Epithelial ovarian cancer is the fifth leading cause of cancer mortality in women and is the leading cause of death due to gynecologic cancer in the United States.1 The incidence of ovarian cancer increases with age and has been shown to be most prevalent among women in their sixth and seventh decades of life.2 The median age at diagnosis is 63 years, and more than 70% of women present with advanced disease.
Ovarian Cancer Treatment Landscape
For ovarian cancer, the standard treatment is maximal cytoreductive surgical debulking, which is followed by platinum-based chemotherapy.3 During the surgery, diagnosis confirmation and disease staging (Figure 1) are performed. Previously, optimal cytoreduction was defined as residual tumor nodules with a diameter measuring ≤1 cm. Results from large, multivariate analyses revealed improved progression-free survival (PFS) and overall survival (OS) for patients who underwent complete resection compared with patients who underwent the so-called optimal (up to 1 cm) and suboptimal cytoreduction.4 These findings resulted in guideline updates that list achieving complete resection of macroscopic disease residuals (complete cytoreduction) as the aim of front-line surgery.5
Patients with advanced disease that is inoperable or patients with poor performance status are treated with 3 cycles of neoadjuvant chemotherapy. If the patient responds, interval debulking surgery (IDS) is performed, followed by up to 6 cycles of chemotherapy.6 Following surgery, first-line chemotherapy consists of platinum/taxane regimens that are administered every 21 days for 6 cycles. Although most patients respond to first-line therapy, many patients develop recurrent disease.
Findings from phase 3 clinical trials have demonstrated that the addition of antiangiogenic treatment with bevacizumab and weekly paclitaxel for the first-line management of ovarian cancer contribute to improved survival outcomes.
The US Food and Drug Administration (FDA) approval of bevacizumab was based on results from the phase 3 GOG-0218 study of 1873 women with previously untreated stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who underwent surgery and were treated with chemotherapy alone, chemotherapy plus bevacizumab followed by placebo, or chemotherapy plus bevacizumab followed by bevacizumab for up to 22 cycles.7,8 In this study, women who received chemotherapy plus bevacizumab followed by bevacizumab exhibited significantly prolonged PFS compared with chemotherapy alone.
Preliminary results from the phase 3 ICON8 study demonstrated that weekly dose-dense chemotherapy (carboplatin area under the curve [AUC] 2 and 80 mg/m2 paclitaxel weekly, or carboplatin AUC 5 or AUC 6 every 3 weeks and 80 mg/m2 paclitaxel weekly) can be delivered successfully as first-line treatment for epithelial ovarian cancer.9 However, this regimen did not significantly improve PFS compared with standard chemotherapy delivered every 3 weeks.
In patients with recurrent disease, selection of second-line chemotherapy is based on platinum sensitivity. Among patients with highly or partially platinum-sensitive tumors, multidrug regimens are often used, including combinations of carboplatin or cisplatin with paclitaxel, pegylated liposomal doxorubicin, or gemcitabine (with or without bevacizumab). For patients with partially sensitive tumors or in whom platinum treatment is not possible, pegylated liposomal doxorubicin with trabectedin has been shown to be an appropriate option, with prolonged PFS and OS in patients with BRCA mutations.10,11 For patients with refractory disease or disease that is resistant to platinum therapy, only the combination of chemotherapy and bevacizumab has been shown to prolong PFS; however, this regimen is only eligible for patients with good performance status.
In epithelial ovarian cancer, greater vascular endothelial growth factor (VEGF) expression is predictive of tumor grade, disease stage, and survival outcomes. Promising results have been reported with bevacizumab, cediranib, pazopanib, and aflibercept.
Bevacizumab, a humanized monoclonal antibody against VEGF, prevents the binding of VEGF to its receptor. Bevacizumab was first approved in 2004 in combination with standard chemotherapy for colon cancer.7
In 2014, the FDA approved the combination of bevacizumab with paclitaxel, topotecan, or pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. Results from GOG-0218 and ICON7 supported the approval, demonstrating that bevacizumab maintenance following standard chemotherapy contributes to prolonged median PFS in patients with advanced epithelial ovarian cancer.12
Results from meta-analyses of the phase 3 AURELIA, OCEANS, and GOG-0213 studies, which included 1502 patients altogether, demonstrated that the addition of bevacizumab to standard chemotherapy contributed to improved overall response rate, PFS, and OS.13,14 Although the combination was associated with a higher incidence of grade 3/4 toxicities, the adverse events were manageable.
