section name header

Info


A. Characteristicsnavigator

  1. Relatively uncommon female cancer
    1. Lifetime risk is ~1 in 70 women
    2. About 25,600 new cases per year of frank ovarian adenocarcinoma in USA
    3. Estimated annual worldwide incidence ~140,000 cases per year
    4. Borderline ovarian tumors (slow growth, low metastasis) have ~3,000 cases/year [5]
  2. Most deadly female urogenital cancer
    1. 12-15,000 deaths per year
    2. Most frequent cause of death from gynecologic malignancy
    3. Median lifespan now beyond 36 months for Stage III / IV disease
  3. Usually asymptomatic until widely metastatic and/or peritoneal carcinomatosis occurs

B. Risk Factorsnavigator

  1. Family history of ovarian cancer
  2. Advancing Age
  3. Hereditary ovarian cancer syndromes
    1. BRCA1 mutations (chromosome 17q) in ~6% of ovarian cancers
    2. BRCA2 mutations (chromosome 13q) in ~3% of ovarian cancers
    3. Overall outcomes with BRCA associated ovarian cancer are better than sporadic [21]
  4. Ovarian cancer risk increased 1.5-2.0X with 10 years of estrogen-only exposure [2,3]
  5. Use of clomiphene citrate in infertility may increase risk
  6. Risk Reduction
    1. Pregnancy and increasing parity [5]
    2. Use of oral contraceptive pills (OCP)
    3. Tubal ligation reduces risk of spontaneous and BRCA1 but not BRCA2 ovarian cancer [6]
  7. Oral Contraceptive Pills (OCP)
    1. Overall reduction in rates of and death from ovarian Ca in nearly all studies [4,17]
    2. Reduces overall rates of ovarian cancer from 1.2 to 0.8 per 100 users over 10 years [17]
    3. Questionable reduced risk of ovarian Ca in patients with BRCA mutations [5,7]
  8. Hormone Replacement Therapy (HRT)
    1. Small increased risk (1 additional case per 2500 users) in ovarian cancer over 5 years [13]
    2. Combination estrogen + progesterone replacement increased ovarian Ca risk 1.58X [30]
  9. Persistent ovarian cysts do NOT appear to be a risk factor for ovarian Ca [8]

C. Screening [11] navigator

  1. CA-125 is a tumor marker detetectable in the serum of many patients with ovarian Ca
    1. ~35% of early stage ovarian Ca has normal CA-125 levels
    2. CA-125 elevated in some patients with pancreatic Ca and endometrial malignancies
    3. Increased CA-125 in benign conditions including endometriosis, leiomyomas, pelvic inflammatory disease, ovarian cysts, other abdominal processes
  2. Transvaginal Ultrasound (TVUS)
    1. Unclear if routine TVUS provide true early detection
    2. TVUS will detect benign masses as well as malignant tumors
    3. Ovarian cysts are commonly found and may persist
    4. Removal of ovarian cysts did not reduce the number of ovarian cancers [8]
  3. No family history of ovarian Ca
    1. TVUS or CA-125 is not recommended in ANY women
    2. Combination of ultrasound AND CA-125 may be of some benefit [10]
  4. Positive Family History
    1. Routine screening not recommended
    2. May be done after counseling: probably TVUS + CA-125
  5. Familial Ovarian Cancer Syndrome: referral to Gyn-Onc specialist
  6. BRCA1
    1. Large gene coding for protein of 1863 bases, probable binds DNA
    2. Increases susceptibility to breast and ovarian cancer
    3. Protein terminating mutations appear to code for cancer risks
    4. Ovarian tumors with germline mutations of BRCA1 are associated with a better clinical course than ovarian cancers with sporadic mutations [8,24]
    5. BRCA1185delAG is common germline mutation in Israeli patients and may confer early onset ovarian cancer
    6. Recommend early screening for ovarian and breast cancer in patients with BRCA1 mutations; no clear recommendation for surgical prophylaxis
  7. Risk of ovarian Ca ~50% reduced by oral contraceptives (OCP) in patients with pathogenic BRCA1 or BRCA2 mutations [7]
  8. Serum proteomic patterns under development for screening general population for any stage early ovarian cancer [14]
  9. Osteopontin levels in plasma may be useful for screening (validation in progress) [15]

