Ovary - Epithelial Carcinoma

Disclaimer

This manual is not a substitute for consultation with an appropriate specialist.
The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

1. Background

Updated June 7, 2024

Ovary - Epithelial Carcinoma (EOC) including Fallopian Tube Cancer and Primary Peritoneal Cancer

Ovarian cancer is the 7th most common malignancy in British Columbia women with a crude incidence rate of 12.2 per 100,000 reported in 2021. The incidence rate has slowly decreased over the last 40 years. The 5-year survival for ovarian cancer is approximately 40-50 %. Epithelial ovarian carcinomas (EOC) account for ~90% of all ovarian malignancies. EOC encompasses 5 distinct diseases, with different presentations (e.g., average age of diagnosis and stage), response to chemotherapy, prognosis, molecular features, and site of origin [1, 2]. While these carcinomas share a common site of tumor growth in the ovary, they are increasingly considered as different diseases in need of disease specific management.

High-grade serous carcinoma (HGSC) is the most common histological subtype (60% of EOC) usually presenting at advanced stage and accounting for most deaths from ovarian cancer. It now recognized that almost all HGSC originate in the distal fallopian tube epithelium and that this histotype is most closely associated with hereditary breast and ovarian cancer syndrome (e.g., BRCA1 or BRCA2 mutations). Fallopian tube carcinoma was previously considered a separate disease site, but the understanding that HGSC of fallopian origin often appear as a dominant mass on the ovary, there is a move to label these tumours “tubo-ovarian”, “pelvic serous”, or “Mullerian serous” (non-uterine) carcinomas [3, 4]. The two next most common types of EOC, clear cell (10%) and endometrioid (10%), are often associate with endometriosis that has implanted on the ovaries or in the peritoneal cavity and undergone malignant transformation. Low grade serous carcinoma (LGSC) and mucinous carcinoma comprise the remaining 2 types of EOC and are very rare (<5% each). LGSC may arise from borderline serous carcinomas (tumours of low malignant potential) or from cells in the fallopian tube. The precursor cell of mucinous of the ovary are not defined.

Reproductive Risk Factors

Higher risk of ovarian cancer has been observed in women with no children or with low numbers of live births. Risk factors that can promote changes at the fallopian tube epithelium include ascending infections (e.g., pelvic inflammatory disease) and retrograde menstruation. Endometriosis is also a well-known risk factor for ovarian cancers, but most strongly associated with clear cell and endometrioid subtypes. Interventions that prevent passage from the lower genital tract or uterus via the fallopian tube to the ovary and peritoneal cavity (e.g., tubal ligation) have shown substantial risk reduction, most notably in clear cell and endometrioid histotypes. These findings support the important role the fallopian tube plays in the development of ovarian cancer, not only as the site of origin for most high-grade serous carcinomas but also as a conduit for inflammatory stimuli including endometriosis and infection.

Genetic Risk Factors

Family history of breast and ovarian cancer has long known to be associated with risk of disease and plays a much more profound role in ovarian HGSC with an estimated 1 in 5 women with HGSC harbouring germline BRCA1 or BRCA2 mutations. Clear cell and endometrioid tumors can be associated with Lynch syndrome (previously referred to as Hereditary Non-Polyposis Colorectal Carcinoma [HNPCC]), which is associated with increased lifetime risks of developing colorectal carcinoma, endometrial carcinoma, ovarian cancer and other primary tumors.

1.1 Screening/ Early Detection and Prevention

Key Message: There are no effective screening/early detection strategies for ovarian cancer.

There are no screening tests proven to detect EOC at an early stage and reduce the number of women who die from this disease. Modalities such as pelvic examination, CA125 measurements and pelvic ultrasound have been tested as screening methods in well executed international clinical trials and have failed to demonstrate a benefit in survival [5, 6] The trials had unacceptably high rate of false positive tests leading to unnecessary surgery. Therefore, ovarian cancer screening is currently not recommended by any jurisdiction, including the Society of Gynecologic Oncology of Canada and the American College of Obstetrics and Gynecology.

UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) This large-scale trial involved over 200,000 postmenopausal women and evaluated multimodal screening with CA125 and transvaginal ultrasound.
Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial This US-based trial included over 78,000 women and assessed annual screening with CA125 and transvaginal ultrasound.

1.2 Opportunistic Salpingectomy

1) Opportunistic salpingectomy for average-risk women: For women who are undergoing any pelvic surgery and who have met their reproductive needs, consideration should be given to removal of the fallopian tubes.

Rationale: Given the lack of effective screening strategies, opportunities for prevention should be considered. Given that the fallopian tube plays a key role in cancer development, both as a site of origin (e.g., HGSCs) and as a conduit for endometriosis (which is associated with clear cell and endometrioid cancers), the fallopian tubes can be removed in women who are undergoing pelvic surgery and no longer need their tubes for reproductive purposes. Titled “opportunistic salpingectomy” this option is directed at women at ‘low risk’ for developing ovarian cancer (i.e., the general population, women not known to have an inherited mutation) and to be performed at the time of hysterectomy for benign conditions or when permanent sterilization is being done (e.g., salpingectomy in lieu of tubal ligation).

Emerging data demonstrate that opportunistic salpingectomy appears to be very safe. There is no noted increased risk of adverse perioperative outcomes or minor complications [7, 8, 9] In addition, there is no apparent impact on the timing of menopause onset, although longer-term hormonal outcomes are still unknown needed [10-14]. A population-based, retrospective cohort study examining OS done for the purpose of ovarian cancer prevention in BC (n=25,88) and comparing to individuals who underwent hysterectomy alone or tubal ligation (n=32,080) reported 0 serous ovarian cancers in the OS group. The age-adjusted expected number, had serous cancers been arising at the same rate in the OS group as in the control group, was 5.27 (95%CI, 1.78-19.29). There were no differences in observed and expected rates of breast or colorectal cancer and the difference in serous cancers could not be explained by differences in known risk and protective factors for ovarian cancer between the groups [15].

2) Risk-reducing surgery in high-risk women: Bilateral removal of ovaries and fallopian tubes by age 40 or when childbearing is complete. Salpingectomy with delayed oopherectomy in this population is unproven but can be considered in well-informed individuals or as part of a clinical trial.

Bilateral removal of the fallopian tubes (salpingectomy) and ovaries (oophorectomy) (BSO) is the standard of care for BRCA1/BRCA2 mutation carriers who have completed childbearing and wish to reduce their future risk of ovarian and fallopian tube cancers. Surgery is typically offered between the ages of 35-40 for BRCA1, and 40-45 for BRCA2.

Those with other lower penetrance hereditary predisposition (e.g., RAD51C/D, BRIP1) or Lynch Syndrome (see section 15.4 Lynch Syndrome (LS) and DNA Mismatch Repair Proteins) have about a 10% risk of ovarian cancer and should be referred to discuss surgical removal of their tubes and ovaries [16].

Surgical menopause induced by the removal of both ovaries is associated with risks such as cardiovascular disease, bone loss, and other comorbidities. Patients should be referred to the Gynecologic Cancer Prevention and Survivorship program, or equivalent, to discuss appropriate hormone replacement treatment to manage the risks of surgical menopause (http://www.bccancer.bc.ca/family-oncology-networks-site/Documents/One%20Pager_Survivorship%20Clinic.pdf).

Because most BRCA-associated cancers appear to arise in the fallopian tubes, it would seem reasonable to offer salpingectomy as a risk-reducing procedure to these high-risk women, with consideration for delayed removal of the ovaries at the time of expected menopause. Modeling studies suggest this approach may be both clinically effective and cost-effective [17, 18]. However, the true effectiveness of this 2-step risk reducing procedure is not yet known. Patients considering the 2-step procedure are strongly encouraged to participate in a clinical trial addressing this strategy (e.g., SOROCk through NRG Oncology: https://www.nrgoncology.org/SOROCk; TUBA-WISP II study through the Dutch Cancer Society: https://www.tuba-wisp.org/).

There are 2 compelling reasons to remove the ovaries: (1) a small proportion of BRCA-associated cancers may arise primarily in the ovaries, and (2) premenopausal oophorectomy reduces breast cancer risk by approximately 50%. Salpingectomy alone in this population should be reserved only for individuals who decline standard of care.

3) Chemoprevention such as oral contraceptive pills may also be considered and are believed to be effective in reducing ovarian/fallopian tube cancer risk by about 50% if used for 5 years by both low-risk and high-risk women [19, 20]. The caveat is that there may be an increased risk of breast cancer associated with oral contraceptives in BRCA1 mutation carriers [19].

References

1. Gilks, C.B., et al., Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol, 2008. 39(8): p. 1239-51.

2. Kobel, M., et al., Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med, 2008. 5(12): p. e232.

3. Singh, N., et al., Primary site assignment in tubo-ovarian high-grade serous carcinoma: Consensus statement on unifying practice worldwide. Gynecol Oncol, 2016. 141(2): p. 195-198.

4. Singh, N., et al., Adopting a Uniform Approach to Site Assignment in Tubo-Ovarian High-Grade Serous Carcinoma: The Time has Come. Int J Gynecol Pathol, 2016. 35(3): p. 230-7.

