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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. 

SOURCE: 4. Management ( )
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