Contents

Search

ovarian cancer

Epithelial carcinomas are the most common of ovarian malignancies. Etiology: Risk factors 1) personal history a) breast cancer b) endometrial cancer c) colorectal cancer 2) family history a) ovarian cancer b) breast cancer c) endometrial cancer d) colorectal cancer 3) BRCA1/BRCA2 mutations (most significant risk factor) 4) hereditary non-polyposis colorectal cancer (HNPCC) [2] 5) infertility or use of infertility agents [12] 6) nulliparity 7) perineal talc exposure 8) hormone replacement therapy [24,39,47] - excess risk 0.1% [39] (see HRT) 9) chronic inflammation a) endometriosis - clear-cell, endometrioid, & low-grade serous ovarian tumors - not mucinous & high-grade serous ovarian tumors [29] b) pelvic inflammatory disease 10) high-fat diet 11) reduced risk of epithelial ovarian cancer with a) oral contraceptives, esp those containing high-dose progestins (protective effect of progestins) [6], RR=0.73; long-term risk-reduction (30 years) after discontinuation [2,23] b) parity 12) douching (RR~2) 13) genital powder use not a risk factor [65] Epidemiology: 1) 5th most common cancer in women 2) median age of diagnosis is 63 years 3) 4th leading cause of cancer deaths in women 4) 1.4% lifetime risk in the general population (women) [2] Pathology: 1) 90% of cancers are epithelial in origin - many high-grade serous ovarian cancers originate from the fimbrial epithelium of the fallopian tube [56] - serous ovarian cancers are the most common type & subtype with highest mortality [56] 2) repeated ovulation & repair at the ovarian surface may increase risk of malignant transformation 3) metastases a) lymph nodes (48% local, 58% distant) b) liver (48%) c) lung (34%) d) bone (12%) e) brain (3%) f) skin (5%) g) adrenal (20%) h) kidney (6%) Microscopic Pathology: 1) epithelial tumors a) serous tumors - benign serous cysadenoma - serous cysadenoma of low malignant potential (borderline malignancy) - serous cystadenocarcinoma - papillary serous cystadenocarcinoma b) mucinous tumors - benign mucinous cystadenoma - mucinous cysadenoma of low malignant potential (borderline malignancy) - mucinous cystadenocarcinoma c) endometrioid tumors - benign endometrioid cystadenoma - endometrioid cysadenoma of low malignant potential (borderline malignancy) - endometrioid adenocarcinoma - secretory variant - ciliated variant d) clear cell tumors - benign clear cell tumor - clear cell cystadenoma of low malignant potential (borderline malignancy) - clear cell cystadenocarcinoma e) Brenner (transitional cell) tumors - benign Brenner tumor - Brenner tumor of borderline malignancy - malignant Brenner tumor f) squamous cell tumor g) undifferentiated carcinoma h) mixed epithelial tumor 2) germ cell tumors a) choriocarcinoma b) dysgerminoma c) embryonal carcinoma d) gonadoblastoma e) teratoma - immature - mature - cystic - dermoid cyst (mature cystic teratoma) - dermoid cyst with malignant transformation - solid - monodermal and highly specialized - struma ovarii - carcinoid - struma ovarii and carcinoid - other (ie malignant neuroectodermal and ependymoma) - malignant teratoma - teratocarcinoma f) yolk sac tumor g) mixed germ cell tumor Genetics: 1) family history of breast cancer, colon cancer, ovarian cancer - risk may be average if genetic testing is negative [2] 2) BRCA1/BRCA2 mutations (most significant risk factor) - BRCA1 mutation: 35-46% lifetime risk - BRCA2 mutation: 13-23% lifetime risk 3) Lynch syndrome (HNPCC) associated with a 3-14% lifetime risk [2] 4) aggressive disease associated with mutations in RSF1 gene [18] 5) high-grade serous ovarian cancer has genetic similarities with basal-like breast cancer [32] 6) normal expression of ARMCX2 is absent 7) overexpression of TPBG, POSTN, EMSY, WFDC2, WDR45L, ATAD2, PRAF2, ERBB2, SLC35C2, kallikrein-7, kallikrein-8, TGIF2 8) loss of expression of DNAJC15, ARMCX1 9) 402C->G point mutation in the FOXL2 gene may be associated adult granulosa-cell tumors of the ovary 10) other implicated genes