D. Presentationnavigator

  1. Primary Care Clinic Presentation [9]
    1. Back pain - most common (45%)
    2. Fatigue (34%)
    3. Bloating (27%)
    4. Constipation (24%
    5. Abdominal pain (22%)
    6. Urinary Symptoms (16%)
  2. Symptoms more severe or frequent than expected should be investigated
  3. Pelvic Mass with Pain and/or Fullness
    1. Organ association of mass
    2. Solid versus cystic
    3. May also present as mass on fallopian tube [18]
  4. Ascites
  5. Non-Specific symptoms due to peritoneal carcinomatosis

E. Evaluationnavigator

  1. History and physical -attempt to localize major symptoms
    1. Uterine
    2. Adnexal
    3. Gastrointestinal
    4. Genitourinary
    5. Symptoms are usually not localized by history and physical
  2. Radiologic Studies
    1. Pelvic ultrasound (superior to computerized tomographic in pelvic area)
    2. Abdominal and computerized tomographic (CT) scans
    3. Urologic studies (including cystoscopy and/or voiding cystourethrogram)
    4. Chest Radiograph
  3. Laboratory
    1. Electrolytes / BUN + Creatinine / Liver Function / Complete Blood Count
    2. HCG (Urine ± Serum)
    3. Elevated CA-125 levels (~50% of patients) See also Card "Tumor Markers"
  4. Cytogenetics
    1. High frequency (~70%) of aneuploidy
    2. Gain of DNA sequences elements on ~90% of chromosomes
    3. Chromosomal element loss occurs on all chromosomes
    4. Loss of heterozygosity reported on up to >70% of chromsome arms
    5. Comparitive genomic hybridization shows changes in 18 regions
  5. Molecular Genetics
    1. Lysophosphatidic Acid levels elevated in close to 100% of ovarian cancer patients [16]
    2. BRCA-1 or -2 mutations found in ~10% of ovarian cancers
    3. BRCA-1 germline mutations associated with improved outcomes
    4. p34cdc2 is overexpressed in epithelial ovarian carcinomas, not in normal ovary
    5. p53 mutations occur in ~60%
    6. Mutations at the NOEY locus found in ~30% of cases

F. Ovarian Neoplasms (Differential) navigator

  1. Epithelial Ovarian Adenocarcinomas are divided into various histological subtypes
  2. Serous Cystomas
    1. Serous cystadenoma (benign)
    2. ...above + proliferation and nuclear anomalies without invasion (low malignant potential)
    3. Serous cystadenocarcinoma
  3. Mucinous Cystomas
    1. Mucinous cystadenoma (benign)
    2. ...above + proliferation and nuclear anomalies without invasion (low malignant potential)
    3. Mucinous cystadenocarcinoma
  4. Endometroid tumors
    1. Related to adenocarcinoma of endometrium
    2. Cysts, benign
    3. Endometroid tumors with proliferation and nuclear anomalies but without invasion
    4. Endometroid cystadenocarcinomas
  5. Mesonephric Tumors
    1. Benign
    2. Mesonephric tumors with proliferation and nuclear anomalies but without invasion
    3. Mesonephric cystadenocarcinomas
  6. Borderline Ovarian Tumors
    1. Ovarian epithelial tumor with low growth rate and low metastatic potential
    2. Tumors appear to originate from Mullarian Duct
    3. About 50% are mucinous and 50% serous types
    4. Surgical resection is generally effective
    5. Better prognosis than typical ovarian tumor types
  7. Krukenberg Tumors
    1. Any tumor which metastasizes to the ovaries
    2. Often bilateral ovarian metastases are found
    3. Most tumors are of gastrointestinal origin
    4. Originally, gastric carcinomas was most common, but incidence decreasing
  8. Miscellaneous
    1. Krukenberg tumors
    2. Germ Cell Tumors
    3. Other metastatic disease
    4. Endometriosis
    5. Non-metastatic disease including abscess, pelvic inflammatory disease, others

G. Good Prognostic Factorsnavigator

  1. Younger Age
  2. Stage I disease
  3. Low tumor grade (particularly for stage I disease) [19]
  4. Low residual tumor volume (following surgery)
  5. Significantly lower CA-125 4 weeks post-operatively
  6. Low growth rate
  7. Germline BRCA1 mutations