5. Menon U et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2021 Jun 5;397(10290):2182-2193. doi: 10.1016/S0140-6736(21)00731-5. Epub 2021 May 12. PMID: 33991479; PMCID: PMC8192829.

6. Buys SS et al.,; PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8;305(22):2295-303. doi: 10.1001/jama.2011.766. PMID: 21642681.

7. McAlpine JN, Hanley GE, Woo MM, Tone AA, Rozenberg N, Swenerton KD, et al. Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. American journal of obstetrics and gynecology. 2014;210(5):471 e1-11.

8. Hanley GE, McAlpine JN, Pearce CL, Miller D. The performance and safety of bilateral salpingectomy for ovarian cancer prevention in the United States. American journal of obstetrics and gynecology. 2017;216(3):270 e1- e9.

9. Hanley GE, Kwon JS, Finlayson SJ, Huntsman DG, Miller D, McAlpine JN. Extending the safety evidence for opportunistic salpingectomy in prevention of ovarian cancer: a cohort study from British Columbia, Canada. American journal of obstetrics and gynecology. 2018;219(2):172 e1- e8.

10. Hanley GE, Kwon JS, McAlpine JN, Huntsman DG, Finlayson SJ, Miller D. Examining indicators of early menopause following opportunistic salpingectomy: a cohort study from British Columbia, Canada. American journal of obstetrics and gynecology. 2020;223(2):221 e1- e11.

11. Morelli M, Venturella R, Mocciaro R, Di Cello A, Rania E, Lico D, et al. Prophylactic salpingectomy in premenopausal low-risk women for ovarian cancer: primum non nocere. Gynecologic oncology. 2013;129(3):448-51.

12. Venturella R, Lico D, Borelli M, Imbrogno MG, Cevenini G, Zupi E, et al. 3 to 5 Years Later: Long-term Effects of Prophylactic Bilateral Salpingectomy on Ovarian Function. Journal of minimally invasive gynecology. 2017;24(1):145-50.

13. Findley AD, Siedhoff MT, Hobbs KA, Steege JF, Carey ET, McCall CA, et al. Short-term effects of salpingectomy during lapa roscopic hysterectomy on ovarian reserve: a pilot randomized controlled trial. Fertility & Sterility. 2013;100(6):1704-8.

14. van Lieshout LAM, Steenbeek MP, De Hullu JA, Vos MC, Houterman S, Wilkinson J, et al. Hysterectomy with opportunistic salpingectomy versus hysterectomy alone. Cochrane Database of Systematic Reviews. 2019;8:CD012858.

15. Hanley GE, Pearce CL, Talhouk A, Kwon JS, Finlayson SJ, McAlpine JN, Huntsman DG, Miller D. Outcomes From Opportunistic Salpingectomy for Ovarian Cancer Prevention. JAMA Netw Open. 2022 Feb 1;5(2):e2147343. Doi: 10.1001/jamanetworkopen.2021.47343

16. Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, Bernards SS, casadei S, Yi Q, Burger RA Chan JK, Davidson SA, Mannel RS, DiSilvestro PA, Lankes HA, Ramirez NC, King MC, Swisher EM, Birrer MJ. Inherited Mutations in Women with Ovarian Carcinoma. JAMA Oncol . 2016 Apr;2(4):482-90. doi: 10.1001/jamaoncol.2015.5495)

17. Kwon JS, Tinker A, Pansegrau G, McAlpine J, Housty M, McCullum M, Gilks CB. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol 2013 Jan;121(1):14-24 doi: 10.1097/aog.0b013e3182783c2f

18. Harmsen MG, et al. Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study. BMC Cancer 2015 Aug 19:15:593. doi: 10.1186/s12885-015-1597-y

19. Narod, S.A., et al., Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med, 1998. 339(7): p. 424-8.

20. Whittemore, A.S., R. Harris, and J. Itnyre, Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol, 1992. 136(10): p. 1212-20.

2. Histological Classification of Ovarian Carcinoma

Updated June 7, 2024

EOC represents a group of heterogeneous disease entities. Five major categories of EOC exist, with differing cellular origins, hereditary implications, molecular alterations and potential for targeted therapies (Figure 1). In general, to promote consistency and uniformity, pathology review by a BC Cancer accredited tumor group pathologist is recommended.

Figure 1: Five major types of EOC

** Other rare subtypes not listed include carcinosarcoma (Malignant Mixed Mullerian Tumor, MMMT), undifferentiated carcinoma, mesonephric-like adenocarcinoma of the ovary and malignant Brenner tumor.

Click here to download a larger version of Figure 1.

3. Diagnosis, Staging and Surgery

Updated June 7, 2024

Diagnosis requires thorough clinical, surgical and pathologic assessment. See Figure 2 (link to Theresa’s flow chart for diagnosis)

3.1 Pre-Operative Assessments

Complete history and physical, including pelvic and pelvic-rectal examinations
CBC, BUN, Cr
Tumor markers: CA125 and CEA in all patients. CA19-9 and CA15-3 are associated with breast and gastrointestinal tract cancers; however, they may also be elevated in clear cell carcinomas, endometrioid carcinomas and dermoid cysts (CA19-9).
AFP, HCG (quantitative), LDH in patients under 40 (associated with germ cell tumours)
Chest X-ray
Imaging is informative. Pelvic ultrasound will help to determine level of suspicion (worrisome features include solid areas, increased vascular flow, bilaterality, ascites, excrescences, mural nodules etc.). CT chest/abdomen/pelvis with contrast is recommended for suspected stage III/IV disease or for suspected HGSC histology, to rule out peritoneal dissemination and for treatment planning and before referral to a gynecologic oncologist for consideration of surgery.

3.2 Surgical Approach

All patients presenting with suspected advanced staged ovarian cancer on imaging should be referred for subspecialist surgical care (Gynecologic Oncologists). Decisions regarding upfront surgery to achieve optimal debulking vs. pre-operative chemotherapy if optimal debulking is not possible or is not medically appropriate should be made in a multidisciplinary team setting.

Surgery provides staging and prognostic information, and it may be therapeutic through the removal of diverse clonal populations. Surgical expertise, specifically surgery by a gynecologic oncologist, has been demonstrated to improve the survival of patients with EOCs. Centres with a high volume of surgical procedures for EOC have better outcomes. If malignancy is suspected, surgery should be performed by a gynecologic oncologist with the intent of optimal debulking.

Successful treatment of EOC often begins with surgical management, including surgical cancer staging for apparent early disease, and tumour debulking for advanced stage disease. Staging procedures have changed over the last decade with an appreciation of i) differences in disease distribution and clinical course according to the histotype, and ii) recognition that fertility sparing staging procedures can be appropriate in some situations. Core components of staging usually include removal of the fallopian tubes and ovaries (BSO), removal of the uterus (hysterectomy), omentectomy, directed biopsies, washings, +/- assessment of retroperitoneal lymph nodes (pelvic and/or para-aortic lymphadenectomy).

Careful review can enable triage of suspected benign adnexal lesions to General Gynecologists and suspicious or indeterminate lesions to Gynecologic Oncologists so that one optimal surgical procedure can be performed. Even in the situation of confirmed malignancy, careful consideration needs to be given to patient wishes, medical urgency, the surgical approach, the possibility of achieving optimal surgical debulking (vs. pre-operative chemotherapy), chemo-responsiveness of the disease, and medical comorbidities of the patient.

The 3 most important clinical prognostic factors influencing outcome of EOC are stage, tumour grade and the presence or absence of visible residual disease at the completion of initial surgery. In apparent early-stage ovarian cancer, complete staging with multiple biopsies and possibly lymphadenectomy is key to ruling out microscopically advanced disease. Fertility sparing surgery in young women may be acceptable with specific histotypes (such as endometrioid carcinoma, LGSC, and borderline tumors) when the contralateral ovary and uterus are uninvolved.

3.3 Staging Classification

Classification Criteria (FIGO) for Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancers is as follows and accessible through FIGO, SGO, and other websites:

Table 1: FIGO (2014) and TNM staging

Other considerations are as follows:

Histologic type including grading should be designated at staging;
Primary site (ovary, fallopian tube or peritoneum) should be designated where possible;
Tumours that may otherwise qualify for stage I but involved with dense adhesions justify upgrading to stage II if tumour cells are histologically proven to be present in the adhesions.

Of note, staging for primary fallopian tube and primary peritoneal carcinomas of high-grade serous type is similar. Indeed, modern pathology criteria now consider ovarian serous, primary peritoneal, fallopian tube serous carcinomas as encompassed by pelvic (non-uterine) serous carcinoma. Table 1 summarizes the criteria for assignment of primary tumor site.

Table 2: Criteria for designation of primary tumour site in high-grade serous carcinoma

3.4 Delayed Primary Debulking and Pre-Operative Chemotherapy

When patients present with apparent advanced stage disease, decisions regarding upfront surgery to achieve optimal debulking vs. pre-operative chemotherapy (if optimal debulking is not possible or is not medically appropriate) are made within a multidisciplinary team. This approach is also reflected in existing cancer management guidelines [21]. Randomized clinical trials demonstrate that clinical outcomes for patients treated by upfront surgery, or by pre-operative chemotherapy followed by surgery are the same [22, 23]. Pre-operative chemotherapy is associated with slightly lower rates of operative complications, higher rates of optimal debulking, and reduced rates of bowel resection [24]. In some cases, a diagnostic laparoscopy may be required to decide whether primary surgery or pre-operative chemotherapy is the best initial strategy, based on distribution and volume of disease.

