Ovary Part 1

Ovarian Cancer
Written By Sydney Oesch

Episode Notes

Epidemiology of Ovarian Cancer

  1. The term “ovarian cancer” encompasses ovarian, fallopian tube, and primary peritoneal cancers.

  2. Ovarian cancer is the deadliest gynecologic malignancy, with >13,000 deaths in 2023.  

    1. Overall 5-year survival is 50.8%. 

    2. 95% of ovarian cancers are epithelial (and 75% of all epithelial tumors are HGS)

    3. In early stage disease, serous, mucinous, and endometrioid histologies are equally common. In late stage disease, serous tumors are the vast majority.

  3. Risk factors:

    1. Factors increasing total incidence of ovulation increase risk: early menarche, late menopause, nulliparity

    2. Age

    3. History of endometriosis

    4. Genetic risk factors: associated with 15% of ovarian cancer cases

      1. BRCA, BRIP1, RAD51C, RAD51D, Lynch syndrome, strong family history without known genetic mutation

  4. Protective factors: largely encompass factors that decrease the amount of lifetime ovulation. Include: use of OCPs, hx BSO/tubal ligation/salpingectomy, increased parity, history of breastfeeding


Background

  1. Prognostic factors (in order of importance)

    1. Stage (most important factor): with early stage disease, 5-year survival is >90%, however 80% of cases are diagnosed as late stage disease.

    2. Grade:

      1. ⅓ of early stage EOC are low grade

      2. 80% of late stage EOC are high grade

    3. Age: 5-year relative survival rate for elderly patients is ~half as long as in patients <65

    4. Extent of residual disease after surgery: the less the better! Ideally, R0 resection (“optimal is technically ≤1cm).

    5. Histologic subtype

  2. Histologic subtypes (epithelial tumors)

    1. Serous

    2. Mucinous

    3. Endometrioid

    4. Mesonephroid/clear cell 

    5. Brenner

    6. Undifferentiated

    7. Carcinosarcoma

    8. Mixed mesodermal tumor

  3. Grade and mutation profile

    1. High grade tumor have high prevalence of p53 mutations

    2. Low grade serous and mucinous tumors commonly have KRAS mutations

    3. Low grade endometrioid and clear cell tumors: PIK3CA, PTEN, ARID1a pathway mutations


Diagnosis

  1. Presentation:

    1. Early disease may be asymptomatic

    2. Late disease: abdominal pain, bloating, pelvic pain, urinary/bowel symptoms, early satiety, ascites, pleural effusions.

    3. VTE can be a presenting sign (3x elevated risk of VTE with ovarian cancer compared to normal population) 

  1. Evaluation

    1. H&P

    2. Imaging: 

      1. TVUS: 

        1. Concerning features: solid components, especially with doppler flow; size of lesion; septations, especially if thick, presence of ascites

      2. Risk stratification tools

        1. O-RADS scoring system: score of 0-5, with associated percentage risk of malignancy (a score of 1 is a physiologic finding, and score of 5 indicates risk of malignancy ≥50%.)

          1. O-RADS scoring is also available for pelvic MRI

        2. IOTA

        3. ADNEX models

      3. CT scan: most helpful for ovarian cancer to determine extent of disease (less helpful for evaluation of primary adnexal lesion). Typically, C/A/P recommended for EOC.

    3. Tumor markers:

      1. CA-125: nonspecific glycoprotein indicating disruption of peritoneum. More reliable in postmenopausal patients

      2. HE4: epithelial protein with similar sensitivity to CA-125 but increased specificity in the presence of a gynecologic malignancy

      3. CEA: useful to aid in determination of GI primary if suspicious, especially with use of CA-125/CEA ratio (higher ratio = less likely primary GI source)

      4. CA 19-9: can help differentiate gastric and pancreatic cancers


Management of early epithelial ovarian cancer

  1. Surgery:

    1. Surgical staging: typically done via laparotomy*, to include abdominal survey, peritoneal biopsies, pelvic wash vs. fluid aspiration, hysterectomy/BSO, omentectomy (at least infracolic), PPALND

      1. *can consider laparoscopic evaluation if apparent early disease, skilled surgeon who can perform MIS staging

      2. LN evaluation? For apparent ovary/tube-confined disease, recommend full PPALND, as stage is the most important prognostic factor and positive LN will upstage patient to at least stage IIIA1 disease.

