Ovarian Cancer Treatment Protocols

Treatment protocols for ovarian cancer are provided below, including the following:

• Treatment by stage ^{[1, 2]}
• Treatment of patients with suboptimal debulking
• Consolidation therapy
• Hyperthermic intraperitoneal chemotherapy
• Treatment of recurrent disease

General treatment approach

Surgery is the initial modality of treatment for stage I-IVA epithelial ovarian cancer. However, only a small percentage of women with epithelial ovarian cancer can be treated with surgery alone. This small percentage includes patients with stage IA or IB (grade 1) serous, mucinous, endometrioid, and Brenner tumors. Treatment of grade 2 tumors remains controversial. ^{[3, 4]}

High-risk features such as stage IC, higher grade, or clear-cell histology should prompt consideration of adjuvant chemotherapy. ^[5] Clear-cell carcinomas are associated with a significantly worse prognosis in stage I; all patients with this histologic subtype should be considered for chemotherapy. ^[6]

Women with any stage of epithelial ovarian cancer should be considered for clinical trials if available.

Chemotherapy recommendations based on stage

Stage I

Consider chemotherapy for stages 1A and 1B grades 2 and 3, and stage 1C. Chemotherapy is usually given after surgery. Regimens are as follows:

• Paclitaxel 175 mg/m² IV over 3 h plus  carboplatin area under the curve (AUC) 5-6 IV (see Carboplatin AUC Dose Calculation [Calvert formula]) over 1 h on day 1; every 21 d for three to six cycles ^[7] or

• Docetaxel 60-75 mg/m² IV over 1 h plus  carboplatin AUC 5-6 IV over 1 h on day 1; every 21 d for three to six cycles ^[8]  or

• Carboplatin AUC 5 IV over 1 h on day 1 plus  pegylated liposomal doxorubicin 30 mg/m² IV up to 1 h; every 28 d for three to six cycles

Stages IIA and IIB

All patients with stage II or higher cancer should be considered for front-line chemotherapy based on burden of disease and ability to achieve optimal primary resection.  These patients should strongly consider participation in clinical trials if the option is available.

• Paclitaxel 175 mg/m² IV over 3 h plus  carboplatin AUC 5-6 IV over 30 min on day 1; every 21 d for three to six cycles ^[7] or

• Dose-dense paclitaxel 80 mg/m² IV over 1 hr on days 1, 8, and 15 plus carboplatin AUC 5-6 IV over 1 h on day 1; every 21 d for six cycles or

• Paclitaxel 60 mg/m² IV over 1 h followed by carboplatin AUC 2 IV over 30 min; weekly for 18 weeks or

• Docetaxel 60-75 mg/m² IV over 1 h plus carboplatin AUC 5-6 IV over 1 h on day 1; every 21 d for three to six cycles  ^[4]  or

• Carboplatin AUC 5 IV over 1 h plus pegylated liposomal doxorubicin 30 mg/m²; every 28 d for six cycles ^[9]

Stage III

Intraperitoneal (IP) chemotherapy remains the preferred treatment for optimally debulked (< 1 cm) stage III ovarian cancer after front-line surgery. A Gynecological Oncology Group trial (GOG 172) that compared IV cisplatin and IV paclitaxel with IP cisplatin and IV/IP paclitaxel determined that IP therapy improved survival and yielded a 25% reduction in the risk of death. However, the trial also showed increased toxicity with IP chemotherapy versus IV chemotherapy. ^[10]

The subsequent GOG 252 trial found no significant difference in progression-free survival (PFS) between patients receiving IV carboplatin/weekly IV paclitaxel; IP carboplatin/weekly IV paclitaxel; or sequential IV paclitaxel, IP cisplatin (dosed at 75 mg/m²), and IP paclitaxel. However, the 28% crossover rate from IP treatment to the IV-only group may have watered down a significant difference in PFS. Furthermore, the addition of bevacizumab to all arms in the study may have contributed to the unexpected results. The GOG 252 authors concluded that the toxicity and patient-reported outcomes support selection of the regimen consisting of IV carboplatin AUC 6 day 1, dose-dense paclitaxel 80 mg/m² IV once weekly, and bevacizumab 15 mg/kg IV day 1 given in 3-week cycles. ^[11]

At this time, there is no standardized regimen for IP therapy; however, the following dosing regimens may be used:

• Paclitaxel 135 mg/m² continuous IV infusion over 3 h or 24 h on day 1 plus cisplatin 75-100 mg/m² IP on day 2 (may reduce dose to 75 mg/m²) plus paclitaxel 60 mg/m² IP on day 8; repeat every 3 weeks for si6 cycles, provided that the disease is responsive ^[10]

• The cisplatin dose may be reduced to 75 mg/m² IP on day 2; some clinicians give paclitaxel 135 mg/m² IV over 3 h followed by cisplatin 75 mg/m² IP, both on day 1 and on an outpatient basis ^[12]

• Normal range of carboplatin AUC for treatment of ovarian carcinoma is from 5 to 7.5; patients who have received extensive prior chemotherapy or radiation should start with an AUC < 5

If the patient cannot tolerate IP delivery, revert to one of the following two drug regimens:

• Paclitaxel 175 mg/m² IV over 3 h plus carboplatin AUC 5-6 IV over 1 h on day 1; every 21 d for six cycles ^[13] or

• Docetaxel 75 mg/m² IV over 1 h plus  carboplatin AUC 5 IV over 1 h on day 1; every 21 d for six cycles ^[8]

Stage IVA:

Treatment recommendations are similar to those for stage III.

Stage IVB:

Patients should be considered for front-line chemotherapy and should strongly consider participation in clinical trials if the option is available. Possible regimens are as follows:

• Paclitaxel 175 mg/m² IV over 3 h plus  carboplatin AUC 5-6 IV over 1 h on day 1; every 21 d for six cycles ^[13] or

• Docetaxel 75 mg/m² IV over 1 h plus  carboplatin AUC 5 IV over 1 h on day 1; every 21 d for six cycles ^[8]

Neoadjuvant Chemotherapy

While neoadjuvant chemotherapy has been demonstrated as noninferior to primary cytoreductive surgery and could be considered in all patients with advanced disease, it may be of particular benefit in certain subgroups of patients. ^{[14, 15]}  Women who are unlikely to achieve optimal up-front surgical debulking due to extensive disease (lung or liver metastasis, disease in the porta hepatis, significant disease in the small bowel mesentery, or massive ascites) or those who are poor candidates to withstand aggressive surgery should be considered for neoadjuvant chemotherapy. ^[16]

Regimens include the following: 

• Paclitaxel 175 mg/m² IV over 3 h plus  carboplatin in AUC 5-6 IV over 1 h on day 1; every 21 d ^{[14, 15]}  or

• Docetaxel 60-75 mg/m² IV over 1 h plus  carboplatin AUC 5 IV over 1 h on day 1; every 21 d ^[8]

Chemotherapy recommendations for patients after suboptimal primary debulking

Given the reduced penetrance of tumors by IP chemotherapy, women with suboptimally debulked disease should be treated with IV chemotherapy, as follows:

• Paclitaxel 175 mg/m² IV over 3 h plus  carboplatin AUC 7.5 IV over 1 h on day 1; every 21 d for six cycles, provided that the disease is responsive ^[13] or

• Docetaxel 75 mg/m² IV over 1 h plus  carboplatin AUC 5 IV over 1 h on day 1; every 21 d for six cycles, provided that the disease is responsive ^[8]

The addition of bevacizumab to front-line therapy is still controversial with benefits of around 4 months PFS but no improvement in OS. ^[17]  However, the addition could be considered particularly in women women with significant ascites.

Dose-dense chemotherapy is an alternative in women who have undergone optimal surgical debulking, but it appears to be of particular benefit in those with greater residual disease, ^[18]  although there may be a greater rate of toxicity resulting in treatment delay or discontinuation. Possible regimens include the following: 

• Carboplatin AUC 6 IV on day 1  plus  paclitaxel 80 mg/m ² IV on day 1, day 8, and day 15 of a 21-day cycle for six cycles ^{[19, 20]}   or
• Carboplatin AUC 2 IV  and  paclitaxel 60 mg/m ² IV on day 1, day 8, and day 15 of a 21-day cycle for six cycles, for those with poor performance status or other comorbidities limiting the capacity to tolerate standard dose-dense regimens ^[21]

Chemotherapy recommendations for consolidation

Consolidation is treatment given after completion of front-line therapy with a complete clinical or pathologic response.

Bevacizumab appears to improve progression-free survival when used as single-agent therapy for consolidation if it was used in a combination regimen as up-front treatment. However, improvements in overall survival appear to be restricted to high-risk subgroups and are not consistent over studies. ^{[17, 22, 23]} Thus, the use of bevacizumab as consolidation therapy remains controversial.