3.5 Biopsy Requirements for Delayed Primary Debulking/Pre-operative Chemotherapy

A core biopsy is the gold-standard diagnostic sample required to establish the disease histology and is required for biomarker testing and treatment planning in patients with advanced stage disease (spread to lymph nodes, peritoneal or pleural spaces or visceral organs).

If the multidisciplinary decision is made to start with pre-operative chemotherapy, a histologic diagnosis, usually by core biopsy (or sometimes by surgical/laparoscopic biopsy), is required. The biopsy is also used for additional molecular testing to guide treatment decisions (see section 3.6).

If a pre-treatment biopsy cannot be obtained, or is not technically successful, consideration can be given to upfront surgery or a laparoscopic biopsy. Cytologic evaluation of fluids (ascites or peritoneal effusions) is considered the least desirable option, but in rare cases cytology can be used. Cell blocks, embedded in FFPE are recommended for better characterization and to facilitate additional testing (see section 3). If a histologic sample cannot be obtained, cytologic evaluation can be accepted, but is considered the less desired option. To differentiate from colorectal cancers, a serum CA125:CEA >25 helps to support the diagnosis of a primary ovarian/primary peritoneal/fallopian tube cancer[25] , but does not help to determine the disease histotype. Care should be taken to rule out other primary cancers. For any patient in whom the response to chemotherapy is poor, pathology should be scrutinized/reconsidered. Low-grade diseases such as low-grade serous carcinoma are unlikely to respond well to chemotherapy and will more likely benefit from surgical debulking (underscoring the value of a good histologic diagnosis, as cytology can seldom discriminate between high and low grade serous ovarian cancers).

3.6 Biomarker Testing for Ovarian Cancers

The standard of care in cancer therapy often includes biomarker testing on tumour tissue. Prognostic and predictive biomarkers are used to counsel patients and plan management. Biomarker expression can also determine eligibility for clinical trials.

A histologic sample is the gold-standard diagnostic material required (e.g., surgical sample or a core biopsy) to make an accurate diagnosis, and to complete all additional biomarker testing.

BRCA1/2 tumour testing is now standard of care for all high-grade EOCs (i.e., high-grade serous, high-grade endometrial, carcinosarcomas, high-grade adenocarcinoma NOS) [26]. This identifies patients with somatic/tumour BRCA mutations and for those with advanced disease (stage III/IV) the finding inform decisions around maintenance treatment following the completion of surgery and first-line chemotherapy. Patients with BRCA1/2 tumour mutations are more likely to harbor germline mutations. All patients with non-mucinous EOC, regardless of tumour testing results, should undergo germline hereditary cancer testing – see section 15. Hereditary Cancer Syndromes).

Homologous Recombination Deficiency (HRD) is present in approximately 50% of high grade serous EOCs. Tumour HRD status may determine prognosis and be used for decision making about maintenance therapy after the completion of surgery and chemotherapy (see section 4.3 Maintenance Therapy). Presently, HRD testing is not funded or available in BC. HRD testing may be accessed through private laboratories (patient self-pay) or occasionally through access programs.

3.7 Fertility Management

For women of childbearing potential, where fertility preservation may be desired, review with a Gynecologic Oncologist is required. An urgent referral to a fertility clinic should be arranged. For most high-grade EOCs, or those with advanced stage disease, fertility-preservation is not usually recommended as optimal cancer management involves removal of all reproductive organs. Some low-grade and early-stage cancers may have the option of fertility preservation (e.g., low grade endometrioid and low grade mucinous). This surgery would involve removal of the affected ovary and fallopian tube, as well as peritoneal washings, peritoneal biopsies, and omental biopsy, while preserving the contralateral ovary and the uterus. This strategy requires careful discussion of the potential risks such as under-staging and cancer recurrence or development of a new cancer in the remaining ovary or in the uterus. These must be weighed against the odds of successful future pregnancy. Sampling of the endometrium should be considered if a hysterectomy is not being performed. Birth control methods should always be used if fertility is/may be intact.

3.8 Special Considerations

In the reproductive age group, extensive pelvic endometriosis can mimic the findings of pelvic malignancy and present a diagnostic challenge.
In the postmenopausal age group, diverticular disease can mimic ovarian cancer.
Patients under 40 with suspected cancer are more likely to have germ cell cancers and initial conservative surgery only is needed (e.g., unilateral BSO). Therefore, preoperative b-HCG, AFP, and LDH are of immense value. When the diagnosis is uncertain, conservative surgery is appropriate.
The objective is to remove tumour masses intact without rupture or spill to avoid the potential for spread of malignant cells. It is recognized that endometrioid and clear cell cancers, which arise in association with endometriosis, are prone to rupture. The impact of intraoperative rupture on prognosis is controversial. No additional treatment is usually recommended for patients with intraoperatively ruptured stage I cancers. If the tumor can be removed intact with the use of endobags, when the procedure is done laparoscopically, this may be appropriate.
Aspiration of pelvic masses preoperatively is NOT recommended for diagnosis. The aspiration of intracystic fluid seldom gives the diagnosis and may compromise prognosis if rupture occurs prior to surgery. Unlike intraoperative rupture, preoperative rupture appears to be associated with a worse outcome and may influence treatment and prognosis.
In stage I ovarian cancer, once the diagnosis of malignancy has been made, a thorough staging procedure should be performed. Peritoneal washings, peritoneal biopsies, pelvic and para-aortic node assessment, and omentectomy are all important in determining the presence of subclinical extra-ovarian spread. Wedge biopsy of the contralateral ovary is not required if the ovary is clinically normal as this may further compromise fertility.
The objective of surgery is to reduce the residual disease to no macroscopic disease/R0 (maximal cytoreduction). Although patients with residual disease < 1 cm (R1) are considered “optimally debulked” the greatest benefit is seen in those with R0 at completion of surgery [19].

References

21. Wright AA, et al. Neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. Gynecol Oncol. 2016 Oct;143(1):3-15. doi: 10.1016/j.ygyno.2016.05.022. Epub 2016 Aug 8. PMID: 27650684; PMCID: PMC5413203.

22. Kehoe, S., et al., Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet, 2015. 386(9990): p. 249-57.

23. Vergote, I., et al., Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med, 2010. 363(10): p. 943-53.

24. Bartels at al. A meta-analysis of morbidity and mortality in primary cytoreductive surgery compared to neoadjuvant chemotherapy in advanced ovarian malignancy, Gynecologic Oncology, Volume 154, Issue 3, 2019, Pages 622-630,

25. Yedema, C.A., et al., Use of serum tumor markers in the differential diagnosis between ovarian and colorectal adenocarcinomas. Tumour Biol, 1992. 13(1-2): p. 18-26.

26. Mosele MF et al. Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2024 Jul;35(7):588-606. doi: 10.1016/j.annonc.2024.04.005. Epub 2024 May 27. PMID: 38834388.

4. Medical Management of High Grade Ovarian Cancers

Updated June 7, 2024

4.1 Adjuvant Systemic Therapy for Stage I and II Ovarian Cancers

Management of stage I and II ovarian cancer aims to maximize survival while minimizing treatment-related morbidity [27]. For stage I ovarian cancer, the cornerstone is surgical staging and cytoreduction (see section 3.2). Some patients with stage IA or IB disease may not require adjuvant therapy, whereas those with high-grade tumors (e.g., HGSC) or stage IC disease typically receive adjuvant chemotherapy, commonly a platinum-based regimen such as carboplatin and paclitaxel (see section 5, Subtype specific management).

Stage II ovarian cancer management also begins with optimal cytoreductive surgery. Due to the higher risk of residual disease and metastasis, adjuvant chemotherapy is indicated for all patients with stage II disease. Standard adjuvant chemotherapy involves six cycles of platinum and taxane agents, mirroring the regimen used for advanced-stage disease (see section 5, Subtype specific management).

The inclusion of targeted therapies, such as PARP inhibitors, is under investigation for early-stage disease but is not standard and not approved in Canada or any other jurisdiction.

4.2 First-Line Systemic Therapy for Advanced Stage (III/V) Ovarian Cancer

Management of stage III and IV ovarian cancer, characterized by extensive peritoneal dissemination or distant metastasis, focuses on maximizing surgical cytoreduction and systemic therapy to improve survival outcomes. Post-surgical management includes platinum-based chemotherapy, typically combining carboplatin and paclitaxel for six cycles and often a decision about maintenance therapy (see section 4.3 Maintenance therapy).