H. Stagingnavigator

  1. Stage I: growth limited to ovaries
    1. Stage Ia: one ovary, no ascites, no tumor on external surfaces, capsule intact
    2. Stage Ib: both ovaries, no ascites, no tumor on external surfaces, capsule intact
    3. Stage Ic: tumor on surface of ovary(s), capsule ruptured, ascites present, or positive peritoneal washings
  2. Stage II: growth involving one or both ovaries with peritoneal extension
    1. Stage IIa: extension or metastases to uterus or tubes
    2. Stage IIb: pelvic extension
    3. Stage IIc: stage IIa or IIb tumors with other findings as for stage Ic
  3. Stage III: peritoneal seeding
    1. Stage IIIa: microscopic peritoneal metastasis outside pelvis
    2. Stage IIIb: macroscopic peritoneal metastasis outside pelvis, largest dimension <2cm
    3. Stage IIIc: peritoneal metastasis outside pelvis >2cm
  4. Stave IV: metastatic disease (distant sites)
  5. Tumor Grade (particularly Stage I) [19]
    1. Low (highly differentiated)
    2. Intermediate (moderately differentiated)
    3. High (aggressive; poorly differentiated)

I. Therapynavigator

  1. Surgery
    1. Mainstay in all stages and types of ovarian cancer
    2. Required for histology, extent, debulking
    3. Includes total hysterectomy and bilateral oopherectomy
    4. Note that large tumors have poor blood supplies and poor chemotherapy delivery
    5. Debulking after induction chemotherapy prolongs overall survival [10]
    6. Most centers use initial debulking surgery followed by induction chemotherapy
    7. Degree of surgical resection has strong prognostic significance
    8. Residual disease >1cm is poor prognosis; <1cm residual is good prognosis
    9. Stage IA or IB, grade 1 tumors don't benefit from post-surgical chemotherapy [20]
    10. Second surgery after 3 cycles of chemotherapy in patients with initial >1cm residual Stage III/IV disease is not beneficial
  2. Radiotherapy
    1. Contraversial role and generally not well tolerated
    2. Low therapeutic index due to damage to liver and intestines
    3. Can be used in Stage II and III disease after debulking
    4. No controlled trials comparing with chemotherapy
  3. Chemotherapy Overview [1]
    1. Patients with Stage 1A grade 1 and Stage 1B grade 1 do not need adjuvant therapy [20]
    2. All other patients (even stage 1) do better with adjuvant chemotherapy
    3. Carboplatin (or cisplatin) containing regimen is mainstay of curative adjuvant therpay
    4. Intraperitoneal cisplatin - more effective and less toxic than intravenous in Stage 3 [14]
    5. Standard of care has been carboplatin (or cisplatin) + paclitaxel [22,23]
    6. Intraperitoneal cisplatinum/paclitaxel with intravenous paclitaxel for Stage III [31]
    7. Intraperitoneal carboplatinum/paclitaxel has been used with good effect in Stage III [18]
  4. Stage III / IV First Line Chemotherapy [24]
    1. Standard of care is 6 cycles of platinum + a taxane following surgery
    2. Paclitaxel + cisplatin improved disease free and overall survival compared with cyclophosphamide + cisplatin [25]
    3. Carboplatin is as effective as cisplatin when combined with paclitaxel with less neurological and other toxicity
    4. Docetaxel can substitute for paclitaxel and has less neurotoxicity
    5. Carboplatin alone may be as effective as cisplatin+cyclophosphamide+adriamycin (CAP) [26]
    6. Carboplatin alone may be as effective carboplatin+paclitaxol (and as CAP) with reduced overall toxicities in one study (not confirmed) [24]
    7. Overall median survival ~36 months and progression free survival ~17 months [24]
    8. Two year survival for Stage III+IV disease was 60% [26]
    9. Significant survival and progression free survival increase in optimally debulked Stage III disease with intraperitoneal cisplatin+paclitaxel with intravenous paclitaxel [31]
    10. Intraperitoneal carboplatinum/paclitaxel after one round of systemic chemotherapy can reduce side effects and provide potentially superior disease control [18]
  5. Recurrent Stage III / IV Disease
    1. "Platinum responsive disease" means that recurrence occurred >6 months after cessation of platinum based chemotherapy
    2. Platinum monotherapy is often used initially for recurrence of platinum-responsive disease
    3. Combined platinum + paclitaxel is superior to platinum alone for recurrent disease [29]
    4. Topotecan (Hycamtin®), a topoisomerase I inhibitor, approved for 1st relapse [27]
    5. Doxorubicin liposomal (Doxil®) approved for disease refractory to 1st line therapy
    6. No clear rationale for treatment of CA-125 elevation without other evidence of relapse
    7. Intraperitoneal chemotherapy may have activity in recurrent disease due to higher local levels with better / longer tumor exposure [18]
  6. Bone Marrow Transplantation
    1. Following high dose chemotherapy for recurrent disease
    2. Autologous marrow transplant ("STAMP") programs are being evaluated
    3. Early results with such programs are mixed [28]
    4. Platinum sensitive tumors in younger patients may have some benefit with STAMP [28]