Hyperthermic intraperitoneal chemotherapy

While used as standard treatment in other malignancies, such as appendiceal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) has been less adopted in the treatment of ovarian cancer, given logistical considerations in administration and concern for postoperative complications.

Several smaller European and Korean studies have demonstrated a benefit in PFS and OS in optimally debulked patients at the time of their primary surgery. ^{[24, 25, 26, 27]}  Additionally, a large-scale study of 245 patients reported longer recurrence-free survival and OS with surgery plus HIPEC than with surgery alone. Study patients were randomized at the time of optimal interval debulking surgery after receiving three cycles of neoadjuvant carboplatin AUC 5-6 IV and paclitaxel 175 mg/m² to either receive HIPEC with cisplatin 100 mg/m² or not. Median recurrence-free survival was 10.7 months in the surgery arm and 14.2 months in the surgery-plus-HIPEC arm; median overall survival was 33.9 months versus 45.7 months, respectively. ^[28]  Patients in the two arms had similar rates of postoperative adverse events.

HIPEC in recurrent ovarian cancer has been studied somewhat more extensively but largely in a retrospective manner with a variety of treatment regimens. It has not been widely adopted as a standard treatment regimen. 

Treatment recommendations for recurrent disease

Stages III and IV disease have a high rate of recurrence. These patients should be considered for clinical trials. Treatment is usually with chemotherapy; the regimen choice depends on the time elapsed since previous complete response to platinum-containing chemotherapy.

Platinum-sensitive recurrence:

If recurrence occurs more than 6 months after initial or subsequent complete clinical response to platinum-containing chemotherapy, the patient should be treated with one of the IV platinum-containing combination regimens below. The choice depends on factors such as pre-existing comorbidity, prior toxicities, and physician and patient preference. Regimens are as follows:

• Carboplatin AUC 5 IV  plus  liposomal doxorubicin 30 mg/m² IV over 30 min; every 28 d for six cycles ^[29] or

• Paclitaxel 175 mg/m² IV over 3 h plus  carboplatin AUC 5 (Calvert) IV over 1 h; every 21 d for six cycles ^[30] or

• Paclitaxel 80 mg/m² IV over 1 h weekly days 1, 8, and 15 plus  carboplatin AUC 6 IV over 1 h on day 1; every 21 days for six cycles ^[31]  or

• Docetaxel 75 mg/m² IV over 1 h plus  carboplatin AUC 5 IV over 1 h; every 21 d for six cycles ^[8] or

• Gemcitabine 1000 mg/m² IV over 30 min on days 1 and 8 plus  carboplatin AUC 4 IV over 1 h on day 1; every 21 days for six cycles ^{[32, 33]}

Consideration may be given to bevacizumab, in combination with carboplatin and paclitaxel ^[34] or with carboplatin and gemcitabine, ^[35] followed by bevacizumab alone, as follows:

• Bevacizumab 7.5 mg/kg IV over 30-90 min on Day 1 plus carboplatin AUC 5-6 IV on day 1 plus paclitaxel 175 mg/m² IV over 3 h on day 1 every 21 days for five to six cycles, followed by continued use of bevacizumab 7.5 mg/kg every 21 days for up to 12 additional cycles ^[34]  or

• Bevacizumab 15 mg/kg IV over 30–90 min on day 1 plus  carboplatin IV AUC 6 on day 1 every 21 days for six cycles, followed by continued use of bevacizumab 15 mg/kg IV over 30–30-90 min every 21 days for up to 22 additional cycles

• Bevacizumab 15 mg/kg IV on Day 1 plus  carboplatin IV AUC 4 on day 1 plus  gemcitabine 1000 mg/m² IV on Days 1 and 8 every 21 days for six to 10 cycles, followed by continued use of bevacizumab 15 mg/kg every 21 days as a single agent until disease progression ^[35]

A minority of patients may be suitable candidates for secondary surgery, including those with limited disease and a long interval to recurrence from original treatment. All patients should be considered for entry into clinical trials.

Platinum-resistant recurrence:

If recurrence occurs less than 6 months after initial or subsequent complete clinical response to platinum-containing chemotherapy, the patient should be treated with one of the regimens below. There is no standard for the number of cycles of treatment given in this situation. Often treatment is changed because of progressive disease or toxicity.