IGF2BP3, HRASLS3, CUZD1, SULF1, PHF20, ANLN, ARID4B, FMR1NB, LETMD1, DPH1, SFRS19, MTUS1, XRRA1, CTNNB1, CAMK4, AKT2, BARD1, VTCN1, TP63, MDM2, C9orf14, OCR1, EGFR, CDH1, LPAR3, ADAM11, RRAS2. PARK2, PDZRN3 Clinical manifestations: 1) occult presentation 2) late stage of disease at the time of diagnosis - 70-75% of women present with advanced disease 3) most patients present with non-specific symptoms a) abdominal distension or bloat*# b) abdominal or pelvic discomfort or pressure*# c) low back pain d) lack of energy e) lack of appetite (anorexia)# f) weight loss# 4) dyspareunia 5) abnormal vaginal bleeding# 6) rectal bleeding# 7) dysuria or urinary urgency may be present [11] 8) ovarian mass 9) nodularity in the cul-de-sac 10) ascites & pleural effusion may occur (late) [20] * most common symptoms [5]; may be presenting symptoms [16] # part of a 9 point screening [28] Laboratory: 1) serum CA-125 antigen may be elevated a) useful for initial evaluation b) useful for follow-up if initially elevated (MKSAP19) [2] - represents shift from prior recommendations (MKSAP18) 2) BRCA1/BRCA2 genotyping with ovarian cancer genotyping - all women [2] - multigene testing proposed [40] - BRCA1/BRCA2 genotyping for survivors of ovarian cancer [50] - BRCA1 promoter methylation in leukocytes [55] 3) HNPCC gene mutation for women with family history of hereditary neoplastic syndrome cancer (before BRCA1/BRCA2 genotyping) - hereditary neoplastic (Lynch) syndrome cancers include - colorectal cancer, small intestinal cancer, endometrial cancer, transitional cell carcinoma of the ureter or renal pelvis [2] - ref [2] refers to DNA mismatch repair mutations 4) proteomic pattern may be discriminatory [7] 5) ovarian biopsy: immunohistochemistry: - CK7: + - CK20: - - calretinin: - (serous adenocarcinoma) [10] - CEA: - (serous cystadenocarcinoma) - CA 125: + - estrogen receptor: + (some) - progesterone receptor: + (some) 6) combined set of 4 serum markers may be useful for early detection [15] - leptin, prolactin, osteopontin, IGF2 7) complete blood count # 8) cytology of ascitic fluid 9) see ARUP consult [31] * only laboratory testing recommended by ref [2] # part of a 9 point screening [28] Special laboratory: - in patients with advanced disease, diagnosis can be made by examination of ascites or pleural effusion [2] - do not obtain biopsy for early ovarian cancer [2] Radiology: - transvaginal or pelvic ultrasound a) little value in screening [14] b) recommended for evaluation of suspected ovarian cancer [2] c) findings suggestive of ovarian cancer include - solid mass, often nodular or papular [2] - cyst with thick septation - ascites [2] - peritoneal masses [2] d) ultrasound-guided biopsy e) also see adnexal mass - many adnexal masses spontaneously resolve - CT or MRI of abdomen, pelvis & thorax - assess extent of disease if pelvic US suggests ovarian cancer - CT of abdomen to assess bowel obstruction * CT-guided biopsy is contraindicated as this may disseminate cancer cells [2] - in patients with advanced disease diagnosis by biopsy of peritoneal mass suggested [2] - stage 3C & 4 epithelial ovarian cancer - CT of abdomen & pelvis with IV & oral contrast - CT of thorax (NGC) Staging: AJCC/TNM/FIGO TNM FIGO TX primary tumor cannot be assessed T0 no evidence of primary tumor T1 I tumor limited to ovaries T1a IA tumor limited to one ovary, capsule intact, no tumor on ovarian surface, no malignant cells in ascites or peritoneal washings T1b IB tumor limited to both ovaries, capsule intact, no tumor on ovarian surface, no malignant cells in ascites or peritoneal washings T1c IC tumor limited to one or both ovaries, with any of: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal washings. T2 II tumor involves one or both ovaries with pelvic extension &/or implants T2a IIA extension &/or implants on uterus &/or tubes, no malignant cells in ascites or peritoneal washings T2b IIB extension &/or implants on other pelvic tissues, no malignant cells in ascites or peritoneal washings T2c IIC pelvic extensions &/or implants (T2a or T2b) with malignant cells in ascites or peritoneal washings T3 III tumor involves one or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis T3a IIIA microscopic peritoneal metastasis beyond pelvis (none macroscopic) T3b IIIB macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatestconfirmed dimension T3c IIIC peritoneal metastasis beyond pelvis, more than 2 cm in greatest dimension &/or regional lymph node metastasis note: - presence of ascites does not affect staging unless maligmant cells present - liver capsule metastasis T3/stage III - liver parencymal metastasis M1/stage IV - pleural effusion must have positive cytology for M1/ stage IV NX regional lymph nodes cannot be assessed N0 no regional lymph node metastasis N1 IIIC regional lymph node metastasis MX distal metastases cannot be assessed M0 no distant metastasis M1 IVB distant metastasis (excludes peritoneal metastasis) stage T N M stage I T1 N0 M0 stage IA T1a N0 M0 stage IB T1b N0 M0 stage IC T1c N0 M0 stage II T2 N0 M0 stage IIA T2a N0 M0 stage IIB T2b N0 M0 stage IIC T2c N0 M0 stage III T3 N0 M0 stage IIIA T3a N0 M0 stage IIIB T3b N0 M0 stage IIIC T3c N0 M0 - any T any N M0 stage IV any T any N M1 Histologic grading: GX grade cannot be assessed GB borderline malignancy G1 well differentiated G2 moderately differentiated G3-4 poorly differentiated or undifferentiated Differential diagnosis: - women with peritoneal carcinomatosis of unknown primary have ovarian cancer until proven otherwise [2] Complications: 1) ascites: paracentesis may be required (up to twice a week) 2) bowel obstruction [70] a) if single focus obstruction, surgery may be indicated especially if post-operative chemotherapy is likely to be effective b) draining gastrostomy option prior to hospice c) CT of abdomen for evaluation Management: 1) surgery by a gynecologic oncologist a) exploratory surgery evaluation of adnexal mass - women with early stage ovarian cancer (stage 1) with favorable histopathology may be treated with surgery alone [2] - survival benefit of intact removal of adnexal mass in patients with early stage ovarian cancer [2] b) total abdominal hysterectomy bilateral salpingo-oophorectomy - women with BRCA1, BRCA2 or HNPCC gene mutation after completion of childbearing or at age 35 years [2] c) surgical staging & debulking 1] exploratory laparotomy for surgical staging 2] enblock resection of primary tumor, ovaries & uterus 3] partial infracolic omentectomy 4] selective lymph node resection (pelvic, para-aortic) 5] bowel resection as indicated 6] appendectomy 7] aggressive surgical debulking improves survival [2,19] 8] 4.1% increase in survival for each 10% reduction in tumor burden 9] peritoneal washings [2] d) stage 1 with favorable histology may be treated with surgery alone [2] 2) chemotherapy a) patients with early-stage (IA) low-grade ovarian cancer do not benefit from adjuvant chemotherapy [2] b) neoadjuvant chemotherapy may be given to patients with initially unresectable ovarian cancer to shrink the size of the tumor for possible resection [2] c) adjuvant chemotherapy 1] cisplatin (Platinol) [2] plus paclitaxel (Taxol) - response to cisplatin better in BRCA2 mutation carriers than either BRCA1 mutation carriers or patients with normal BRCA1 & BRCA2 genes [26] - response rate 100% vs 80-85% - duration of remission 18 months vs 12 months [26]; 2] improves disease-free survival in patients with advanced stage ovarian cancer (IC or higher) [2] about 10% [8] 3] intraperitoneal cisplatin may improve survival in stage 3 ovarian cancer [17] at a cost of higher toxicity [2] - benefit for patients with residual disease after surgery confined to the peritonal cavity (MKSAP19) [2] 4] maintenance chemotherapy with poly ADP-ribose polymerase (PARP) inhibitor a] olaparib, niraparib, rucaparib [52] - maintnance with bevacizumab + olaparib (with or without BRCA mutation) [69] b] may increase survival in recurrent, platinum-sensitive ovarian cancer c] indicated for advanced epithelial ovarian cancer with BRCA1/BRCA2 mutation 5] use of hematopoietic cell growth factors to maintain adequate blood counts during chemotherapy improvesquality of life & decreases complications [2] 6] niraparib (Zejula) + pembrolizumab (Keytruda) may elicit a