J. Prognosis and Follow Upnavigator

  1. Followup
    1. CA-125 levels followed q3-4 months in patients with initially elevated levels
    2. Pelvic Examination (with general physical exam) is useful
    3. Radiologic exams routinely are generally not indicated
  2. Prognostic Factors
    1. Highly dependent on stage and grade of tumors
    2. Stage I - patients with low grade tumors probably have normal lifespan
    3. Stage I intermediate grade has 3.1X and high grade has 8.9X risk of recurrence versus low grade (well differentiated) tumors [19]
    4. Debulking to <1 cm or no apparent tumor is associated with best overall survival
    5. Optimally debulked Stage III disease with intraperitoneal chemotherapy >5 year median survival [31]
  3. Five Year Survival After Surgical Debulking in Stage III Disease [18]
    1. No Residual Disease: ~50%
    2. Residual Disease <1cm: ~40%
    3. Residual Disease 1-2cm: ~30%
    4. Residual Disease >2cm: ~20%

References navigator

  1. Cannistra SA. 2004. NEJM. 351(24):2519 abstract
  2. Rodriguez C, Patel AV, Calle EE, et al. 2001. JAMA. 285(11):1460 abstract
  3. Lacey JV Jr, Mink PJ, Lubin JH, et al. 2002. JAMA. 288(3):334 abstract
  4. Vessey M, Painter R, Yeates D, et al. 2003. Lancet. 362(9379):185 abstract
  5. Modan B, Hartge P, Hirsh-Yechezkel G, et al. 2001. NEJM. 345(4):235 abstract
  6. Narod SA, Sun P, Ghadirian P, et al. 2001. Lancet. 357(9267):1467 abstract
  7. Narod SA, Risch H, Moslehi R, et al. 1998. NEJM. 339(7):424 abstract
  8. Crayford TJB, Campbell S, Bourne TH, et al. 2000. Lancet. 355(9209):1060
  9. Goff BA, Mandel LS, Melancon CH, Muntz HG. 2004. JAMA. 291(22):2705 abstract
  10. Jacobs IJ, Skates SJ, MacDonald N, et al. 1999. Lancet. 353(9161):1207
  11. Testing for Ovarian Cancer. 2007. Med Let. 49(1264):53
  12. Rose PG, Nerenstone S, Brady MF, et al. 2004. NEJM. 351(24):2489 abstract
  13. Million Women Study Collaborators. 2007. Lancet. 369(9574):1703 abstract
  14. Petricoin EF, Ardekani AAM, Hitt BA, et al. 2002. Lancet. 359(9305):573
  15. Kim JH, Skates SJ, Uede T, et al. 2002. JAMA. 287(13):1671 abstract
  16. Xu Y, Shen Z, Wiper DW, et al. 1998. JAMA. 280(8):719 abstract
  17. Collaborative Group on Epidemiological Studies of Ovarian Cancer. 2008. Lancet. 371(9609):303 abstract
  18. Krasner CN, Roche M, Horowitz NS, et al. 2006. NEJM. 354(15):1615 (Case Record) abstract
  19. Vergote I, De Brabanter J, Fyles A, et al. 2001. Lancet. 357(9251):176 abstract
  20. Penson RT, Sahani D, Bell DA. 2004. NEJM. 351(24):2531 (Case Record) abstract
  21. Boyd J, Sonoda Y, Federici MG, et al. 2000. JAMA. 283(17):2260 abstract
  22. Crown J and O'Leary M. 2000. Lancet. 355(9210):1176 abstract
  23. Drugs of Choice for Cancer Chemotherapy. 2000. Med Let. 42(1087):83
  24. International Collaborative Ovarian Neoplasm (ICON) Group. 2002. Lancet. 360(9332):505 abstract
  25. McGuire WP, Hoskins WJ, Brady MF, et al. 1996. NEJM. 334(1):1 abstract
  26. International Collaborative Ovarian Neoplasm (ICON) Group. 1998. Lancet. 352(9140):1571 abstract
  27. Topotecan. 1996. Med Let. 38(986):96 abstract
  28. Stiff PJ, Veum-Sonte J, Lazarus HM, et al. 2000. Ann Intern Med. 133(7):504 abstract
  29. ICON and AGO Collaborators. 2003. Lancet. 361(9375):2099 abstract
  30. Anderson GL, Judd HL, Kaunitz AM, et al. 2003. JAMA. 290(13):1739 abstract
  31. Armstrong DK, Bundy B, Wenzel L, et al. 2006. NEJM. 354(1):34 abstract