LongForm
Skip to main content
Close

 Ovary - Epithelial Carcinoma

1. Background

Updated May 8, 2018

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 17.3 per 100,000. The incidence rate has remained relatively stable over the past 30 years with a 5-year relative survival of about 35%. Epithelial ovarian carcinomas (EOC) account for ~90% of all ovarian malignancies. During the last decade it has become apparent that EOC encompasses 5 distinct diseases, with different presentations (age of development, distribution of disease), response to chemotherapy, prognosis, molecular features, and site of origin1, 2. While these carcinomas share a common site of tumor growth in the ovary, they represent diverse diseases entities. This has driven the move towards more histotype specific management strategies.  

High-grade serous carcinoma (HGSC) is the most common (70% of EOC) histological subtype usually presenting at advanced stage and accounting for the majority of deaths from ovarian cancer. It is believed that the majority of 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) carcinomas3, 4. The two next most common types of EOC, clear cell (10%) and endometrioid (10%), may arise from 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 much more rare (<5% each). LGSC may arise from borderline serous carcinomas (tumours of low malignant potential).  

1.1 Predisposing Risk Factors 

Established risk factors for EOC are reproductive and genetic in nature. An appreciation of the distinct subtypes of EOC has provided a new framework through which to interpret risk factors in ovarian cancer.  

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 the majority of 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 (also 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. 

1.2 Screening/ Early Detection

There are no screening tests proven to detect ovarian cancer at an early stage and reduce the number of women who die from this disease. Screening modalities tested have included pelvic examination, CA125 and ultrasound and thus far three well executed international clinical trials on screening for ovarian cancer (ultrasound +/- CA125) have failed to demonstrate a significant benefit in survival from these interventions and have yielded an unacceptably high rate of false positive tests leading to unnecessary surgery5, 6, 7. Therefore, ovarian cancer screening is currently not recommended by either the Society of Gynecologic Oncology of Canada, or the American College of Obstetrics and Gynecology.  

1.3 Prevention

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 options is directed at women at ‘low-risk’ (i.e. the general population, women not know to have an inherited mutation) for developing ovarian cancer 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). 

Uptake and short-term safety of this strategy have been demonstrated8, 9. Opportunistic salpingectomy does not appear to increase perioperative morbidity or risk of premature menopause; however, long-term outcomes are still unknown.  Salpingectomy (for other indications such as sterilization) appears to be associated with decreased ovarian cancer risk, based on population-based data and case-control studies10, 11, 12.

2) Risk-reducing surgery in high-risk women: Bilateral Removal of ovaries and fallopian tubes by age 40 or when childbearing is complete. Salpingectomy alone in this population is unproven but can be considered in individuals who refuse standard of care.

Bilateral removal of the fallopian tubes and ovaries is the standard recommendation for BRCA1/BRCA2 mutation carriers who have completed childbearing and wish to reduce their future risk of ovarian and fallopian tube cancers. However, surgical menopause following bilateral BSO (BSO) includes cardiovascular disease, bone loss, and other comorbidities. Because the majority of 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. However, there are 2 compelling reasons to recommend removal of the ovaries: (1) some BRCA-associated cancers 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 strategies 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 women13, 14. The caveat is that there may be an increased risk of breast cancer associated with oral contraceptives in BRCA1 mutation carriers15


2. Histological Classification of Ovarian Carcinoma

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

Figure 1: Five major types of EOC

** Other rare subtypes not listed include carcinosarcoma (Malignant Mixed Mullerian Tumor, MMMT), undifferentiated carcinoma and malignant Brenner tumor.

Click here to download a larger version of Figure 1.


3. Diagnosis and Staging

Diagnosis requires thorough clinical, surgical and pathologic assessment.

3.1 Pre-Operative Assessments

  • Complete history and physical, including pelvic and pelvi-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
  • Some type of 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/or the need for referral to a gynecologic oncologist for consideration of surgery.