durable response in refractory (platinum-resistant) ovarian cancer [58] d) maintenance chemotherapy in women who have achieved remission of greater benefit with BRCA1/BRCA2 mutation than without but recommended for all [2] e) second look laparotomy to assess response to chemotherapy not indicated [2] 3) stage IIIC & stage IV ovarian cancer - standard of care is neoadjuvant chemotherapy (carboplatin + paclitaxel + bevacizumab) followed by cytoreductive surgery [3,44] - no evidence for dose adjustment of chemotherapy for age [3,38,69] - neoadjuvant chemotherapy followed by cytoreductive surgery is associated with reduced mortality [53] - hyperthermic intraperitoneal chemotherapy with cytoreductive surgery [54] - additional cycles of carboplatin & paclitaxel + bevacizumab administered postoperatively [54,69] - see maintenance therapy above 4) follow-up a) history & physical exam & pelvic exam every 4 months for 1st 2 years [2] - serum CA-125 if initially elevated (MKSAP19) [2] - represents shift from prior recommendations (MKSAP18) b) no role for routine imaging, laboratory or 2nd look surgery [2] c) recurrence of gynecologic cancer most often detected by symptoms or physical examination (GRS9) [3] 5) replase a) secondary surgical debulking [2,57] or cytoreductive surgery [67] may improve survival b) chemotherapy should be based upon - performance status [2] - drugs already used - residual toxicity - status of GI tract - toxicities of contemplated agents - convenience c) agents: [NICE] - paclitaxel or pegylated liposomal doxorubicin alone or in combination with platinum - gemcitabine, grabectedin, topotecan not recommended - rucaparib (Rubraca) FDA-approved for patients with deleterious BRCA1 mutation or BRCA2 mutation after >= 2 courses of chemotherapy d) relapse > 6 months after platinum-based chemotherapy - treat with platinum-based combination chemotherapy [2] 6) screening for ovarian cancer: a) screening not recommended [2,30] b) annual pelvic exam beginning at age 18 (might be considered a form of screening) c) transvaginal ultrasound & serum CA-125 - not yet useful for reducing ovarian cancer mortality [25,27] d) annual screening for ovarian cancer might lower ovarian cancer-related mortality [46] - serum CA-125 with rising levels interpreted using an ovarian cancer algorithm & ultrasound as indicated - risk reduction of 20% realized after 7 years - for each ovarina cancer detected by screening, 2 women underwent surgery for false positive screening [46] 7) prevention a) salpingo-oophorectomy after childbearing or by age 35-40 for women with BRAC1 mutation or 2 or more 1st degree relatives with ovarian cancer - oophorectomy by age 45 for BRAC2 mutations - relative risk reduction = 80%, similar for mortality [37,64] b) bilateral salpingo-oophorectomy before age 40 years 1] risk reduction ~95% [2] 2] reduces risk of cancer in patients with BRCA-1 mutations; however, peritoneal carcinoma histologically indistinguishable from ovarian cancer may develop in 1-3% of women with hereditary cancer syndromes [2,21] c) oral contraceptives - after oophorectomy until age of menopause (unless breast cancer risk) [64] - may reduce risk 30-60% d) aspirin (< 100 mg/day) may reduce risk; other NSAIDs increase risk [59] 8) prognosis: a) 5 year survival is poor when presenting with advanced disease b) disease is potentially curable even when presenting with malignant ascites c) survival by stage at presentation 1] stage 1: 75 to >90% (5 year) [2]; 82% (10 year) [41] 2] stage 2: 60-70% (5 year) [2]; 52% (10 year) [41] 3] stage 3: 25-40% (5 year) [2]; 19% (10 year) [41] 4] stage 4: 10-15% (5 year) [2]; 7% (10 year) [41] d) 30-50% of patients with early stage disease confined to ovaries or pelvis, have micrometastases, & eventually relapse after ovariectomy & die [8] e) treatment by a gynecologic oncologist improves prognosis [22] f) overall survival better in BRCA2 mutation carriers than either BRCA1 mutation carriers or patients with normal BRCA1 & BRCA2 genes [26]; 61% vs 25% 5 year survival g) predictors of long-term survival include - younger age at diagnosis - stage I or II disease - low-grade tumors - endometrioid, clear-cell, or mucinous histology [41] h) lipophilic statins may confer a survival advantage across different histologic sybtypes [66] Comparative biology: - losartan treatment enhances chemotherapy efficacy & reduces ascites in mouse model of ovarian cancer by normalizing tumor stroma [63]