Pre-operative chemotherapy is appropriate for selected patients with advanced and biopsy-proven ovarian/fallopian tube/primary peritoneal malignancy who are not appropriate for immediate maximal debulking. The decision to delay surgery should be made following consultation with a gynecologic oncologist, in a multidisciplinary team setting (see sections 3 Surgery and 3.4 Delayed Primary Debulking). We recommend routine monitoring of CA125 or other relevant marker with each cycle, and that patients are referred back to Gynecologic Oncology (surgeon) after 2-3 cycles to be evaluated for delayed debulking surgery and to arrange timely care. A CT chest/abdomen/pelvis should be performed prior to the assessment by the Gynecologic Oncologist to determine response to chemotherapy and the distribution of disease. If the chemotherapy has reduced the burden of disease, the distribution is accessible, and the patient’s performance status is satisfactory, then surgery is usually planned post cycle 3 or 4. If there is progressive disease on pre-operative chemotherapy, there is generally no role for surgery, except for bowel or ureteric obstruction. Generally, total number of chemotherapy cycles is 6. Historically, at least 2 additional cycles were given after delayed primary debulking, thus sometimes exceeding 6 cycles, however, currently, with the use of maintenance therapy (see section 4.3 Maintenance therapy) chemotherapy treatment is often completed with cycle 6. Ultimately, the number and timing of cycles will depend on disease status, patient preference and physician preference. There are no data to demonstrate improved patient outcomes beyond 6 cycles of standard chemotherapy.

Timing of initiation of post-operative chemotherapy: Treatment should be started as soon as it is felt safe to do so after surgery, with the goal of completing 6 cycles of chemotherapy in total, when possible. For most patients who have an uncomplicated post-operative course, this is often safe and feasible within 14-21 days of the operation. Early treatment initiation prevents the re-accumulation of ascites and is not associated with delays in surgical healing or post-operative complications. Randomized data are not available to define the optimal interval of time for treatment initiation, but retrospective analyses show worse prognosis when treatment delays are excessive.

Maintenance therapy has shown to improve progression-free survival (PFS) and in some cases impact overall survival and is often recommended for stage III and IV disease - see below (section 4.3 Maintenance therapy).

In recurrent disease, treatment is guided by the platinum-free interval, with platinum-sensitive recurrences favoring re-treatment with platinum-based regimens, potentially combined with PARP inhibitors or bevacizumab. Ongoing research is focused on optimizing therapeutic combinations and sequencing to enhance overall survival and quality of life.

4.3 Maintenance Therapy

4.3.1 First-Line Maintenance for Advanced Stage (III and IV) High-Grade Ovarian Cancer

Patients with stage I and II high-grade EOC are not eligible for maintenance therapy after the completion of adjuvant chemotherapy.

Maintenance therapy in the first-line treatment setting of advanced-stage ovarian cancer (stage III/IV) predominantly involves the use of PARP inhibitors or bevacizumab which have shown efficacy in improving patient outcomes. PARP inhibitors, such as olaparib and niraparib, leverage synthetic lethality in tumors with homologous recombination deficiencies (HRD), including BRCA1/2 mutations. The SOLO1 trial revealed that maintenance olaparib significantly enhanced PFS and improves 7-year overall survival in cases with BRCA mutations (germline or tumour/somatic) post-response to platinum-based chemotherapy [28]. Similarly, the PRIMA trial established niraparib’s impact on PFS in BRCA1/2 mutated ,HRD-positive and BRCA-wild-type populations, and even in HRD-negative populations [29]. However, recent data demonstrate that maintenance niraparib made no improvement on OS in any molecular subgroup [30]. The reasons for this are unclear and may be multiple. One hypothesis is that high rates of treatment with PARP inhibitors in subsequent lines of therapy may have confounded the results. Both olaparib and niraparib are approved for use in Canada and are available in BC.

Bevacizumab is an anti-angiogenic agent that inhibits vascular endothelial growth factor (VEGF), thus curtailing tumor angiogenesis. The GOG-0218 and ICON7 trials demonstrated that adding bevacizumab to chemotherapy, followed by maintenance bevacizumab, significantly improved PFS in newly diagnosed advanced ovarian cancer [31-33]. ICON7 identified a high-risk population that benefited most from the addition of bevacizumab (i.e., stage IV disease, sub-optimally debulked patients with visible residual disease and patient who were never felt to be candidates for surgery due to disease distribution or other factors). Bevacizumab is approved for use by Health Canada for the high-risk population.

Choice of first-line maintenance therapy: The optimal choice of maintenance therapy for advanced stage (stage III/IV) high-grade ovarian cancer is not known in each case [35]. The decision requires review with an oncologist to integrate treatment, biomarker and patient factors to personalize care.

The following principles may be used to guide decision making:

Table 3: First-line Advanced EOC - Maintenance Therapy Approach in Patients Treated with Pre-Operative Chemotherapy

Note: The final treatment decision should be made in consultation with an oncologist, considering individual patient factors and eligibility criteria.

*For patients with stage III or IV high grade serous ovarian carcinomas treated with pre-operative carboplatin – paclitaxel regimen (every 3 weeks or weekly) in first-line setting. A minimum of 3 values of CA-125 within 100 days are required, starting with Cycle 1 day 1 . https://www.biomarker-kinetics.org/CA-125-neo

1Olaparib GOOVFOLAM Protocol up to 2 yrs of therapy (patients with partial response who are still deriving benefit from olaparib at 2 years may be considered for extension of therapy).

2Niraparib GOOVFNIRM Protocol up to 3 yrs of therapy.

3Bevacizumab GOOVCATB Protocol up a maximum of 17 total doses of bevacizumab.

Table 4: First-line Advanced EOC - Maintenance Therapy Approach in Patients Treated with Post-Operative Chemotherapy

Note: The final treatment decision should be made in consultation with an oncologist, considering individual patient factors and eligibility criteria.

*For patients with stage III or IV high grade serous ovarian carcinomas treated with adjuvant carboplatin – paclitaxel regimen (every 3 weeks or weekly) in first-line setting, after primary debulking surgery. A minimum of 3 values of CA-125 within 100 days are required, starting with Cycle 1 day 1. https://www.biomarker-kinetics.org/CA-125

1Olaparib GOOVFOLAM Protocol up to 2 yrs of therapy (patients with partial response who are still deriving benefit from olaparib at 2 years may be considered for extension of therapy).

2Niraparib GOOVFNIRM Protocol up to 3 yrs of therapy.

3Bevacizumab GOOVCATB Protocol up a maximum of 17 total doses of bevacizumab.

4.3.2 Maintenance for Recurrent Platinum-Sensitive and Responsive High-Grade Ovarian Cancer

Most patients being diagnosed with EOC today will have been exposed to a PARP inhibitor during first-line therapy. However, some patients (e.g., initially diagnosed with stage I or II disease, or had first-line treatment before maintenance therapy for advanced disease was routinely available) may have disease recurrence and for them, maintenance therapy may be considered once chemotherapy is completed.

The pivotal NOVA trial demonstrated that niraparib significantly prolonged progression-free survival (PFS) in both BRCA-mutated and non-BRCA patients with recurrent platinum-sensitive (recurrence > 6 months from the time of the last platinum-based therapy) and platinum-responsive (evidence of response to the last line of platinum-based therapy) ovarian cancer [35]. There was no improvement in overall survival The SOLO2/ENGOT-Ov21 trial further established the efficacy of olaparib in BRCA-mutated recurrent ovarian cancer, showing a significant improvement in PFS and overall survival (OS) compared to placebo [36].

References

27. Colombo, N., Sessa, C., Du Bois, A., Ledermann, J., McCluggage, W. G., McNeish, I., ... & Vergote, I. (2019). ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Annals of Oncology, 30(5), 672-705.

28. Moore K, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018 Dec 27;379(26):2495-2505. doi: 10.1056/NEJMoa1810858. Epub 2018 Oct 21. PMID: 30345884.

29. González-Martín A, at al.; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2391-2402. doi: 10.1056/NEJMoa1910962. Epub 2019 Sep 28. PMID: 31562799.

30. Monk BJ, Barretina-Ginesta MP, Pothuri B, Vergote I, Graybill W, Mirza MR, McCormick CC, Lorusso D, Moore RG, Freyer G, O'Cearbhaill RE, Heitz F, O'Malley DM, Redondo A, Shahin MS, Vulsteke C, Bradley WH, Haslund CA, Chase DM, Pisano C, Holman LL, Pérez MJR, DiSilvestro P, Gaba L, Herzog TJ, Bruchim I, Compton N, Shtessel L, Malinowska IA, González-Martín A. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Ann Oncol. 2024 Sep 14:S0923-7534(24)03762-1. doi: 10.1016/j.annonc.2024.08.2241. Epub ahead of print. PMID: 39284381.

31. Burger, R. A., Brady, M. F., Bookman, M. A., Fleming, G. F., Monk, B. J., Huang, H., ... & Liang, S. X. (2011). Incorporation of bevacizumab in the primary treatment of ovarian cancer. New England Journal of Medicine, 365(26), 2473-2483.

32. Oza AM, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):928-36. doi: 10.1016/S1470-2045(15)00086-8. Epub 2015 Jun 23. PMID: 26115797; PMCID: PMC4648090.

33. Perren TJ, et al.. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011 Dec 29;365(26):2484-96. doi: 10.1056/NEJMoa1103799. Erratum in: N Engl J Med. 2012 Jan 19;366(3):284. PMID: 22204725.

34. Banerjee S, Gonzalez-Martin A, Harter P, Lorusso D, Moore KN, Oaknin A, Ray-Coquard I. First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion. ESMO Open. 2020 Nov;5(6):e001110. doi: 10.1136/esmoopen-2020-001110. PMID: 33310779; PMCID: PMC7783599.