3.2 Surgery

It is highly recommended that patients presenting with apparent advanced staged ovarian cancer on imaging be referred for subspecialist 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 are made within a multidisciplinary team.

Surgery provides staging and prognostic information, and it may be therapeutic through removal of diverse clonal populations. Successful treatment of EOC often begins with surgical management, including surgical cancer staging for early apparent 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).  

The 3 most important 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.

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 with a multidisciplinary team. Well-conducted RCTs demonstrate that clinical outcomes for women treated by upfront surgery, or by pre-operative chemotherapy followed by surgery are the same16, 17. In fact, those receiving pre-operative chemotherapy experience slightly lower rates of surgical complications. 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.  

3.3 Biopsy for patients requiring delayed debulking

If the decision is made to start with pre-operative chemotherapy, a histologic diagnosis is required before treatment is initiated. For this, a core biopsy is preferred. Any elevated tumour marker should be monitored during therapy (e.g. CA-125, CA15-3, CA 19-9) and re-evaluation for surgery is recommended after the patient has had 2-3 cycles of chemotherapy delivered. A CT scan is important prior to a consultation with the Gynecologic Oncologist after these 2-3 cycles to determine response to chemotherapy as well as the likelihood of optimal debulking at the time of delayed primary surgery.

If a pre-treatment biopsy cannot be obtained, or is not technically successful, consideration can be given to upfront surgery or a laparoscopic biopsy. Although not ideal, cytologic evaluation of fluids (ascites or peritoneal effusions) can be used. In such cases, we consider measuring serum CA125:CEA ratio as some studies shows this ratio >25 to support the diagnosis of a primary ovarian/primary peritoneal/fallopian tube cancer18. Care should be taken to rule out other primary cancers. In addition, low-grade diseases such as low-grade serous carcinoma are unlikely to respond to chemotherapy and will more likely benefit from surgical debulking. For any patient in whom the response to chemotherapy is poor, pathology should be scrutinized/reconsidered. 

Delayed primary debulking surgery is best performed after 3 or 4 cycles of pre-operative chemotherapy. Post-delayed debulking, it is customary to deliver chemotherapy to complete at least 6 cycles in total, with no fewer than 2 post-operative cycles given (i.e., sometimes the total number of cycles will exceed 6).

3.4 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 and TNM staging


FIGO
Definition
TNM
IA
Tumour limited to one ovary (capsule intact) or fallopian tube
No tumour on ovarian or fallopian tube surface
No malignant cells in the ascites or peritoneal washings
T1a
IB
Tumour limited to both ovaries or fallopian tubes
No tumour on ovarian or fallopian tube surface
No malignant cells in the ascites or peritoneal washings
T1b
IC
Tumour limited to one or both ovaries or fallopian tubes, with any of the followings:
IC1 – surgical spill intraoperatively
IC2 – capsule ruptured before surgery or tumour on ovarian or fallopian tube surface
IC3 – malignant cells present in the ascites or peritoneal washings
T1c
II
Tumour involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal cancer (Tp)
T2
IIA
Extension and/or implants on the uterus and/or fallopian tubes and/or ovaries
T2a
IIB
Extension to other pelvic intraperitoneal tissues
T2b
III
Tumour involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside of the pelvis and/or metastasis to the retroperitoneal lymph nodes
T3
IIIA
Metastasis to the retroperitoneal lymph nodes with or without microscopic peritoneal involvement beyond the pelvis
IIIA1 - Positive retroperitoneal lymph nodes only (cytologically or histologically proven)
IIIA1(i) metastasis <= 10mm in greatest dimension 
IIIA1(ii) metastasis > 10mm in greatest dimension

IIIA2 - Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
oneal lymph nodes
T3a N0/1
IIIB
Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen.
T3b N0/1
IIIC
Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen.
T3c N0/1
IV
Distant metastasis excluding peritoneal metastasis
TX NX M1
IVA
Pleural effusion with positive cytology
TX NX M1
IVB
Metastasis to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of abdominal cavity) or parenchymal metastasis
TX NX M1