Related

germ cell neoplasm mucin-16 (ovarian carcinoma antigen CA125, ovarian cancer related tumor marker CA125, CA-125, MUC16, CA125) ovarian cancer genotyping screening for ovarian cancer

Specific

Krukenberg's tumor secondary ovarian cancer

General

urogenital malignancy (urogenital cancer) ovarian neoplasm

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 30
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998,2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 521, 607
  5. Journal Watch 21(18):145, 2001 Brewster WR Intent-to-treat analysis of stage Ib and IIa cervical cancer in the United States: radiotherapy or surgery 1988-1995. Obstet Gynecol. 2001 Feb;97(2):248-54. PMID: 11165590
  6. Journal Watch 22(5):39, 2002 Schildkraut JM et al Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 94:32, 2002 PMID: 11773280
  7. Journal Watch 22(5):40, 2002 Petricoin EF et al Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359:572, 2002 PMID: 11867112
  8. Journal Watch 23(5):44, 2003 International Collaboratice Ovarian Neoplasm, J Natl Cancer Inst 95:105, 2003 International Collaboratice Ovarian Neoplasm, J Natl Cancer Inst 95:125, 2003 Trimbos JB et al, J Natl Cancer Inst 95:113, 2003 Young RC, J Natl Cancer Inst 95:94, 2003
  9. AJCC Cancer Staging Manual 6th ed. Springer 2002
  10. Attanoos et al. Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum. Histopathology 40:237-44, 2002 PMID: 11895489
  11. Journal Watch 24(14):112, 2004 Goff BA, Mandel LS, Melancon CH, Muntz HG. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA. 2004 Jun 9;291(22):2705-12. PMID: 15187051
  12. Journal Watch 24(15):117, 2004 Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE, Westhoff CL. Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol. 2004 Jun;103(6):1194-203. PMID: 15172852
  13. U.S. Preventive Services Task Force. Screening for ovarian cancer: recommendation statement. U.S. Preventive Services Task Force. Am Fam Physician. 2005 Feb 15;71(4):759-62. PMID: 15756773 Corresponding NGC guideline withdrawn Jan 2011
  14. Journal Watch 25(11):85, 2005 Fishman DA, Cohen L, Blank SV, Shulman L, Singh D, Bozorgi K, Tamura R, Timor-Tritsch I, Schwartz PE. The role of ultrasound evaluation in the detection of early- stage epithelial ovarian cancer. Am J Obstet Gynecol. 2005 Apr;192(4):1214-21; discussion 1221-2. PMID: 15846205
  15. Internal Medicine News, July 2005, pg 5 Journal Watch 25(14):112, 2005 Mor G, Visintin I, Lai Y, Zhao H, Schwartz P, Rutherford T, Yue L, Bray-Ward P, Ward DC. Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7677-82. Epub 2005 May 12. PMID: 15890779
  16. Smith LH, Morris CR, Yasmeen S, Parikh-Patel A, Cress RD, Romano PS. Ovarian cancer: Can we make the clinical diagnosis earlier? Cancer. 2005 Oct 1;104(7):1398-407. PMID: 16116591
  17. Armstrong DK et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006 Jan 5; 354:34-43. PMID: 16394300 - Cannistra SA. Intraperitoneal chemotherapy comes of age. N Engl J Med 2006 Jan 5; 354:77-9. PMID: 16394306
  18. Internal Medicine World Report, Dec 2005 cites le-M Singh, PNAS 2005; 102:14004
  19. Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO, Podratz KC, Cliby WA. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol. 2006 Jan;107(1):77-85. PMID: 16394043
  20. UpToDate 14.1 http://www.utdol.com
  21. Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, Murphy J, Ghadirian P, Friedman E, Foulkes WD, Kim-Sing C, Wagner T, Tung N, Couch F, Stoppa-Lyonnet D, Ainsworth P, Daly M, Pasini B, Gershoni-Baruch R, Eng C, Olopade OI, McLennan J, Karlan B, Weitzel J, Sun P, Narod SA; Hereditary Ovarian Cancer Clinical Study Group. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA. 2006 Jul 12;296(2):185-92. PMID: 16835424