Although liposomal doxorubicin is a good first choice, many other agents with similar efficacy are available; the final choice depends on individual circumstance and patient and physician preference. Some of the choices include the following:

• Liposomal doxorubicin 40-50 mg/m² IV over 30 min; every 21 d ^{[36, 37, 38]} or

• Gemcitabine 1000 mg/m² IV over 30 min on Days 1 and 8; every 21 d ^{[37, 38, 39]} or

• Topotecan 1.25-1.5 mg/m² IV over 30 min on Days 1-5; every 21 d ^{[36, 40]} or

• Paclitaxel 80 mg/m² IV over 1 h weekly ^{[41, 42, 43]} or

• Docetaxel 75-100 mg/m² IV over 1 h every 21 days ^{[44, 45]} or

• Etoposide 50 mg/m²/day PO for 21 days every 28 days ^[46] or

• Nanoparticle albumin-bound paclitaxel 100 mg/m² IV over 30 min given weekly (Days 1, 8, and 15) every 28 days ^[47]

Alternatively, consideration may be given to bevacizumab as a single agent or in combination, as follows:

• Bevacizumab 10 mg/kg IV every 14 d in combination with one of the following IV chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (topotecan is given weekly) ^[48]  or

• Bevacizumab 15 mg/kg IV every 21 d in combination with topotecan (every 21 d) ^[48] or

• Bevacizumab 15 mg/kg IV (initially over 90 min, then over 60 min, and finally over 30 min for subsequent infusions); every 21 d until progression ^{[34, 49]} or

• Bevacizumab 10 mg/kg IV on days 1 and 15 plus  topotecan 4 mg/m² IV on Days 1, 8, and 15, every 28 days ^[50]

• Bevacizumab 15 mg/kg IV on Day 1 every 21 days plus  olaparib 300 mg PO BID; continue olaparib until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Bevacizumab should be given for a total of 15 months including with chemotherapy and given as maintenance. Discontinue olaparib in patients with a complete response (no radiological evidence of disease) at 2 years. ^[51]

PARP inhibitors

PARP inhibitors are FDA approved as maintenance therapy in patients who have had at least a partial platinum response.

Olaparib (Lynparza) is available as either tablets or capsules with distinct indications. Do not substitute olaparib tablets with olaparib capsules on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation. Olaparib maintenance indications are as follows:

• Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, in patients who have in complete or partial response to platinum-based chemotherapy
• First-line maintenance treatment of deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to first-line platinum-based chemotherapy
• Tablets only: 300 mg PO BID
• First-line maintenance treatment, in combination with bevacizumab, in adults with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is homologous recombination deficiency (HRD) positive, as defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability ^[52]

Rucaparib (Rubraca) 600 mg PO BID continuously is indicated for maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to platinum-based chemotherapy. ^{[53, 54]}

Niraparib (Zejula) 300 mg PO daily is approved for maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in women who have had complete or partial response to platinum-based chemotherapy independent of BRCA status. ^[55]  

Tumors with high folate receptor alpha (FRα) expression 

Mirvetuximab soravtansine (Elahere) 6 mg/kg (adjusted IBW) IV q3weeks is indicated for women with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1-3 prior systemic treatment regimens 

Hormonal therapy

Hormonal therapy may be considered for patients who have asymptomatic recurrence or who require a break from regular chemotherapy if they are not tolerating treatment well, as follows:

• Tamoxifen ^{[56, 57, 58]} 20 mg PO twice a day daily or

• Letrozole ^[59] 2.5 mg PO daily

All patients should be considered for entry into clinical trials.

Special considerations

Elderly patients may not tolerate chemotherapy as well as younger patients. Comorbid conditions also affect tolerance to chemotherapy and necessitate close monitoring and dose reductions; such conditions may include liver or kidney dysfunction. Possible regimens include the following:

• Carboplatin AUC 5 IV plus paclitaxel 135 mg/m²; every 21 d ^[60] or

• Paclitaxel 60 mg/m² over 1 h followed by carboplatin at AUC 2 IV over 30 min; weekly for 18 weeks ^[61]

Single-agent carboplatin has been recommended for this patient population. However, the open-label, phase II, randomized EWOC-1 trial, which evaluated carboplatin monotherapy versus two other carboplatin combination regimens, was terminated prematurely because of significantly worse survival outcomes with carboplatin monotherapy compared with carboplatin combination regimens. ^[62]