Ovarian%20cancer Treatment

Neoadjuvant Chemotherapy for Epithelial Ovarian Carcinoma

• Should be considered in patients with advanced-stage ovarian cancer who are not good candidates for upfront primary debulking surgery due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced
• Recommended neoadjuvant chemotherapy regimens include Paclitaxel/Carboplatin, dose-dense Paclitaxel/Carboplatin, Docetaxel/Carboplatin, Carboplatin/pegylated liposomal Doxorubicin and Paclitaxel/Carboplatin/Bevacizumab
  • Regimens that include Bevacizumab should be used with caution before IDS due to its effect on postoperative healing
    • Bevacizumab if used as part of neoadjuvant therapy should be withheld for at least 6 weeks before IDS
• Hyperthermic intraperitoneal chemotherapy (HIPEC) may be considered in patients with stage III disease being given neoadjuvant therapy at the time of IDS
  • A procedure wherein chemotherapy is administered in a heated solution perfused throughout the peritoneal space resulting to increased penetration of chemotherapy at the peritoneal surface and enhanced sensitivity of cancer cells to chemotherapy
  • Option for stage III patients with response or stable disease after 3 cycles of neoadjuvant therapy
  • Recommended agent for HIPEC is Cisplatin

Systemic Therapy for Epithelial Ovarian Carcinoma

• Most patients should receive postoperative systemic chemotherapy
• After surgical cytoreduction, platinum-based chemotherapy is the treatment of choice for patients with advanced epithelial ovarian cancer which is initiated within 6 weeks after surgery
  
  • Monotherapy with Carboplatin every 3 weeks for 6 cycles as adjuvant therapy can be given in early-stage epithelial ovarian cancer; Cisplatin may be an alternative to Carboplatin

• Recommendations for the number of cycles of treatment vary with the stage of the disease
  
  • Earlier stage disease (stage I): 3-6 cycles; advanced stages (II-IV): 6 cycles

Recommended Primary Therapy Regimens for Stage I Disease

• Preferred regimens:
  • Paclitaxel/Carboplatin
  • Fluorouracil (5-FU)/Leucovorin/Oxaliplatin: Mucinous carcinoma stage IC
  • Capecitabine/Oxaliplatin: Mucinous carcinoma stage IC
  • Hormone therapy (eg Anastrozole, Letrozole, Exemestane): Low-grade serous (stage IC) or grade I endometrioid (stage IC)
• Other recommended regimens:
  • Carboplatin/liposomal Doxorubicin
  • Docetaxel/Carboplatin
  • Hormone therapy (eg Leuprolide acetate, Tamoxifen): Low-grade serous (stage IC) or grade I endometrioid (stage IC)
• Conditional regimens:
  • Carboplatin or Cisplatin or Paclitaxel plus Ifosfamide: For carcinosarcoma

Recommended Primary Therapy Regimens for Stage II-IV Disease

• Preferred regimens:
  • Paclitaxel/Carboplatin
  • Paclitaxel/Carboplatin/Bevacizumab plus maintenance Bevacizumab
    • A Bevacizumab biosimilar (eg Bevacizumab-awwb, Bevacizumab-bvzr) may be used in place of Bevacizumab
    • Maintenance with Bevacizumab monotherapy is recommended only for patients who have not progressed during the 6 cycles of upfront Paclitaxel/Carboplatin/Bevacizumab therapy
  • 5-FU/Leucovorin/Oxaliplatin with or without Bevacizumab: Mucinous carcinoma
  • Capecitabine/Oxaliplatin with or without Bevacizumab: Mucinous carcinoma
  • Paclitaxel/Carboplatin with or without maintenance Letrozole or other hormone therapy (aromatase inhibitors, Leuprolide acetate, Tamoxifen): Low-grade serous or grade I endometrioid
  • Hormone therapy (eg Anastrozole, Letrozole, Exemestane): Low-grade serous or grade I endometrioid
• Other recommended regimens:
  • Weekly Paclitaxel/weekly Carboplatin
  • Docetaxel/Carboplatin
  • Carboplatin/liposomal Doxorubicin
  • Weekly Paclitaxel/3-weekly Carboplatin
  • Hormone therapy (eg Leuprolide acetate, Tamoxifen): Low-grade serous or grade I endometrioid
• Conditional regimens:
  • Intraperitoneal (IP) or IV Paclitaxel/Cisplatin: For optimally-debulked stage II-III disease
  • Carboplatin or Cisplatin or Paclitaxel plus Ifosfamide: For carcinosarcoma
  • Carboplatin monotherapy: For patients >70 years of age and/or with comorbidities