  22. Chan JK, Kapp DS, Shin JY, Husain A, Teng NN, Berek JS, Osann K, Leiserowitz GS, Cress RD, O'malley C. Influence of the gynecologic oncologist on the survival of ovarian cancer patients. Obstet Gynecol. 2007 Jun;109(6):1342-50. PMID: 17540806
  23. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008, 371:303 PMID: 18294997
  24. Morch LS Hormone Therapy and Ovarian Cancer JAMA. 2009;302(3):298-305. PMID: 19602689 http://jama.ama-assn.org/cgi/content/short/302/3/298?home
  25. Buys SS et al Effect of Screening on Ovarian Cancer Mortality JAMA. 2011;305(22):2295-2303 PMID: 21642681 http://jama.ama-assn.org/content/305/22/2295.full
  26. Yang D et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 2011 Oct 12; 306:1557. PMID: 21990299
  27. van Nagell JR Jr et al. Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol 2011 Dec; 118:1212. PMID: 22105249 - Jacobs I and Menon U. Can ovarian cancer screening save lives? The question remains unanswered. Obstet Gynecol 2011 Dec; 118:1209. PMID: 22105248
  28. Hippisley-Cox J and Coupland C. Identifying women with suspected ovarian cancer in primary care: Derivation and validation of algorithm. BMJ 2012 Jan 4; 344:d8009. PMID: 22217630 http://www.bmj.com/content/344/bmj.d8009
  29. Pearce CL et al Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies The Lancet Oncology, Early Online Publication, 22 February 2012 PMID: 22361336 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70404-1/abstract# - Gourley C Link between endometriosis and ovarian-cancer subtypes The Lancet Oncology, Early Online Publication, 22 February 2012 PMID: 22361335 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70029-3/fulltext
  30. U.S. Preventive Services Task Force Screening for Ovarian Cancer: U.S. Preventive Services Task Force Reaffirmation Recommendation Statement DRAFT http://www.uspreventiveservicestaskforce.org/draftrec.htm - U.S. Preventive Services Task Force Screening for Ovarian Cancer Evidence Update for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement http://www.uspreventiveservicestaskforce.org/uspstf12/ovarian/ovarart.htm
  31. ARUP Consult: Ovarian Cancer The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/ovarian-cancer - ARUP Consult: Hereditary Breast and Ovarian Cancer https://arupconsult.com/ati/hereditary-breast-and-ovarian-cancer
  32. The Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours Nature (2012) Sept 23, PMID: 23000897 http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11412.html
  33. Morgan RJ Jr, Alvarez RD, Armstrong DK et al Ovarian cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2008 Sep;6(8):766-94. PMID: 18926089
  34. Trimbos JB, Parmar M, Vergote I et al International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early- stage ovarian carcinoma. J Natl Cancer Inst. 2003 Jan 15;95(2):105-12. PMID: 12529343
  35. Giede KC, Kieser K, Dodge J, Rosen B. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol. 2005 Nov;99(2):447-61 PMID: 16126262
  36. Parmar MK, Ledermann JA, Colombo N et al Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003 Jun 21;361(9375):2099-106. PMID: 12826431
  37. Finch AP et al Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation. J Clin Oncology. Feb 24, 2014 PMID: 24567435 http://jco.ascopubs.org/content/early/2014/02/24/JCO.2013.53.2820.full.pdf+html
  38. Eisenhauer EL, Tew WP, Levine DA et al Response and outcomes in elderly patients with stages IIIC-IV ovarian cancer receiving platinum-taxane chemotherapy. Gynecol Oncol. 2007 Aug;106(2):381-7. Epub 2007 May 16. PMID: 17509673
  39. Collaborative Group on Epidemiological Studies of Ovarian Cancer Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. The Lancet. February 12, 2015 PMID: 25684585 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961687-1/abstract
  40. Desmond A et al Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. JAMA Oncol. Published online August 13, 2015 PMID: 26270727 http://oncology.jamanetwork.com/article.aspx?articleid=2425836 - Swisher EM Usefulness of Multigene Testing. Catching the Train That's Left the Station. JAMA Oncol. Published online August 13, 2015 PMID: 26270409 http://oncology.jamanetwork.com/article.aspx?articleid=2425834