35. Mirza MR, et al.. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. doi: 10.1056/NEJMoa1611310. Epub 2016 Oct 7. PMID: 27717299.

36. Pujade-Lauraine E, et al.. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2. Epub 2017 Jul 25. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. doi: 10.1016/S1470-2045(17)30639-3. PMID: 28754483.

5. Subtype Specific Medical Management

Updated June 7, 2024

5.1 First-Line High Grade Serous Carcinoma of Ovary/Fallopian Tube/Peritoneum

Table 3: First-line chemotherapy for High-Grade Serous Carcinoma

Note:

**GOOVIPCC: Intra-peritoneal Chemotherapy (IP) chemotherapy is no longer recommended in BC. Recent phase 3 data demonstrate no meaningful improvement in PFS or OS, and the delivery of IP therapy is very resource intensive with a higher risk of catheter related complications [37].

GOOVDDCAT: Dose dense (DD) chemotherapy involves delivering paclitaxel on a weekly basis, and the platinum every 3 weeks. Recent trials have failed to demonstrated superiority of this treatment over standard 3 weekly therapy [38]. GOOVCATM or GOOVCATX should be used for most cases; however, this protocol remains available and can be selected at the discretion of the treating physician.

5.2 Recurrent High Grade Serous Carcinoma of Ovary/Fallopian Tube/Peritoneum

Ovarian cancer commonly relapses, especially in women with stage III or IV disease, and 10-15% of stage III patients have primary refractory disease. If the patient is not already being followed at BC Cancer, then referral to either a regional cancer centre or to a community oncology centre is highly recommended.

The management of relapsed EOC will depend on the duration of time from finishing platinum-based chemotherapy to the time of recurrence of disease. This is known as the progression-free interval (PFI). Patients with a PFI greater than 6 months are referred to as platinum sensitive, while patients with a PFI less than 6 months are platinum resistant. Platinum refractory cancer progresses during chemotherapy and is generally treated like platinum-resistant disease, although the prognosis may be worse.

For women with a long interval to the first recurrence (e.g. ≥ 12 months since completion of primary therapy), surgery should be considered, and review with a Gynecologic Oncologist is recommended (based on the results of the DESKTOPIII trial, showing improved PFS from second-debulking surgery in appropriately selected patients) [39]. Surgery may be considered if the patient has a PFI of at least 6 months, ECOG performance status 0, ascites < 500 cc, and complete resection at initial surgery). In addition, surgery may be the most appropriate modality in chemo-resistant histotypes such as mucinous carcinoma and LGSC. Decisions must be individualized. Clinical trials should be considered for all patients with recurrent EOC.

Platinum-Sensitive Disease (progression-free from last platinum- therapy > 6 months):

Combination therapy is recommended. Options include carboplatin with any of paclitaxel (GOOVCATR), docetaxel (GOOVCADR), pegylated liposomal doxorubicin (GOOVPLDC), or gemcitabine (GOOVCAG). Other combinations may be used depending on the desired side effect profile, schedule, and past or emergent allergies.
Single agent options include carboplatin (GOOVCARB), paclitaxel (GOOVTAX3), PLD (GOOVLDOX), topotecan (GOOVTOP), cisplatin (GOOVCIS), and cyclophosphamide (GOOVCYCPO).
Maintenance treatment with a PARPi may be considered in patients who have evidence of BOTH platinum-sensitive and platinum-responsive relapsed HGSC and who have not been previously treated with a PARP inhibitor in an earlier line of therapy. See section: 9.3.2 .
Maintenance bevacizumab is not funded in the setting of platinum-sensitive recurrent ovarian cancer.

Platinum-Resistant (progression free from last platinum- therapy < 6 months) or Refractory Disease (progression free from last platinum- therapy <3 months):

Treatment initiation is recommended when patients are symptomatic or are anticipated to become symptomatic.
There is no known benefit to starting chemotherapy in asymptomatic patients (e.g. with Ca-125 rise, or low-bulk disease).

Well conducted clinical trials have established that single agent chemotherapy, combined with a bevacizumab leads to better outcomes than chemotherapy alone appropriately selected patients. Bevacizumab inhibits binding of VEGF to its receptor, which is important for neovascularization and angiogenesis. Studies have demonstrated an improved progression-free survival in platinum-resistant disease when bevacizumab is added to chemotherapy [26], but no improvement in overall survival has been demonstrated. Patient selection for treatment is important because of the risk of bowel perforation, hypertension and proteinuria. Bevacizumab can be combined with:

paclitaxel (UGOOVBEVP)
liposomal doxorubicin (UGOOVBEVLD)
gemcitabine (UGOOVBEVG)
vinorelbine (GOOVBEVV)

For patients not able to have bevacizumab (or who have experienced disease progression on prior bevacizumab) single-agent chemotherapy , selecting from the following based on toxicities and time since last exposure is appropriate, with the caveat that response to therapy decreases with multiple drug exposures and in some cases best supportive care is also an appropriate option:

3-weekly paclitaxel (GOOVTAX3)
pegylated liposomal doxorubicin (GOOVLDOX)
topotecan (GOOVTOP)
gemcitabine (GOOVGEM)
etoposide (GOOVETO)
docetaxel, (GOOVDOC)
vinorelbine (GOOVVIN)
cyclophosphamide (GOOVCYCPO)

Hormonal therapies such as tamoxifen (GOOVTAM) and letrozole (GOOVAI) have shown modest activity in EOC.

Future Options: At the time of the development of this version of the management manual, mirvetuximab soravtansine [MIRV, a first-in-class antibody–drug conjugate targeting folate receptor α (FRα)] had been demonstrated to improve overall survival in FRα positive, platinum-resistant HGSC of the ovary. In the landmark trial, 62% of patients had had prior bevacizumab exposure and 55% had had prior PARP inhibitor [40]. Once available, MIRV is expected to be integrated into the care pathway for platinum resistant HGSC of the ovary once review and approval from Health Canada has been obtained.

5.3 Systemic Treatment of Rare Histologies

Table 4: Adjuvant/First-line chemotherapy recommendations for non-HGS histologies

5.3.1 Clear cell histology

The benefits of post-operative chemotherapy in the treatment of clear cell carcinoma of the ovary have not been proven in part due to lack of large-scale studies for this rare subtype [41]. In a multi-institutional retrospective cohort study 3 cycles of adjuvant platinum-based chemotherapy had similar outcomes to 6 cycles [42]. A retrospective analysis of GOG 157 (a trial in early stage ovarian cancer) likewise suggested that 3 cycles may be adequate for non-serous histologies [43].

If recurrent, systemic treatment is generally similarly to recurrent HGSC, although, again, high level evidence is lacking. Palliative or salvage RT may have a role given sensitivity to radiation. Clinical trial participation, if possible, is encouraged.

5.3.2 Endometrioid histology

The use of post-operative chemotherapy in the treatment of early-stage high grade endometrioid carcinoma of the ovary is associated with improved patient outcomes [41].

If recurrent, systemic treatment is generally similar to recurrent HGSC, as high grade endometrioid ovarian cancer is similar in behavior to HGSC. Palliative or salvage RT may have a role given sensitivity to radiation. Clinical trial participation, if possible, is encouraged.

Young women with clinical stage I endometrioid ovarian carcinoma may be appropriate candidates for fertility-sparing surgery. See Section 7 Fertility.

5.3.3 Mucinous histology

The benefits of adjuvant chemotherapy in the treatment of early-stage mucinous carcinoma of the ovary remain unproven [44].

If recurrent, systemic treatment is generally similarly to recurrent HGSC, although level I evidence is lacking. Treatment with fluorouracil, oxaliplatin and leucovorin or fluorouracil, irinotecan and leucovorin with or without bevacizumab, is sometimes considered, but evidence of substantial activity is lacking. Her-2 directed therapy may have a role if tumour has positive staining for Her-2/neu receptor [45]. Clinical trial participation, if possible, is encouraged.

Young women with clinical stage I mucinous ovarian carcinoma may be appropriate candidates for fertility-sparing surgery. See Section 7. Fertility.

Genetics: Patients with mucinous histology are not eligible for referral to the Hereditary Cancer Program, however all patients with a concerning family history are eligible for referral to the Hereditary Cancer Program, irrespective if disease histology.

5.3.4 Low Grade Serous

Because of the rarity of this disease, the optimal post-operative treatment of LGSC of the ovary remains the subject of clinical trials and ongoing multicenter collaborative efforts. However, there is a suggestion that for women with advanced stage disease, maintenance hormonal therapy following chemotherapy may prolong survival and time to recurrence after completion of chemotherapy [46].

Recurrent disease: Surgery remains the backbone of management for many cases of LGSC of the ovary, necessitating a review with a gynecologic oncologist when recurrence is first detected and evidence of any subsequent disease progression. Systemic therapy options include hormone therapy using aromatase inhibitors (GOOVAI), chemotherapy as used for recurrent HGSC, and possibly targeted therapy with MEK inhibitors.