In the ATHALYA study, the addition of bevacizumab to neoadjuvant carboplatin-paclitaxel contributed to significantly higher complete resection rates in patients with advanced initially unresectable ovarian cancer.15 Grade 3 treatment-related adverse events were reported in a similar proportion of patients receiving bevacizumab versus chemotherapy alone (62% vs 63%, respectively).
Using data from the ICON7 trial, cost-effectiveness analyses were conducted based on the US Medicare system,16 the UK National Health Service,17 and the Canadian public healthcare system.18 Patients with ovarian cancer at a high risk of progression who were treated with bevacizumab plus standard chemotherapy had an average incremental quality-adjusted life-year (QALY) gain of 0.374 years. The incremental cost-effectiveness ratio of bevacizumab was $167,771 per life-year saved (Medicare), $95,942 per QALY (Canadian public healthcare system), and £48,975 (UK National Health Service). This was above the standard cost-effectiveness threshold of £20,000 to £30,000 per QALY that is accepted by the British National Institute for Health and Care Excellence.
Cediranib is a multikinase angiogenesis inhibitor that is active against all 3 VEGF receptors (VEGFR1-3). Results from the phase 3 ICON6 study demonstrated activity and manageable toxicity for the combination of cediranib and platinum-based chemotherapy, with cediranib continued as maintenance therapy for up to 18 months in patients with platinum-sensitive relapsed ovarian cancer.19,20 The combination of cediranib and chemotherapy followed by cediranib once-daily maintenance led to a median PFS of 11.0 months compared with 8.7 months in the chemotherapy-alone group (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.44-0.72; P <.0001). Frequently reported side effects included diarrhea, neutropenia, hypertension, and voice changes.
Pazopanib is a multikinase inhibitor with activity against VEGFR1-3, platelet-derived growth factor receptors α and β (PDGFRA and PDGFRB), and c-Kit. The phase 2 MITO-11 study demonstrated significantly longer PFS in patients treated with pazopanib combined with paclitaxel compared with paclitaxel alone (6.35 vs 3.49 months; HR, 0.42; 95% CI, 0.25-0.69; P = .0002) in patients with platinum-resistant ovarian cancer.21 Frequently reported adverse events included neutropenia, fatigue, leukopenia, hypertension, and anemia.
The phase 3 AGO-OVAR16 study demonstrated improved PFS in patients receiving pazopanib monotherapy compared with placebo in patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who did not progress following first-line chemotherapy (17.9 vs 12.3 months; HR, 0.77; 95% CI, 0.64-0.91; P = .0021).22,23 Frequently reported adverse events included hypertension, neutropenia, liver-related toxicity, and diarrhea.
Nintedanib is an angiokinase inhibitor of VEGFR1-3, FGFR1-3, and PDGFRA/B, with a lower level of activity against Src, RET, and Flt-3.3 Nintedanib was approved by the FDA in 2014 for the treatment of idiopathic pulmonary fibrosis. In the phase 3 LUME-OVAR 1 study, the combination of nintedanib plus standard first-line therapy followed by nintedanib maintenance led to significantly improved median PFS compared with chemotherapy alone in patients with advanced epithelial ovarian cancer (17.2 vs 16.6 months; HR, 0.84; 95% CI, 0.72-0.98; P = .0239).24 Frequently reported adverse events included diarrhea, neutropenia, thrombocytopenia, and anemia.
There are currently 3 poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of patients with recurrent ovarian cancer (Table 1).25-28
Olaparib (AZD2281) has been shown to be active in select patients. Those with mutated BRCA1 and BRCA2 have exhibited higher response rates than patients with wild-type BRCA. Olaparib has been shown to be particularly active in patients with platinum-sensitive disease.29 A lower level of response following olaparib treatment has been observed in patients with disease that is resistant or refractory to platinum.30,31 Olaparib is approved for patients with advanced ovarian cancer who have received treatment with at least 3 lines of chemotherapy and who have a germline BRCA mutation.
