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

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