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;
  • Tumors that may otherwise qualify for stage I but involved with dense adhesions justify upgrading to stage II if tumor 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 tumor site in high-grade serous carcinoma

Fallopian tube
Ovary
Primary Peritoneal Carcinoma
  • STIC present
  • Tumor involving fallopian tube mucosa
  • Fallopian tube encased in tubo-ovarian mass
  • Ovarian tumor without STIC or fallopian tube mucosal involvement
  • Both ovaries and fallopian tubes normal and examined in entirety




4. Management

4.1 Surgery Ovarian/Fallopian Tube/Primary Peritoneal Cancer

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.

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, and placement of an intraperitoneal catheter for delivery of chemotherapy for high-grade serous carcinomas. 

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. However, the effect 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 if 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 surgery19.

4.2 Medical treatment

4.2.1 General principles

a) If possible, all patients with suspected ovarian/fallopian tube/primary peritoneal malignancy should be treated with maximal debulking followed by appropriate post-operative management. Post-operative therapy is given to eradicate microscopic cancer cells, and therefore, there is no measure of treatment effectiveness. 

b) Pre-operative chemotherapy is appropriate for selected patients with biopsy-proven ovarian/fallopian tube/primary peritoneal malignancy who are not appropriate for immediate maximal debulking. We recommend that routine monitoring of CA125 or other relevant marker with each cycle, and that patients are reviewed by gynecologic oncology surgeon after 2-3 cycles to ensure timely surgery. A CT chest/abdomen/pelvis should be performed prior to assessment by the gynecologic oncologist to assess response to chemotherapy and 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, with the exception of bowel or ureteric obstruction. Routine monitoring of CA125 or other relevant marker is recommended with each cycle. Generally total number of chemotherapy cycles is 6, of which at least 2 are post-operative. Ultimately, the number and timing of cycles will depend on disease status, patient preference and physician preference.

c) Timing of initiation of post-operative chemotherapy: Treatment should be started as soon as it is felt safe to do so after surgery. For most patients who have an uncomplicated post-operative course, this is usually safe and feasible within 7-14 days of the operation. Early treatment initiation prevents the re-accumulation of ascites and has not been associated with any 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.  

d) When treating a patient with recurrent disease, the duration of therapy on a protocol is determined by treatment tolerance, treatment response typically gauged clinically at each cycle by assessing cancer signs and symptoms (e.g. improvement in pain, bloating, appetite, ascites, pleural effusions, and regression of measurable disease such as abdominal or pelvic masses, or enlarged lymph nodes) and treatment tolerance. Assuming there is treatment benefit and reasonable treatment tolerance, 6 cycles of chemotherapy are usually delivered.  

e) 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. Birth control methods should always be used if fertility is/may be intact.

4.2.2 High Grade Serous Carcinoma of Ovary/Fallopian Tube/Peritoneum

a) Primary systemic therapy

Table 3: First-line chemotherapy guidelines for high-grade serous carcinoma

Stage
Treatment
Post primary surgery, stage I-II, residual disease <1cm
GOOVCATM x 6 cycles
(OR GOOVIPPC)
Post primary surgery, stage III-IV, residual disease <1cm
GOOVIPCC (preferred) 
OR 
GOOVCATM OR GOOVDDCAT x 6 cycles
Post primary surgery, stage I-IV, residual disease >=1cm
GOOVCATX 
OR 
GOOVDDCAT x 6 cycles
Prior to delayed primary debulking surgery
GOOVCATX OR GOOVDDCAT x usually 3-4 cycles 
** Number and timing of cycles will depend on disease status, patient preference and physician preference
Post delayed primary debulking surgery, any stage
GOOVCATX OR GOOVCATM OR GOOVDDCAT for a total of 6 cycles including pre-operative chemotherapy
Not a candidate for debulking surgery
GOOVCATX OR GOOVDDCAT x 6 cycles
** GOOVCARB may be considered for patients with suboptimal performance status