MEK inhibition: LGSOC is characterized by mutations in the KRAS and BRAF genes, leading to the activation of the MAPK/ERK signaling cascade, promoting cell proliferation and survival. MEK inhibitors, namely trametinib, inhibit the MEK1 and MEK2 enzymes, effectively blocking the downstream signaling and reducing tumor growth. Clinical studies have demonstrated that MEK inhibitors are active in LGSCO. Trametinib has been demonstrated to improve progression-free and overall survival when compared to physician choice of therapy [47].

5.3.5 MMMT/Undifferentiated

Patients are treated as per HGS carcinoma, but with poorer responses and outcomes.

References

37. Walker JL et al. Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy Plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol. 2019 Jun 1;37(16):1380-1390. doi: 10.1200/JCO.18.01568. Epub 2019 Apr 19. Erratum in: J Clin Oncol. 2019 Sep 1;37(25):2299. PMID: 31002578; PMCID: PMC6544459.

38. Clamp, A. R., James, E. C., McNeish, I. A., Dean, A., Kim, J. W., O'Donnell, D. M., ... & Ledermann, J. A. (2020). Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. The Lancet, 395(10226), 2077-2085.

39. Harter P, et al.. Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer. N Engl J Med. 2021 Dec 2;385(23):2123-2131. doi: 10.1056/NEJMoa2103294. Erratum in: N Engl J Med. 2022 Feb 17;386(7):704. PMID: 34874631.

40. Moore KN, Angelergues A, Konecny GE, García Y, Banerjee S, Lorusso D, Lee JY, Moroney JW, Colombo N, Roszak A, Tromp J, Myers T, Lee JW, Beiner M, Cosgrove CM, Cibula D, Martin LP, Sabatier R, Buscema J, Estévez-García P, Coffman L, Nicum S, Duska LR, Pignata S, Gálvez F, Wang Y, Method M, Berkenblit A, Bello Roufai D, Van Gorp T; Gynecologic Oncology Group Partners and the European Network of Gynaecological Oncological Trial Groups. Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer. N Engl J Med. 2023 Dec 7;389(23):2162-2174. doi: 10.1056/NEJMoa2309169. PMID: 38055253.

41. Oseledchyk, A., et al., Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000-2013. Ann Oncol, 2017. 28(12): p. 2985-2993

42. Prendergast, E.N., et al., Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort. Gynecol Oncol, 2017. 144(2): p. 274-278

43. Chan JK, Tian C, Fleming GF, Monk BJ, Herzog TJ, Kapp DS, Bell J. The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study. Gynecol Oncol. 2010 Mar;116(3):301-6. doi: 10.1016/j.ygyno.2009.10.073. Epub 2009 Nov 28. PMID: 19945740.

44. Nasioudis D., Haggerty A.F., Giuntoli R.L., Burger R.A., Morgan M.A., Ko E.M., Latif N.A. Adjuvant chemotherapy is not associated with a survival benefit for patients with early stage mucinous ovarian carcinoma. Gynecol. Oncol. 2019;154:302–307. doi: 10.1016/j.ygyno.2019.05.009

45. McAlpine, J.N., et al., HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy. BMC Cancer, 2009. 9: p. 433

46. Gershenson, D.M., et al., Hormonal Maintenance Therapy for Women With Low-Grade Serous Cancer of the Ovary or Peritoneum. J Clin Oncol, 2017. 35(10): p. 1103-1111.

47. Gershenson DM, Miller A, Brady WE, Paul J, Carty K, Rodgers W, Millan D, Coleman RL, Moore KN, Banerjee S, Connolly K, Secord AA, O'Malley DM, Dorigo O, Gaillard S, Gabra H, Slomovitz B, Hanjani P, Farley J, Churchman M, Ewing A, Hollis RL, Herrington CS, Huang HQ, Wenzel L, Gourley C. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022 Feb 5;399(10324):541-553. doi: 10.1016/S0140-6736(21)02175-9. PMID: 35123694; PMCID: PMC8819271.

6. Management of Serous Tubal Intraepithelial Carcinoma (STIC)

More extensive examination of the fallopian tubes and increased uptake of risk reducing procedures (BRCA1/2 mutation carriers) or opportunistic salpingectomies (general population) have resulted in the increased detection of serous tubal intraepithelial carcinoma (STIC) in the fallopian tubes, the putative precursor lesion to high-grade serous carcinomas of the ovary.

When performing a risk reducing bilateral BSO for women with a BRCA1 or BRCA2 mutation, a STIC will be found in approximately 3.5-5.5% of patients [48-49]. In women having an opportunistic salpingectomy for benign disease or in women with a high-risk family history, STIC may be found in approximately 0.6-1.1% of patients.

When an isolated STIC is identified during risk-reducing BSO for BRCA1 or BRCA2, a referral should be made to BC Cancer for consideration of completion surgical staging (minimum washings, omentectomy, directed biopsies, +/- hysterectomy). Approximately 10% of high-risk women (with BRCA1 or BRCA2 mutations) with a STIC will have a concurrent HGSC of the ovary following surgical staging [51]. In addition, these patients are at risk of developing primary peritoneal carcinoma, the median time to the development being 4-6 years. The 5-year risk is 10.5%, and the 10-year risk is 27.5% [52]. However, based on currently knowledge, only those with invasive disease found at the time of completion surgery should be offered post-operative chemotherapy.

When an isolated STIC is identified in a patient at 'low risk'/general population, a referral should be made to both BC Cancer Surgical Gynecologic Oncology for consideration of completion surgical staging as well as to the BC Cancer Hereditary Cancer Program. These women have an elevated risk (~30%) of carrying a germline BRCA1 or BRCA2 mutation. These patients also are at risk of developing subsequent primary peritoneal carcinoma [53].

References

48. Chay, W.Y., et al., Outcomes of Incidental Fallopian Tube High-Grade Serous Carcinoma and Serous Tubal Intraepithelial Carcinoma in Women at Low Risk of Hereditary Breast and Ovarian Cancer. Int J Gynecol Cancer, 2016. 26(3): p. 431-6.

49. Long Roche, K.C., et al., Risk-reducing salpingectomy: Let us be opportunistic. Cancer, 2017. 123(10): p. 1714-1720.

50. Patrono, M.G., et al., Clinical outcomes in patients with isolated serous tubal intraepithelial carcinoma (STIC): A comprehensive review. Gynecol Oncol, 2015. 139(3): p. 568-72.

51. Ruel-Laliberté J, Kasasni SM, Oprea D, Viau M. Outcome and Management of Serous Tubal Intraepithelial Carcinoma Following Opportunistic Salpingectomy: Systematic Review and Meta-Analysis. J Obstet Gynaecol Can. 2022 Nov;44(11):1174-1180. doi: 10.1016/j.jogc.2022.08.018. Epub 2022 Sep 12. PMID: 36099965.

52. Steenbeek MP, van Bommel MHD, Bulten J, Bogaerts J, Garcia C, Cun HT, Lu KH, van Beekhuizen HJ, Minig L, Gaarenstroom KN, Nobbenhuis M, Krajc M, Rudaitis V, Norquist BM, Swisher EM, Mourits MJE, Massuger LFAG, Hoogerbrugge N, Hermens RPMG, IntHout J, de Hullu JA. Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis. J Clin Oncol 2022;40(17). https://doi.org/10.1200/JCO.21.02016

53. Stewart KT, Hoang L, Kwon JS. Serous tubal intraepithelial carcinoma (STIC) outcomes in an average risk population. Gynecol Oncol Rep. 2024 Feb 8;51:101334. doi: 10.1016/j.gore.2024.101334. PMID: 38370398; PMCID: PMC10869241.

7. Borderline Ovarian Tumors/Tumours of Low Malignant Potential

Ovarian borderline tumors have also been referred to as “tumors of low malignant potential” or “atypical proliferative tumors”; however, “borderline tumor” is the preferred terminology. Borderline tumors exhibit epithelial proliferation and cytologic atypia, beyond that acceptable for a benign neoplasm, but do not exhibit the destructive growth seen in carcinomas. Approximately 15% of all epithelial ovarian neoplasms are borderline tumors and the majority (~70%) are stage I at diagnosis.

Serous and mucinous borderline ovarian tumors are the two most common types, while endometrioid, seromucinous, Brenner, and clear cell borderline ovarian tumors are much less common. Seromucinous is a confusing name, but merely refers to the mixed epithelial types present (i.e., serous, mucinous, endometrioid, etc.). The “seromucinous” subtype of borderline tumor is officially included in the most current WHO classification and like all the histotypes of borderline tumor other than serous, is almost always associated with a benign course.