        1. Up to 14% of patients with apparent early stage disease will have nodal metastases on PPALND.

        2. Grade III lesions, and serous adenocarcinomas, have highest rates of LN metastases

        3. Evidence points towards improved survival in patients undergoing systematic lymphadenectomy

      3. Management of patients diagnosed postoperatively after surgery for presumed benign disease?

        1. If completely resected EOC, not necessary to return to the OR for completion staging if planning for adjuvant therapy

        2. If the patient is a possible candidate for observation, then consider completion staging to potentially avoid exposure to chemotherapy

        3. Complete surgical staging also provides better information for treatment options for adjuvant management

        4. If initial surgery did not have complete resection, should return to the OR for debulking and staging (unless unresectable).

      4. Fertility sparing management?

        1. Can be considered for patients with stage IA-IB disease in whom fertility is desired. 

          1. Stage IA: can avoid hysterectomy and can consider USO

          2. Stage IB: can avoid hysterectomy

          3. Staging should otherwise be completed in the same fashion

        2. Successful pregnancy outcomes are possible after fertility sparing surgery and after adjuvant therapy

  2. Adjuvant therapy

    1. Chemotherapy is recommended in most cases. 

      1. Early stage trials: 

        1. GOG 7601, 7602, Bolis, GOG95: no OS benefit to adjuvant treatment regimens evaluated in these trials (including melphalan, IP chromic phosphate, cisplatin, cyclophosphamide/cisplatin)

          1. Chromic phosphate has high rates of small bowel perforation and is no longer evaluated/condered 

        2. EORTC Action, ICON1 (and combined ICON/ACTION): 

          1. ICON1: platinum vs. observation for early stage disease for patients in whom the attending physician was unsure whether chemo was necessary. Extent of surgical staging not well documented.

          2. EORTC ACTION: early stage OC with complete or incomplete staging >randomized to adjuvant chemo vs. observation. Only ⅓ of patients were optimally staged. 

            1. Benefit to chemo in patients who did not have surgical staging and in grade III disease

          3. Combined ICON/Action: OS 82% vs. 74% in chemo group, significant, with no differences in any subgroup.  This analysis informed decision to recommend adjuvant treatment for early stage EOC

        3. GOG 157: 3 vs. 6 cycles adjuvant carbo/taxol for early EOC.  Overall, no OS benefit with 6 vs. 3 cycles. However, in serous subgroup analysis, there was a PFS (but no OS!) benefit with 6 cycles. In other subgroups, no PFS or OS benefit.

        4. GOG 175: maintenance taxol after 3 cycles adjuvant carbo/taxol in early stage disease: no benefit.

      2. Trials from advanced stage disease guided decisions for choice of adjuvant therapy in early stage EOC (SOC is carbo/taxol). Will review these trials in our next episode.

      3. Observation for anyone?

        1. Recommend observations: Stage IA/IB mucinous,  Stage IA/IB grade I endometrioid, Stage IA/IB low grade serous

        2. Consider observation vs. chemo: stage IA clear cell, stage IC mucinous, stage IC grade I endometrioid, stage IC low grade serous

        3. *no grade III tumors have an option for observation!

references

1.       Young RC, Walton LA, Ellenberg SS, et al. Adjuvant Therapy in Stage I and Stage II Epithelial Ovarian Cancer. New England Journal of Medicine. 1990;322(15):1021-1027. doi:10.1056/NEJM199004123221501

2.       Young RC, Brady MF, Nieberg RK, et al. Adjuvant treatment for early ovarian cancer: a randomized phase III trial of intraperitoneal 32P or intravenous cyclophosphamide and cisplatin--a gynecologic oncology group study. J Clin Oncol. 2003;21(23):4350-4355. doi:10.1200/JCO.2003.02.154

3.       Trimbos JB, Vergote I, Bolis G, et al. Impact of Adjuvant Chemotherapy and Surgical Staging in Early-Stage Ovarian Carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm Trial.; 2003. https://academic.oup.com/jnci/article/95/2/113/2912344

4.       Bell J, Brady MF, Young RC, et al. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol. 2006;102(3):432-439. doi:10.1016/j.ygyno.2006.06.013

5.       Mannel RS, Brady MF, Kohn EC, et al. A randomized phase III trial of IV carboplatin and paclitaxel x 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: A Gynecologic Oncology Group Study. In: Gynecologic Oncology. Vol 122. ; 2011:89-94. doi:10.1016/j.ygyno.2011.03.013

6.       Swenerton KD, Santos JL, Gilks CB, et al. Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers. Annals of Oncology. 2011;22(2):341-347. doi:10.1093/ANNONC/MDQ383

Sydney Oesch
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Uterine Cytotoxic Therapies