Note:
** GOOVIPCC: Intra-peritoneal Chemotherapy (IP) chemotherapy is suitable for some EOC patients. Past studies primarily in patients with high-grade serous carcinoma diagnosed with stage III disease and <1 cm residual disease following primary surgery has demonstrated improved survival rates with IV/IP treatment compared to exclusively IV chemotherapy. Six cycles of treatment post primary debulking is the standard. IV/IP chemotherapy is not routinely used after delayed primary debulking. If unable to complete chemotherapy via the IP route, then therapy should be completed with one of the standard IV options. There is little evidence to support its use in ovarian cancer with clear cell or low-grade serous histology or stage I-II (although BC Cancer policy permits IP therapy in stages I-III following optimal primary debulking).
** GOOVDDCAT: Dose dense (DD) chemotherapy involves delivering paclitaxel on a weekly basis, and the platinum every 3 weeks. This regimen has been shown to be clinically equivalent to q3 weekly chemotherapy in one trial and superior in another20, 21. There is little evidence to support its use in ovarian cancer with clear cell or low-grade serous histology or stage I-II.

b) Recurrent HGSC

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. 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)22. 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:

  • 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).
Platinum-responsive disease:

For patients with a BRCA mutation who also have BOTH platinum-sensitive and platinum-responsive relapsed HGSC, PARP inhibitor maintenance therapy is the standard of care, as this has shown significant delay in disease progression23, 24. There is evidence of benefit for this strategy even in women who are not BRCA mutation carriers, who also have platinum-sensitive and platinum-responsive disease. At this time, olaparib is the only Health Canada approved PARP-inhibitor available in Canada.

Platinum-Resistant or Refractory Disease25

  • 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). 
  • The standard of care is to use sequential single-agents, selecting from the following based on toxicities and time since last exposure: 
    • 3-weekly paclitaxel (GOOVTAX3) 
    • pegylated liposomal doxorubicin (GOOVLDOX)
    • topotecan (GOOVTOP)
    • gemcitabine (GOOVGEM)
    • etoposide (GOOVETO)
    • docetaxel, (GOOVDOC)
    • vinorelbine (GOOVVIN)
    • cyclophosphamide (GOOVCYCPO)
  • Some patients may also benefit from treatment bevacizumab. Bevacizumab can be combined with paclitaxel (UGOOVBEVP), liposomal doxorubicin (UGOOVBEVLD), gemcitabine (UGOOVBEVG) and vinorelbine (GOOVBEVV). Bevacizumab inhibits binding of VEGF, which is important for neovascularization and angiogenesis. Studies have demonstrated an improved progression-free survival in platinum-resistant disease when bevacizumab is added to chemotherapy26, but no improvement in overall survival has been demonstrated. 
  • Hormonal therapies such as tamoxifen (GOOVTAM) and letrozole (GOOVAI) have shown modest activity in indolent EOC.

4.2.3 Other histologies

Table 4: First-line chemotherapy guidelines for non-HGS histologies


NO TREATMENT
CHEMOTHERAPY
/XRT
CHEMOTHERAPY ALONE
Clear cell
(not graded)
IA or IB
IC1 (surgical spill or pre-operative rupture)

**If initially “under-staged” disease, surgical restaging (to potentially avoid chemotherapy) should be considered.
GOOVCATX x 3 cycles then XRT if:

IC surface positivity
IC washings positive
II
I with surgical understaging or use of sharp dissection

GOOVCATX or GOOVCATM x 6 cycles if:

III-IV

Consider additional RT on individual basis (Tumour Board Round discussion required)

Endometrioid
IA or IB AND grade 1 or 2
IC due to rupture alone AND grade 1 or 2

**If initially “under-staged” disease, surgical restaging (to potentially avoid chemotherapy) should be considered.
GOOVCATM x 3 cycles then XRT if:

I grade 3
IC surface positivity and/or cytologically positive, ANY grade
II
I but surgical understaging

**If radiation is declined, 3 additional cycles of chemotherapy can be considered.
If residual <1cm, GOOVCATM or GOOVIPPC x 6 cycles

With residual > 1 cm disease: GOOVCATX or GOOVDDCAT x 6 cycles if:

III-IV
Undifferentiated endometrioid grade 3 ANY stage
Macroscopic residual disease, any stage
Mucinous
IA or IB or IC (rupture alone) AND grade 1 or 2

**If initially “under-staged” disease, surgical restaging (to potentially avoid chemotherapy) should be considered.
GOOVCATM x 3 cycles then XRT if:

I grade 3 
IC (preoperative or intraoperative rupture)
II
I but surgical understaging

**If radiation is declined, 3 additional cycles of chemotherapy can be considered.
GOOVCATM OR GOOVCATX x 6 cycles if:

III-IV

**Women with advanced stage, residual disease, or metastatic mucinous carcinoma can have tumors tested for HER2 IHC overexpression (+/-HER2 amplification). HER2 positivity is observed in approximately 20% of mucinous carcinomas, HER 2 is targetable with trastuzumab.
Low grade serous (previously G1)
IA or IB or 
IC due to rupture alone
-
GOOVCATM or GOOVCATX x 6 cycles if: 
IC (not due to rupture)
II 
III-IV

**Consider GOOVAI if ER positive
MMMT/ undifferentiated
-
-
As per HSG guideline, with poorer prognosis

a) Clear cell histology

The benefits of post-operative chemotherapy in the treatment of clear cell carcinoma of the ovary have not been proven27. The benefits of post-operative radiation therapy for early stage clear cell carcinoma of the ovary have been explored retrospectively. The above recommendations are based on existing practice patterns.

There is no role for additional chemotherapy if the patient declines RT28. External beam pelvic radiation therapy will cover the pelvic lymph node regions (common iliac, external and internal iliac, obturator nodes), parametrium, and upper vagina.  Treatment takes place daily for 25 treatments over approximately 5 weeks.

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

b) Endometrioid histology

The use of post-operative chemotherapy in the treatment of early stage endometrioid carcinoma of the ovary is associated with improved patient outcomes27. The benefits of post-operative radiation therapy for early stage endometrioid carcinoma of the ovary have been explored retrospectively. The above recommendations are evidence-based when evidence exists, or based on existing practice patterns.

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

Fertility: Young women with clinical stage I endometrioid ovarian carcinoma may be appropriate candidates for fertility-sparing surgery. 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 have to be weighed against the odds of successful future pregnancy. Sampling of the endometrium should be considered if a hysterectomy is not being performed.

c) Mucinous histology

The benefits of post-operative chemotherapy in the treatment of early stage mucinous carcinoma of the ovary remain unproven. The benefits of post-operative radiation therapy for early stage mucinous carcinoma of the ovary have been explored retrospectively. The above recommendations are evidence-based when evidence exists, or based on existing practice patterns.

If recurrent, systemic treatment is generally similarly to recurrent HGSC, although level I evidence is lacking. Her-2 directed therapy may have a role if tumour has positive staining for Her-2/neu receptor29. Clinical trial participation, if possible, is encouraged.

Fertility: Young women with clinical stage I mucinous ovarian carcinoma may be appropriate candidates for fertility-sparing surgery. 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 have to be weighed against the odds of successful future pregnancy. 