  41. Cress RD et al. Characteristics of long-term survivors of epithelial ovarian cancer. Obstet Gynecol 2015 Sep; 126:491 PMID: 26244529
  42. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002 Mar 1;20(5):1248-59 PMID: 11870167
  43. Rustin GJ, van der Burg ME, Griffin CL et al Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010 Oct 2;376(9747):1155-63. PMID: 20888993
  44. Vergote I, Trope CG, Amant F et al Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010 Sep 2;363(10):943-53. PMID: 20818904
  45. Engelen MJ, Kos HE, Willemse PH et al Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma. Cancer. 2006 Feb 1;106(3):589-98. PMID: 16369985
  46. Jacobs IJ et al Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. Dec 17, 2015 PMID: 26707054 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2901224-6/abstract - Verheijen RH, Zweemer RP. Screening to improve ovarian cancer prognosis? Lancet. Dec 17, 2015 PMID: 26707055 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2901236-2/abstract
  47. Lee AW, Ness RB, Roman LD et al Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk. Obstet Gynecol. 2016 May;127(5):828-36. PMID: 27054934 - Power L, Lefas G, Lambert P et al Hormone Use After Nonserous Epithelial Ovarian Cancer: Overall and Disease-Free Survival. Obstet Gynecol. 2016 May;127(5):837-47. PMID: 27054933
  48. American Society of Clinical Oncology and the Society of Gynecologic Oncology. August 2016 New guidelines on treating newly diagnosed, advanced ovarian cancer. PMID: 26734446 Free PMC Article http://jco.ascopubs.org/content/early/2016/08/04/JCO.2016.68.6907.full
  49. Gonzalez NL et al. Douching, talc use, and risk of ovarian cancer. Epidemiology 2016 Jun 20 PMID: 27327020
  50. Childers CP, Childers KK, Maggard-Gibbons M, Macinko J National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer. J Clin Oncol. 2017 Aug 18:JCO2017736314 PMID: 28820644 http://ascopubs.org/doi/abs/10.1200/JCO.2017.73.6314 - Jenkins K Huge Underuse of Genetic Testing Among Cancer Survivors. Medscape. Aug 24, 2017. http://www.medscape.com/viewarticle/884645
  51. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 182 Summary: Hereditary Breast and Ovarian Cancer Syndrome. Obstetrics & Gynecology. 130(3):657-659, SEP 2017 PMID: 28832475 https://insights.ovid.com/crossref?an=00006250-201709000-00035
  52. Bankhead C Another Win for PARP Inhibition in Ovarian Cancer Rucaparib maintenance extends PFS in all subgroups. MedPage Today. September 11, 2017 https://www.medpagetoday.com/MeetingCoverage/ESMO/67807
  53. Melamed A, Fink G, Wright AA et al Effect of adoption of neoadjuvant chemotherapy for advanced ovarian cancer on all cause mortality: quasi-experimental study. BMJ 2018;360:j5463 PMID: 29298771 http://www.bmj.com/content/360/bmj.j5463
  54. van Driel WJ, Koole SN, Sikorska K. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med 2018; 378:230-240. January 18, 2018 PMID: 29342393 http://www.nejm.org/doi/full/10.1056/NEJMoa1708618
  55. Lonning PE, Berge EO, Bjornslett M et al White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk. Ann Intern Med. 2018 Jan 16. PMID: 29335712
  56. Narod SA Is There a Future for Ovarian Cancer Screening? JAMA Intern Med. Published online Feb 13, 2018 PMID: 29450456 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2672543 - Lu KH Screening for Ovarian Cancer in Asymptomatic Women. JAMA. 2018;319(6):557-558 PMID: 29450509 https://jamanetwork.com/journals/jama/fullarticle/2672614
  57. Szczesny W, et al Survival after secondary cytoreductive surgery and chemotherapy compared with chemotherapy alone for first recurrence in patients with platinum-sensitive epithelial ovarian cancer and no residuals after primary treatment: A registry-based study. Acta Obstet Gynecol Scand 2018; PMID: 29790149