Recommended IV Regimens

• Have different toxicity profiles
  
  • Paclitaxel followed by Carboplatin given every 3 weeks for 3-6 cycles (preferred regimen)
  • Paclitaxel followed by Carboplatin weekly for 18 weeks
  • Docetaxel followed by Carboplatin given every 3 weeks for 3-6 cycles
  • Dose-dense Paclitaxel on days 1, 8 and 15 plus Carboplatin on day 1 every 3 weeks for 6 cycles
  • Carboplatin plus pegylated liposomal Doxorubicin every 4 weeks for 3-6 cycles
  • Paclitaxel followed by Carboplatin and Bevacizumab every 3 weeks for 5-6 cycles
    
    • Continue Bevacizumab for up to 12 additional cycles
  • Paclitaxel followed by Carboplatin every 3 weeks for 6 cycles; add Bevacizumab starting cycle 2
    
    • Continue Bevacizumab up to 22 cycles

Intraperitoneal (IP) Systemic Therapy

• Allows the possibility of targeting therapy to the site of disease while minimizing systemic toxicities
• Recommended for all stage III patients with optimally debulked (<1 cm residual) disease
• Optimally debulked stage II patients may also receive IP chemotherapy
• Recommended regimen: Cisplatin on day 2 after IV Paclitaxel on day 1, then Paclitaxel on day 8, every 3 weeks for 6 cycles
• IP Carboplatin given with IV Paclitaxel on day 1, followed by IP Paclitaxel on day 8 is a treatment option for patients who received neoadjuvant chemotherapy and interval debulking surgery
• Women unable to complete IP therapy should receive IV therapy
• Catheter complications, nausea, vomiting, dehydration, or abdominal pain are common reasons for discontinuing the IP treatment

• Additional chemotherapeutic option is hormone therapy including aromatase inhibitors (Anastrozole, Letrozole), Leuprolide and Tamoxifen

• Recommended treatment options depend on disease stage, primary systemic therapy agents used, primary treatment response and BRCA1/2 mutation status
• Patients without Bevacizumab during primary treatment:
  • With BRCA1/2 wild-type or unknown mutation with complete or partial response: Niraparib
  • With germline or somatic BRCA1/2 mutation with complete or partial response: Olaparib or Niraparib
• Patients with Bevacizumab as part of primary treatment:
  • With BRCA1/2 wild-type or unknown mutation with complete or partial response
    • HR proficient or unknown status: Bevacizumab
    • HR deficient: Bevacizumab with Olaparib
  • With germline or somatic BRCA1/2 mutation with complete or partial response: Bevacizumab with Olaparib or Olaparib or Niraparib

Systemic Therapy for Germ Cell Ovarian Carcinoma

• Patients with embryonal or endodermal sinus tumors, stage II-IV dysgerminoma or stage I, grade 2-3 or stage II-IV immature teratoma should receive postoperative chemotherapy with Bleomycin/Etoposide/Cisplatin for 3-4 cycles
• In some patients with stage IB-III dysgerminoma for whom minimizing toxicity is critical, 3 courses of Etoposide/Carboplatin combination can be used: Carboplatin on day 1 plus Etoposide on days 1-3 every 4 weeks for 3 cycles

Systemic Therapy for Sex Cord Stromal Ovarian Carcinoma

• For patients with stage II-IV tumors, Paclitaxel/Carboplatin regimen is preferred
• Platinum-based chemotherapy should be considered for patients with high-risk stage 1 tumors (stage IC, poorly-differentiated tumor, tumor size >10-15 cm, tumor rupture)
• Patients with limited stage II-IV tumors should undergo radiotherapy

Recurrence Therapy for Epithelial Ovarian Carcinoma

Cytotoxic Therapy

• Combination platinum-based chemotherapy
  
  • Preferred for first recurrence in platinum-sensitive patients (ie patients who relapse ≥6 months after initial chemotherapy)
  • The decision regarding which combination to use should be based on the toxicity experienced with primary therapy, patient preference and other factors
  • Preferred agents for platinum-sensitive disease include:
    • Carboplatin/Paclitaxel with or without Bevacizumab
    • Carboplatin/Gemcitabine with or without Bevacizumab
    • Carboplatin/liposomal Doxorubicin with or without Bevacizumab
    • Cisplatin/Gemcitabine

• Preferred non-platinum-based agents for platinum-resistant disease include:
  
  • Docetaxel
  • Oral Etoposide
  • Gemcitabine
  • Liposomal Doxorubicin
  • Weekly Paclitaxel
  • Topotecan
  • Topotecan/Bevacizumab
  • Weekly Paclitaxel/Bevacizumab
  • Liposomal Doxorubicin/Bevacizumab
  • Oral Cyclophosphamide/Bevacizumab