Surgery for borderline ovarian tumours (BOT) is often performed in the community as they commonly arise in young women with a low index of suspicion of cancer. Detailed operative reports should describe all peritoneal surfaces in the pelvis and upper abdomen, contralateral ovary, omentum, and adjacent structures. When these findings are adequately documented, patients may not need repeat surgical staging procedures. Washings and unilateral cystectomy or USO can be considered for young women wishing to maintain childbearing. Research suggests cystectomy for BOT is associated with increased reoperation rate e.g., for subsequent cystectomies, or unilateral salpingo-oophorectomies, but does not negatively impact survival. Staging for BOT has evolved in the last decades, recognizing that lymph node metastases are exceedingly rare, and the most common distribution of disease is in the ovaries, adjacent pelvic structures, peritoneal fluid and/or omentum. Thus, modern staging procedures involve sampling these areas. In women who did not have this staging performed at initial operation, then re-operation is warranted unless there are significant co-morbidities. Women who are peri-or postmenopausal should consider removal of both ovaries, omental sampling and washings. In patients with pathology confirmed serous BOT without evidence of carcinoma, extraovarian disease, or invasive implants, surgery results in cure with very low risk of recurrence. Discussion with one of the BC Cancer team members or electronic triage for review of operative report and pathology can be requested. However, formal appointment for patients with confirmed stage I BOT is rarely needed. Additional surgery may be recommended in individuals with: (1) micropapillary component, as there is an increased risk of invasive extraovarian implants; (2) advanced stage disease or residual tumor. Post-operative systemic treatment, e.g., chemotherapy or hormonal, is recommended only for women with invasive implants. Follow-up is recommended at 6-month intervals, decreasing to yearly after the 2nd year from surgery.

Patients with BOT should not be referred to the Hereditary Cancer Program as there is no known hereditary predisposition to these.

8. Allergy and Poor Treatment Tolerance

8.1 Taxanes

Most of grade 1 and 2 taxane reactions prevented in the future using dexamethasone 20mg PO 12 and 6hr before chemo in future cycles, in conjunction with a slow infusion start (see: SCDRUGRX (http://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents/Supportive%20Care/SCDRUGRX_Protocol.pdf).

For those unable to tolerate taxanes due to significant toxicities (e.g. significant neuropathy), Grade 3 or 4 hypersensitivity/allergy or due to contra-indications/excess risk to high dose dexamethasone several alternatives can be considered depending on the clinical scenario.

Alternate taxane- doublet protocols may be suitable:

GOCABR: Alternative Treatment of Gynecological Malignancies Using CARBOplatin and PACLitaxel NAB (ABRAXANE)
GOCABRBEV: Alternative Treatment of Gynecological Malignancies Using Bevacizumab, CARBOplatin and PACLitaxel NAB (ABRAXANE)
GOOVCAD

Alternate non-taxane doublet protocols may be suitable:

GOOVPLDC – carboplatin and liposomal doxorubicin
GOOVCAG – carboplatin and gemcitabine

Alternate single agent protocols may also be suitable under some circumstances:

GOOVCARB –carboplatin
GOOVLDOX – liposomal doxorubicin
GOOVTOP – topotecan
GOOVGEM - gemcitabine
GOOVETO) - etoposide
GOOVVIN – vinorelbine
GOOVCYCPO - cyclophosphamide

In some instances, a request to the Compassionate Access Program may be required.

8.2 Carboplatin Hyper-sensitivity/Allergy

Carboplatin allergic reactions/hypersensitivity require special consideration. Protocol SCPLATRX is developed to address the management of carboplatin hypersensitivity. This protocol contains more detailed background information, a grading system and management options.

It is important for treating clinicians to understand that most platinum reactions are IgE mediated, differentiating them from other drug infusion reactions which are more commonly anaphylactoid and not IgE mediated. IgE mediated reactions can progress to anaphylaxis and unlike other hypersensitivity reactions, cannot be reduced in frequency with pre-medications (e.g., steroids, H1 inhibitors, anti-histamines).

Platinum reactions tend to occur upon re-exposure to platinums (e.g., not usually with the first or second infusion as can be the case with most other chemotherapy hypersensitivity reactions) and typically start within minutes of infusion (rather than being delayed to hours/days)4. Symptoms can start as mild and escalate to severe (e.g., anaphylaxis) upon rechallenge. Initial symptoms can be difficult to interpret (e.g., itchy palms). The timing relative to the infusion and onset upon drug re-exposure (see below) should raise the index of suspicion.

Non-platinum options should be considered. However, in appropriate cases, cisplatin may be substituted for carboplatin.

Desensitization is not an option available at BC Cancer.

9. Palliative Considerations

Radiation therapy can be used for palliation in cases of metastatic deposits causing mass effect and related symptoms (e.g. spinal cord compression, subcutaneous lesions or lymph nodes that have grown through the skin, compression of major vessels or airways). In the setting of isolated metastatic disease, stereotactic body radiation therapy (SBRT) may be considered for increased local control. Early referral to multidisciplinary palliative care services has been associated with better patient outcomes, including improve quality of life and in some cancer types, improved survival [54,55].

References

54. Sullivan DR, Chan B, Lapidus JA, Ganzini L, Hansen L, Carney PA, Fromme EK, Marino M, Golden SE, Vranas KC, Slatore CG. Association of Early Palliative Care Use With Survival and Place of Death Among Patients With Advanced Lung Cancer Receiving Care in the Veterans Health Administration. JAMA Oncol. 2019 Dec 1;5(12):1702-1709. doi: 10.1001/jamaoncol.2019.3105. PMID: 31536133; PMCID: PMC6753505.

55. Haun MW, Estel S, Rücker G, Friederich HC, Villalobos M, Thomas M, Hartmann M. Early palliative care for adults with advanced cancer. Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD011129. DOI: 10.1002/14651858.CD011129.pub2. Accessed 12 June 2024.

10. Hereditary Cancer Syndromes: Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/2) and Lynch Syndrome

10.1 Hereditary Breast and Ovarian Cancer Syndrome (BRCA1/2 Germline Mutations)

We recommend that all women with non-mucinous EOC have testing for high-risk hereditary cancer genes predisposition genes (e.g. germline BRCA1/2)

BRCA1 and BRCA2 are tumour suppressor genes important for DNA repair (through the homologous recombination repair pathway). Less commonly, patients with hereditary ovarian carcinoma may carry germline mutations in genes other than BRCA1 or BRCA2 that are also involved in DNA repair (e.g., PALB2, RAD51C, BRIP1).

Individuals with mutations in these genes are at increased risk for cancers, particularly breast and ovarian cancers. In British Columbia, all women with ovarian cancer (except for mucinous histology) are eligible for BRCA mutation testing, and should be referred to the Hereditary Cancer Program for counseling and genetic testing by their clinical care team. In women with BRCA mutations who do not have cancer, and have finished childbearing, prophylactic BSO (removal of both tubes and ovaries) has been shown to reduce risk of EOC cancer by 80%.

10.2 Pathologic assessment of fallopian tubes following prophylactic BSO

In patients with known BRCA1/BRCA2 mutations (or other rarer germline mutations which can occur in hereditary breast and ovarian cancer syndrome, e.g., BRIP1, PALB2, etc.) who undergo prophylactic BSO, the ovaries and fallopian tubes should be immediately fixed in formalin and submitted in entirety for histologic examination. The fallopian tubes are examined by SEE-FIM (Sectioning and Extensively Examining the Fimbriated End of the Fallopian Tube) protocol (www.cap.org). This protocol increases the detection of early serous carcinoma precursor lesions (serous tubal intraepithelial carcinoma, STIC) by 4-fold.

10.3 Recommendations about breast cancer screening and mastectomy following ovarian cancer treatment

Key Message:

In the first 5 years following treatment for advanced (stage 3 and 4) ovarian cancer, intensive screening with breast MRI and risk-reducing mastectomy are not routinely recommended in BRCA1/2 carriers.

BRCA1/2 mutation carriers have an increased risk of developing breast cancer. In BRCA1/2 carriers who have been treated for high-grade serous carcinoma of the ovary (or fallopian tube/primary peritoneum), the risk of developing a subsequent breast cancer is lower than in unaffected BRCA carriers [56-61].

For these patients, overall survival is largely dictated by their ovarian cancer risk, as the 10-year breast cancer incidence following an ovarian cancer diagnosis is less than 10%. In one retrospective cohort of 184 BRCA1/2 carriers with epithelial ovarian cancer, only 16 (8%) developed breast cancer at a median of 7 years’ follow-up. Another multi-institutional cohort of 164 patients with BRCA-associated ovarian cancer demonstrated a 10-year breast cancer-free survival of 91%, with no deaths due to breast cancer [58]. A third review of 232 women with BRCA1/2 related ovarian cancer, 33 were diagnosed with breast cancer (14%), with the majority (30/33, or 91%) having stage I or II disease [61]. The median interval to breast cancer diagnosis was 80 months (6.6 years) from the time of ovarian cancer diagnosis, with only 4/33 (12%) being diagnosed within 2 years. Possible explanations for these findings include the putative preventive effect of platinum-based chemotherapy for ovarian cancer on the subsequent breast cancer incidence.

Early-stage ovarian cancer: For patients who were treated for early stage (stage I or II) ovarian cancer, intensified breast cancer screening using MRI and mammography may be considered. Risk-reducing mastectomies (RRM) have not been demonstrated to improve survival, and are not routinely recommended, but can be considered on a case-by-case basis after treatment for ovarian cancer has been completed.

Advanced stage ovarian cancer: Given the low breast cancer risk in the first 5 years following treatment for ovarian cancer, intensive screening with breast MRI is not routinely considered in patients with advanced stage (stages III and IV) ovarian cancers, regardless of patient age and factors like breast density. Likewise, RRM is not routinely considered in BRCA carriers treated for stage III or IV ovarian cancer. In this patient group, annual mammography is sufficient for the first 5-8 years after ovarian cancer therapy has been completed, and if there is no evidence of ovarian cancer recurrence.