  58. Susman E. Non-Chemo Combo Active in Ovarian Cancer. 25% objective response among patients with refractory disease. MedPage Today. June 04, 2018 https://www.medpagetoday.com/meetingcoverage/asco/73271 - Konstantinopoulos P, et al TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients with advanced triple- negative breast cancer or recurrent ovarian cancer (ROC) -- Results from ROC cohort. American Society of Clinical Oncology (ASCO) 2018; Abstract 106. - Fuerst ML with expert critique by Sumrall AL Advanced TNBC: 'Durable Activity' for Niraparib + Pembrolizumab. Also benefit for platinum-resistant/refractory ovarian cancer. MedPage Today. ASCO Reading Room 06.21.2018 https://www.medpagetoday.com/reading-room/asco/immunotherapy/73611
  59. Barnard ME, Poole EM, Curhan GC et al Association of Analgesic Use With Risk of Ovarian Cancer in the Nurses' Health Study. JAMA Oncol. Published online October 4, 2018. PMID: 30286239 https://jamanetwork.com/journals/jamaoncology/fullarticle/2704211
  60. Wright AA, Cronin A, Milne DE et al Use and Effectiveness of Intraperitoneal Chemotherapy for Treatment of Ovarian Cancer. J Clin Oncol. 2015 Sep 10;33(26):2841-7. Epub 2015 Aug 3. PMID: 26240233 Free PMC Article
  61. Alsop K, Fereday S, Meldrum C et al BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. PMID: 22711857 Free PMC Article
  62. Candido-dos-Reis FJ, Song H, Goode EL et al for EMBRACE; kConFab Investigators; Australian Ovarian Cancer Study Group. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res. 2015 Feb 1;21(3):652-7. PMID: 25398451 Free PMC Article
  63. Zhao Y et al. Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc Natl Acad Sci U S A 2019 Feb 5; 116:2210. PMID: 30659155 https://www.pnas.org/content/116/6/2210
  64. Walker M, Jacobson M, Sobel M Management of ovarian cancer risk in women with BRCA1/2 pathogenic variants. CMAJ August 12, 2019 191 (32) E886-E893; PMID: 31405835 http://www.cmaj.ca/content/191/32/E886
  65. O'Brien KM, Tworoger SS, Harris HR, et al Association of Powder Use in the Genital Area With Risk of Ovarian Cancer. JAMA. 2020;323(1):49-59 PMID: 31910280 https://jamanetwork.com/journals/jama/article-abstract/2758452 - Gossett DR, del Carmen MG Use of Powder in the Genital Area and Ovarian Cancer Risk. Examining the Evidence. JAMA. 2020;323(1):29-31 PMID: 31910265 https://jamanetwork.com/journals/jama/article-abstract/2758434
  66. Ingram I Yet Another Reason to Take Statins? - Retrospective study showed 40% reduction in mortality for ovarian cancer patients. MedPage Today June 23, 2020 https://www.medpagetoday.com/meetingcoverage/aacr/87219 - Visvanathan K, et al Lipophilic statins show promise for treatment of epithelial ovarian cancer. American Association for Cancer Research (AACR) 2020; Abstract 5782.
  67. Harter P, Sehouli J, Vergote I et al. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med 2021 Dec 2; 385:2123. PMID: 34874631 https://www.nejm.org/doi/10.1056/NEJMoa2103294 - Gardner GJ, Chi DS. Recurrent ovarian cancer - Sculpting a promising future with surgery. N Engl J Med 2021 Dec 2; 385:2187. PMID: 34874635 https://www.nejm.org/doi/10.1056/NEJMe2116353
  68. von Gruenigen VE, Huang HQ, Beumer JH et al. Chemotherapy completion in elderly women with ovarian, primary peritoneal or fallopian tube cancer - an NRG oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2017;144(3):459-467 PMID: 28089376 PMCID: PMC5570471 Free PMC article https://www.gynecologiconcology-online.net/article/S0090-8258(16)31602-X/fulltext
  69. NEJM Knowledge+ - Ray-Coquard I, Pautier P, Pignata S et al Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2416-2428. doi: 10.1056/NEJMoa1911361. PMID: 31851799 Clinical Trial. https://www.nejm.org/doi/pdf/10.1056/NEJMoa1911361
  70. Mooney SJ, Winner M, Hershman DL et al Bowel obstruction in elderly ovarian cancer patients: a population-based study. Gynecol Oncol. 2013 Apr;129(1):107-12. PMID: 23274561 PMCID: PMC3731031 Free PMC article.
  71. National Cancer Institute Ovarian Germ Cell Tumors (PDQ): Treatment http://www.nci.nih.gov/cancerinfo/pdq/treatment/ovarian-germ-cell/healthprofessional/ - Ovarian, Fallopian Tube, and Primary Peritoneal Cancer -Health Professional version https://www.cancer.gov/types/ovarian/hp