Targeted Therapy

• Bevacizumab is the preferred agent which was shown to slow down the growth of advanced ovarian cancer
  • Recommended for patients with platinum-resistant recurrent disease with history of ≤2 prior chemotherapy regimens, to be given in combination with Paclitaxel, pegylated liposomal Doxorubicin or Topotecan
  • May be used as maintenance therapy in patients with stage II-IV disease with wild-type or unknown BRCA1/2 mutation who were responsive to initial recurrence chemotherapy until disease progression or unacceptable toxicity
• Olaparib/Bevacizumab combination maintenance therapy may be considered in patients with BRCA1/2 mutations or genomic instability previously given Bevacizumab-containing platinum-based chemotherapy 
• Olaparib may be given to patients with advanced ovarian cancer with germline BRCA mutation with complete or partial response after ≥2 lines of chemotherapy
• Niraparib may be given to patients with homologous recombination (HR) status-positive advanced ovarian cancer for those who have undergone treatment with ≥3 lines of chemotherapy 
• Rucaparib (platinum-resistant disease) may be given to patients with advanced ovarian cancer with germline and/or somatic BRCA mutation who have undergone treatment with ≥2 lines of chemotherapy 
• Poly-adenosine diphosphate (ADP)-ribose (PARP) inhibitors Olaparib, Niraparib and Rucaparib are maintenance therapy options for patients with recurrent disease with complete or partial response to platinum-based chemotherapy
  • Niraparib maintenance therapy is an option for patients with wild-type or unknown BRCA1/2 mutation

Other Agents 

• Other therapeutic agents for recurrence include Capecitabine, Cyclophosphamide, Doxorubicin, hormonal therapy (eg aromatase inhibitors, Leuprolide acetate, Megestrol acetate, Tamoxifen), Ifosfamide, Irinotecan, Melphalan, Oxaliplatin, Paclitaxel, albumin-bound Paclitaxel, Pazopanib, Pemetrexed, Vinorelbine
  • Carboplatin, Carboplatin/Docetaxel, Carboplatin/Paclitaxel weekly combination, Cisplatin, Nirapanib may also be used for platinum-sensitive disease
  • Sorafenib/Topotecan may also be used for platinum-resistant disease
• Other agents to be considered in certain circumstances:
  • Mucinous carcinoma: 5-FU/Leucovorin/Oxaliplatin with or without Bevacizumab and Capecitabine/Oxaliplatin with or without Bevacizumab
  • Clear cell carcinoma: Irinotecan/Cisplatin
  • NTRK gene fusion-positive carcinoma: Entrectinib, Larotrectinib
  • Confirmed taxane hypersensitivity: Carboplatin/albumin-bound Paclitaxel
  • Low-grade serous carcinoma: Binimetinib, Fulvestrant, Trametinib
  • Microsatellite instability-high [MSI-H] or mismatch, repair-deficient [dMMR] solid tumors or patients with tumor mutational burden-high (TMB-H) tumors ≥10 mutations/megabase: Pembrolizumab
  • MSI-H/dMMR recurrent or advanced tumors: Dostarlimab-gxly
  • For patients >70 years of age: Carboplatin/Paclitaxel

Recurrence Therapy for Germ Cell Ovarian Carcinoma

• Recommended in patients with recurrent or residual disease after multiple chemotherapeutic regimens for whom no curative options are considered possible
• Preferred options which are potentially curative regimens are high-dose chemotherapy and Paclitaxel/Ifosfamide/Cisplatin (TIP)
• Other recommended options which is for palliation only may include Vincristine/Dactinomycin/Cyclophosphamide (VAC), Vinblastine/Ifosfamide/Cisplatin (VeIP), Etoposide/Ifosfamide/Cisplatin (VIP), Cisplatin/Etoposide (if not previously used), Docetaxel/Carboplatin, Gemcitabine/Paclitaxel/Oxaliplatin, Gemcitabine/Oxaliplatin, Paclitaxel/Carboplatin, Paclitaxel/Gemcitabine, Paclitaxel/Ifosfamide, Pembrolizumab (if with MSI-H/dMMR or TMB-H), oral Etoposide, Docetaxel, Paclitaxel, radiation therapy, or supportive care
  • Combination chemotherapy is not recommended in patients with recurrent or residual disease who have no curative options
  • Ifosfamide/platinum-based chemotherapy with or without Paclitaxel should be considered as 2nd-line option for patients with platinum-sensitive relapsed disease whose progression occurred >4-6 weeks after completion of primary therapy

Recurrence Therapy for Sex Cord-Stromal Ovarian Carcinoma

• Preferred regimen is Paclitaxel/Carboplatin 
• Other recommended regimens include Bevacizumab, Docetaxel, Etoposide/Cisplatin (if not previously used), Paclitaxel, Paclitaxel/Ifosfamide, VAC, or supportive care
  • Other regimens which may be useful in certain circumstances include: 
    • Bleomycin/Etoposide/Cisplatin (if not previously used)
    • Aromatase inhibitors (eg Anastrozole, Exemestane, Letrozole) 
    • Leuprolide may be used for granulosa cell tumors
    • Tamoxifen
    • VAC