Survival following ovarian cancer typically plateaus beyond 8–10 years, after which RRM may be considered on a case-by-case basis in ovarian cancer survivors. The impact of 2–3 years of adjuvant PARP inhibitors on subsequent breast cancer risk remains an area of ongoing investigation in this select patient population.

Recurrent ovarian cancer: There is no role for breast cancer screening of any form or RRM in patients who have experienced a recurrence of their ovarian cancer.

BRCA mutation carriers diagnosed with ovarian cancer, particularly those with stage I or II ovarian cancer, and those who have completed follow up at BC Cancer and have not experienced a recurrence of ovarian cancer, can be referred to the BC Cancer High Risk Clinic to discuss the best management of their risk of breast cancer. http://www.bccancer.bc.ca/our-services/services/hereditary-cancer/high-risk-clinic [with modifications, from Wong SM et al. [62]]

10.4 Lynch Syndrome (LS) and DNA Mismatch Repair Proteins

We recommend that all endometrioid and clear cell ovarian carcinomas undergo immunohistochemical testing for mismatch repair (MMR) proteins (MSH6 and PMS2, and if abnormal, then MSH2 or MLH1). Immunohistochemistry is the preferred method of screening (over MSI assay) due to its widespread availability. When abnormal MMR immunohistochemical results are found, a reflex statement is issued in the pathology report recommending referral to the Hereditary Cancer Program, and the referral is made by the submitting clinician/surgeon. If a patient then undergoes germline testing after genetic counseling and is confirmed to have LS, they can consider additional early detection interventions against colorectal cancer.

DNA mismatch repair (MMR) genes can be impaired by methylation events (epigenetic mechanisms), acquired (somatic) mutations or inherited (germline) mutations. Screening for defective/loss of MMR proteins can be done using 1) immunohistochemistry or 2) microsatellite instability (MSI) assays. MLH1 hypermethylation testing, if available, can be done to determine if loss of MLH1 detected by immunohistochemistry is sporadic or not. Confirmation of LS requires direct sequencing of the MMR gene, which requires both tumor tissue and patient blood samples.

Patients with LS have an inherited mutation in an MMR gene. The major MMR genes in humans are MLH1, PMS2, MSH2 and MSH6. Patients with LS have a 40-60% lifetime risk of colorectal and endometrial carcinoma, 6-12% lifetime risk of ovarian carcinoma and increased lifetime risks of many other cancer types (stomach, hepatobiliary, urinary, etc.)

LS-associated ovarian cancers present differently than typical ovarian cancer. Generally, women with LS-associated ovarian cancers are younger (median 43 years of age) and develop early stage endometrioid or clear cell histology.

10.5 Unaffected Carriers of Hereditary Syndromes

Cascade testing of family members should ensue if a patient is found to carry a hereditary cancer syndrome. There are published guidelines on screening and interventions for carries of hereditary cancer mutations, developed in a syndrome specific fashion. For example, individuals with Lynch syndrome need to have increased screening for colorectal carcinoma. Women should be counseled about considering risk reducing surgery (hysterectomy and BSO) after childbearing. Female family members with BRCA1/2 mutations should be counseled about risk-reducing interventions against breast cancer (mammography +/- breast MRI if premenopausal, and bilateral mastectomy), as well as ovarian cancer (BSO). Age of penetrance varies by affected gene and can be part of the discussion regarding timing of procedures. More information is available from the BC Cancer Hereditary Cancer Program.

References

56. Gangi A., Cass I., Paik D., Barmparas G., Karlan B., Dang C., Li A., Walsh C., Rimel B.J., Amersi F.F. Breast cancer following ovarian cancer in BRCA mutation carriers. JAMA Surg. 2014;149:1306–1313. doi: 10.1001/jamasurg.2014.1081.

57. Nanez A., Stram D.A., Bethan Powell C., Garcia C. Breast cancer risk in BRCA mutation carriers after diagnosis of epithelial ovarian cancer is lower than in carriers without ovarian cancer. Gynecol. Oncol. Rep. 2022;39:100899. doi: 10.1016/j.gore.2021.100899.

58. Domchek S.M., Jhaveri K., Patil S., Stopfer J.E., Hudis C., Powers J., Stadler Z., Goldstein L., Kauff N., Khasraw M., et al. Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer. Cancer. 2013;119:1344–1348. doi: 10.1002/cncr.27842.

59. Vencken P.M., Kriege M., Hooning M., Menke-Pluymers M.B., Heemskerk-Gerritsen B.A., van Doorn L.C., Collee M.M., Jager A., van Montfort C., Burger C.W., et al. The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers: Implications for counseling. Cancer. 2013;119:955–962. doi: 10.1002/cncr.27839.

60. McGee J., Giannakeas V., Karlan B., Lubinski J., Gronwald J., Rosen B., McLaughlin J., Risch H., Sun P., Foulkes W.D., et al. Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted? Gynecol. Oncol. 2017;145:346–351. doi: 10.1016/j.ygyno.2017.02.032.

61. Nañez A, Stram DA, Bethan Powell C, Garcia C. Breast cancer risk in BRCA mutation carriers after diagnosis of epithelial ovarian cancer is lower than in carriers without ovarian cancer. Gynecol Oncol Rep. 2021 Dec 4;39:100899. doi: 10.1016/j.gore.2021.100899. PMID: 34917730; PMCID: PMC8666339.

62. Wong SM, Apostolova C, Eisenberg E, Foulkes WD. Counselling Framework for Germline BRCA1/2 and PALB2 Carriers Considering Risk-Reducing Mastectomy. Curr Oncol. 2024 Jan 9;31(1):350-365. doi: 10.3390/curroncol31010023. PMID: 38248108; PMCID: PMC10814079.

11. Estrogen Replacement Therapy

The relationship between estrogen and ovarian cancer is obscure. It is known that there are both estrogen and progesterone receptors present in many epithelial ovarian tumours. Unfortunately, the effects of exogenous hormones on these receptors are not well defined. There is no convincing evidence that estrogen has either the potential to promote recurrence or to decrease the time to recurrence.

In the absence of scientific evidence to the contrary, it is not necessary to withhold estrogen replacement therapy from any symptomatic woman with ovarian malignancy regardless of risk category.

Recommendations:

In the absence of a uterus and when the cancer is not endometriosis-associated, estrogen alone can be considered.
Estrogen plus progesterone or estrogen with bazedoxifine [63] are both suitable options in o patients with a retained uterus.
o Endometriosis-associated cancers with residual endometriosis even if the uterus has been removed.

Reference

63. Raina PM, Patel P, Parmar M. Bazedoxifene. [Updated 2024 Feb 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585122/

12. Follow-up/Surveillance

There are no data that prove that follow-up in an asymptomatic individual will improve survival. Most guidance on post-treatment surveillance is based upon retrospective data or expert opinion. Imaging for patients on post therapy follow up/surveillance should only be performed based upon clinical need (e.g., patient symptoms, clinical exam findings or rising CA125) as routing imaging has not been proven to impact cure or response to salvage therapy [64].

The role of CA-125 surveillance is also noted to be controversial and the use of CA125 for surveillance is considered optional. The use of CA15-3 and CA19-9 as surveillance is not validated and is not recommended (note: CA15-3 and/or CA19-9 may be elevated in rare ovarian cancer histologies, therefore, may be useful to assess if recurrence is suspected during follow up).

Below is a suggested guide for post-treatment surveillance:

Note: follow-up consists of general exam and pelvi-rectal exam. Annual Pap smear screening is not required in women who have undergone a hysterectomy as part of their treatment. Women who have not had a hysterectomy should have cervical screening as per BC Cancer recommendations, unless they have experienced recurrence of their ovarian cancer, is which case no additional screening for cancer is required.

Other investigations, such as tumor markers, are not required in otherwise asymptomatic patients. Monitoring of CA125 has been shown to result in early intervention with chemotherapy, without any improvement in overall survival but an adverse effect on quality of life [65].

There may be exceptions to these guidelines, such as extended follow up for those with an indolent type of cancer including advanced granulosa cell tumor or low grade serous carcinoma, at the discretion of the clinician and patient.

Issues pertaining to survivorship in ovarian cancer are not well-studied. This may be due to the overall poor prognosis of patients with ovarian cancer and smaller populations surviving without recurrence. While some studies of ovarian cancer survivors define difficulties, there are few data to guide management. Nevertheless, survivorship-related issues are important to address in this growing population of patients.

References

64. Salani R, Khanna N, Frimer M, Bristow RE, Chen LM. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol. 2017 Jul;146(1):3-10. doi: 10.1016/j.ygyno.2017.03.022. Epub 2017 Mar 31. PMID: 28372871.

65. Rustin GJ, van der Burg ME, Griffin CL, Guthrie D, Lamont A, Jayson GC, Kristensen G, Mediola C, Coens C, Qian W, Parmar MK, Swart AM; MRC OV05; EORTC 55955 investigators. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010 Oct 2;376(9747):1155-63. doi: 10.1016/S0140-6736(10)61268-8. PMID: 20888993.

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