently recommend the use of these biomarkers f determining the status of an undiagnosed pelvic mass Although no direct evidence exists that chest radiography CT is necessary, panel members felt that it should be part of the overall evaluation of a patient befe surgical staging if clinically indicated. Gastrointestinal tract evaluation should be done f mucinous histology to determine if patients have metastases to the ovary primary mucinous carcinoma of the ovary (see Mucinous Carcinomas, page 1152). 80 Pri Diagnosis of Malignancy: Patients are often referred to NCCN Member Institutions after a previous diagnosis of ovarian cancer through surgery tissue biopsy (cytopathology). Often these patients have undergone cyteductive surgery and comprehensive staging procedures. However, referral may occur after incomplete surgery and/ staging; f example, the uterus and/ adnexa may still be intact (see OV-2; page 1137). The components of surgical staging are listed in the algithm (see Principles of Surgery in the complete version of these guidelines, available at NCCN.g [OV-A]). Identical wkup procedures are recommended f patients with undiagnosed diagnosed pelvic masses at the time of referral. Tissue diagnosis of metastatic sites can be considered. Histologic Subtypes Epithelial ovarian cancer has 4 main histologic subtypes: serous, endometrioid, mucinous, and clear cell; however, most patients (about 70%) have serous histology. 3,47,51,81,82 F the 2016 update, primary treatment recommendations f the LCOH subtypes mucinous, clear cell, and grade 1 (low-grade) serous/endometrioid may be different from the treatment recommendations f the high-grade serous/endometrioid subtypes (see OV-3 and LCOH-1; JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016

17 1150 NCCN Clinical Practice Guidelines in Oncology pages 1138 and 1139, respectively). 51 Recent molecular characterization of clear cell, mucinous, grade 1 (low-grade) tums suggests that mutations in these histologies are different from those in highergrade tums Ovarian cancer can be divided into types 1 and 2 based on these molecular alterations. Data suggest that serous tums can be categized as either low grade (most grade 1 serous tums) high grade (most grade 2 3 serous tums) ,86,87 High-grade endometrioid tums are difficult to distinguish from high-grade serous tums. 51 Grade 1 (low-grade) serous tums are relatively resistant to standard chemotherapy regimens. 51,88 Pathology review at NCCN Member Institutions is recommended f all patients. The CAP protocol is a useful tool f pathology repts; it was recently revised f ,54 F the 2016 update, the complete histologic classification from the WHO was added to the NCCN Guidelines (see WHO Histologic Classification in the complete version of these guidelines, available at NCCN.g [OV-D]). 1 The WHO pathology manual is also a useful resource. 1,89 Primary Treatment Primary treatment f presumed ovarian cancer consists of appropriate surgical staging and cyteduction, followed in most (but not all) patients by systemic therapy Neoadjuvant therapy refers to drugs, radiation, other treatment that is given to reduce the tum burden befe cancer surgery. The therapeutic benefit of neoadjuvant chemotherapy followed by interval cyteduction remains controversial f epithelial ovarian cancer Neoadjuvant chemotherapy may be considered (categy 1) f patients with bulky stage III to IV disease who are not surgical candidates; however, a gynecologic oncologist should make this assessment befe neoadjuvant chemotherapy is administered Because many patients with LCOH are diagnosed after surgery and/ present with early-stage disease, neoadjuvant chemotherapy does not apply f the LCOHs. Initial surgery should be a comprehensive staging laparotomy, including a total abdominal hysterectomy and BSO (see LCOH-1 and Principles of Surgery in the complete version of these guidelines [OV-A]) Based on published improved outcomes, it is recommended (categy 1) that a gynecologic oncologist perfm the primary surgery F a young patient who wishes to maintain fertility, a unilateral salpingooophectomy (USO; preserving the uterus and contralateral ovary) may be adequate f select unilateral stage I tums (stage 1A and 1C, but not stage 1B) and/ low-risk ovarian tums (ie, early-stage, grade 1 tums; bderline tums; see LCOH-6, LCOH-9, LCOH-10; pages 1141, 1143, and 1144, respectively) Comprehensive staging may not be necessary f select patients, such as those with bderline epithelial tums (see LCOH- 6, page 1141). Most patients have a hysterectomy with BSO, omentectomy, and lymphadenectomy of suspicious/ enlarged nodes. Cyteductive surgery is the initial treatment recommendation f patients with clinical stage II, III, IV disease (see OV-1, page 1136, and Principles of Surgery in the complete version of these guidelines, available at NCCN.g [OV- A]). 92,93,114,117, These procedures also apply to many of the LCOHs. Surgical cyteduction is optimal if the residual tum nodules are less than 1 cm in maximum diameter thickness 97,111,117,125,126 ; extensive resection of upper abdominal ovarian metastases is recommended f patients who can tolerate this surgery. 123,127 In select patients, minimally invasive procedures may be used to assess whether cyteductive surgery is feasible and to achieve cyteduction. 110, F young patients who will abruptly enter menopause after surgery, various supptive care measures may be used to help decrease hot flashes and other symptoms Procedures that may be considered f optimal surgical cyteduction (in all stages) include radical pelvic dissection, bowel resection and/ appendectomy, diaphragm other peritoneal surface stripping, splenectomy, partial hepatectomy, partial gastrectomy, partial cystectomy and/ ureteroneocystostomy, cholecystectomy, and/ distal pancreatectomy. 123,127,135 F patients with incomplete previous surgery and/ staging, treatment recommendations are outlined in the algithm (see OV-2 and LCOH-7; pages 1137 and 1142, respectively). Less Common Ovarian Histopathologies F the 2016 update, the NCCN Panel extensively revised the section on LCOHs. As previously mentioned, new algithms f clear cell carcinoma, mucinous carcinoma, and grade 1 (low-grade) serous/ endometrioid epithelial carcinoma were added to JNCCN Journal of the National Comprehensive Cancer Netwk Volume 14 Number 9 September 2016