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. 

d) Low Grade Serous Carcinoma 

Because of the rarity of this disease, the optimal post-operative treatment of LGSC of the ovary is uncertain and remains the subject of clinical trials and ongoing multicenter collaborative efforts. However, there is a suggestion that for women with advanced stage disease, hormonal therapy as maintenance may prolong survival and time to recurrence after completion of chemotherapy30

Recurrent disease: Hormone therapy using aromatase inhibitor (GOOVAI), chemotherapy similar to recurrent HGSC, and/or consideration of debulking surgery if possible.

e) MMMT/Undifferentiated

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

4.2.4 Allergy and Poor Treatment Tolerance

For those unable to tolerate taxanes due to toxicities or hypersensitivity/allergy, a non-taxane doublet (i.e. GOOVPLDC) can be used as an alternative regimen, with similar expected efficacy31. Single agent carboplatin (GOOVCARB), or other single agent therapies such as pegylated liposomal doxorubicin (GOOVLDOX), topotecan (GOOVTOP), gemcitabine (GOOVGEM), etoposide (GOOVETO), vinorelbine (GOOVVIN), cyclophosphamide (GOOVCYCPO) can be considered in circumstances where doublets may not be tolerated.

If taxanes are felt to be of particular clinical relevance, but hypersensitivity/allergy prevent use, a special request for nab-paclitaxel could be considered.

In cases of carboplatin sensitivity/allergy, cisplatin may be substituted as a single agent, or as part of a doublet. A non-platinum strategy, such as GOOVLDOX (liposomal doxorubicin) or GOOVTAX3 (paclitaxel) or GOOVGEM (gemcitabine) can also be considered in circumstances where doublets may not be tolerated.

4.2.5 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).  Some ovarian cancer histologies, like clear cell and endometrioid, may be particularly sensitive to radiation, and a greater response to palliative XRT would be expected.  In the setting of isolated metastatic disease, stereotactic body radiation therapy (SBRT) may be considered for increased local control. 

5. Hereditary Cancer Syndromes

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

We recommend that all women with non-mucinous EOC have BRCA testing and be referred for genetic counselling due to the risk of hereditary breast and ovarian cancer syndrome (e.g., germline BRCA1/BRCA2 mutations). 

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. 

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%.

5.1.1 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.

5.1.2 Recommendations about breast cancer screening following ovarian cancer diagnosis

BRCA1 and 2 carriers have an increased risk of developing breast cancer. For women with stage III or IV ovarian cancer, particularly HGSC, the risk of developing breast cancer in the first 5 years after ovarian cancer diagnosis is low (3-4%), and as such we do not routinely recommend breast surgery or MRI; yearly mammograms are sufficient32, 33. Five years after diagnosis of ovarian cancer, if there has not been an ovarian cancer recurrence, the risk of developing breast cancer increases and intensified screening or prophylaxis may be reconsidered.

5.2 Lynch Syndrome (LS) and DNA Mismatch Repair Proteins

We recommend that all endometrioid and clear cell ovarian ovarian carcinomas undergo immunohistochemical testing for MMR proteins (MSH6 and PMS2, and if abnormal, then MSH6 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, she can consider additional risk-reducing 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.)

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

5.3 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.

6. 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, Brenner, and clear cell borderline ovarian tumors are much less common. The term “seromucinous” has a confusing name, but merely refers to a tumor of mixed epithelial types (i.e. serous, mucinous, endometrioid, etc.). Although “seromucinous” is officially included in the most current WHO classification, the name will likely fall out of favor in the future, and replaced by specifically listing the epithelial components present.

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 BSO 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 tumours.

7. 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 known. 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.
  • With uterus in situ, continuous estrogen plus progesterone.
  • For endometriosis-associated cancers with residual endometriosis, estrogen plus progesterone may be considered even if the uterus has been removed.

8. Management of Serous Tubal Intraepithelial Carcinoma (STIC)

More extensive examination of the fallopian tubes and increased uptake of risk reducing procedures (BRCA1, BRCA2 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 patients34, 35, 36. 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 a referral should be made to BC Cancer for consideration of completion surgical staging (minimum washings, omentectomy, directed biopsies, +/- hysterectomy). Approximately 4.5% of high-risk women (with BRCA1 or BRCA2 mutations) with a STIC will later develop of primary peritoneal carcinoma, and the median time to the development 4-6 years. Only women with invasive disease found at the time of completion surgery should be offered post-operative chemotherapy. 

When an isolated STIC is identified in ‘low-risk’/general population of women, a referral should be made to both BC Cancer for consideration of completion surgical staging as well as to the Hereditary Cancer Program. These women have a 10% chance of carrying a germline BRCA1 or BRCA2 mutation, which, if discovered would encourage consideration of surgical staging34.

9. Follow-up

There are no data that prove that follow-up in an asymptomatic individual will improve survival. Therefore, the rationale is embedded in the clinical opinion of the oncologist and the wishes of the patient. As such the following are suggestions only.

Years 1 + 2
4 months
Years 3 - 5
6 months
Years 5+
Annually

Note: follow-up consists of general exam and pelvirectal 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.

Other investigations, such as tumor markers, are not required other than for fulfilment of research protocols. 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 life37.


10. 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. Buys, S.S., et al., Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA, 2011. 305(22): p. 2295-303.
  6. Jacobs, I.J., et al., Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet, 2016. 387(10022): p. 945-956.
  7. Kobayashi, H., et al., A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer, 2008. 18(3): p. 414-20.
  8. McAlpine, J.N., et al., Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. Am J Obstet Gynecol, 2014. 210(5): p. 471 e1-11.
  9. Morelli, M., et al., Prophylactic salpingectomy in premenopausal low-risk women for ovarian cancer: primum non nocere. Gynecol Oncol, 2013. 129(3): p. 448-51.
  10. Falconer, H., et al., Ovarian cancer risk after salpingectomy: a nationwide population-based study. J Natl Cancer Inst, 2015. 107(2).
  11. Lessard-Anderson, C.R., et al., Effect of tubal sterilization technique on risk of serous epithelial ovarian and primary peritoneal carcinoma. Gynecol Oncol, 2014. 135(3): p. 423-7.
  12. Madsen, C., et al., Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study. Acta Obstet Gynecol Scand, 2015. 94(1): p. 86-94.
  13. 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.
  14. 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.
  15. Narod, S.A., et al., Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst, 2002. 94(23): p. 1773-9.
  16. 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.
  17. 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.
  18. 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.
  19. Vermeulen, C.K.M., et al., Only complete tumour resection after neoadjuvant chemotherapy offers benefit over suboptimal debulking in advanced ovarian cancer. Eur J Obstet Gynecol Reprod Biol, 2017. 219: p. 100-105.
  20. Katsumata, N., et al., Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet, 2009. 374(9698): p. 1331-8.
  21. Pignata, S., et al., Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol, 2014. 15(4): p. 396-405.
  22. Harter, P., et al., Prognostic and predictive value of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score in surgery for recurrent ovarian cancer. Gynecol Oncol, 2014. 132(3): p. 537-41.
  23. 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. 18(9): p. 1274-1284.
  24. Swisher, E.M., et al., Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol, 2017. 18(1): p. 75-87.
  25. Davis, A., A.V. Tinker, and M. Friedlander, "Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol Oncol, 2014. 133(3): p. 624-31.
  26. Pujade-Lauraine, E., et al., Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol, 2014. 32(13): p. 1302-8.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. Pignata, S., et al., Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol, 2011. 29(27): p. 3628-35.
  32. Narod, S.A., et al., Screening mammography and risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet Oncol, 2006. 7(5): p. 402-6.
  33. Warner, E., et al., Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA, 2004. 292(11): p. 1317-25.
  34. 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.
  35. Long Roche, K.C., et al., Risk-reducing salpingectomy: Let us be opportunistic. Cancer, 2017. 123(10): p. 1714-1720.
  36. 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.
  37. Rustin, G.J., et al., Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet, 2010. 376(9747): p. 1155-63.


SOURCE: Ovary - Epithelial Carcinoma ( )
Page printed: . Unofficial document if printed. Please refer to SOURCE for latest information.

Copyright © BC Cancer. All Rights Reserved.

    Copyright © 2018 Provincial Health Services Authority