The phase 3 SOLO2/ENGOT-Ov21 trial was designed to assess the efficacy of olaparib tablets (vs capsules) as maintenance therapy for women who have received at least 2 lines of chemotherapy.32 In these patients, the median PFS was significantly longer in women treated with olaparib compared with placebo (19.1 vs 5.5 months; HR, 0.30; 95% CI, 0.22-0.41; P <.0001); however, more serious adverse events were reported among patients treated with olaparib maintenance therapy, including anemia, fatigue or asthenia, and neutropenia.
Olaparib tablets are approved by the FDA for maintenance therapy for women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved complete or partial responses to platinum-based chemotherapy.33 Notably, olaparib is transitioning from capsules to tablets for both the maintenance and recurrence therapy indications. However, olaparib tablets (100 and 150 mg) should not be substituted with olaparib capsules (50 mg) due to differences in the bioavailability and dosing of the formulations.34
On May 8, 2020, the FDA expanded olaparib’s indication to include the combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic stability.25
Rucaparib is an oral PARP inhibitor that was investigated in the phase 2 ARIEL2 trial as therapy for recurrent platinum-sensitive ovarian cancer.26,27 The study compared 3 groups of patients: BRCA mutant, BRCA wild-type/high loss of heterozygosity (LOH), and BRCA wild-type/low LOH. Median PFS after rucaparib treatment was 12.8 months in the BRCA mutant subgroup, 5.7 months in the high LOH subgroup, and 5.2 months in the low LOH subgroup. PFS was signiﬁcantly longer in the BRCA mutant (HR, 0.27; 95% CI, 0.16-0.44; P <.0001) and high LOH (HR, 0.62; 95% CI, 0.42-0.90; P = .011) groups. Serious adverse events reported by women treated with rucaparib include small intestinal obstruction, malignant neoplasm progression, and anemia.
The oral PARP inhibitor niraparib was assessed as maintenance therapy for patients with platinum-sensitive ovarian cancer who responded to recurrence therapy in the phase 3 NOVA trial.28 Repeat imaging is recommended for assessing response to treatment. There were 3 efficacy populations in the study: germline BRCA mutation (gBRCA), overall non-BRCA, and a non-BRCA subgroup with homologous recombination deficiency (HRD).
Median PFS for the gBRCA group was 21.0 months in patients who received niraparib versus 5.5 months in patients who received placebo (HR, 0.27; 95% CI, 0.17-0.41; P <.001). Median PFS for the overall non-BRCA cohort was 9.3 months versus 3.9 months (HR, 0.45; 95% CI, 0.34-0.61; P <.001) and 12.9 months versus 3.8 months in the non-BRCA/HRD subgroup (HR, 0.38; 95% CI, 0.24-0.59; P <.001).
Among women treated with niraparib, commonly reported grade 3/4 adverse events included thrombocytopenia, anemia, and neutropenia.
The phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial was designed to assess the efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer following response to first-line platinum-based chemotherapy.35
Among patients with tumors with HRD, median PFS was significantly longer with niraparib treatment versus placebo (21.9 vs 10.4 months; HR, 0.43; 95% CI, 0.31-0.59; P <.001). In the overall population, median PFS with niraparib treatment was 13.8 months versus 8.2 months with placebo (HR, 0.62; 95% CI, 0.50-0.76; P <.001).
At the 24-month interim analysis, OS rates were 84% and 77% in patients treated with niraparib and placebo, respectively. Frequently reported adverse events of grade 3 or higher included anemia, thrombocytopenia, and neutropenia.
On April 29, 2020, the FDA approved niraparib for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.36
Molecular Tumor Testing
With the development of targeted therapies, there has been renewed focus on germline and somatic tumor testing for patients with ovarian cancer. The National Comprehensive Cancer Network® (NCCN®), the American Society of Clinical Oncology (ASCO), and others have presented guidelines related to testing (Table 2).37,38
Prior to initiating therapy in patients with persistent or recurrent disease, tumor molecular testing is recommended if not previously done.37 Validated molecular testing should be performed using the most recent tumor tissue sample in a Clinical Laboratory Improvement Amendments (CLIA)-approved facility. Testing should include, at minimum, BRCA1/2, and microsatellite instability (MSI) or deficient mismatch repair (dMMR), if not previously completed.
Additional testing can be conducted at the discretion of the treating physician to identify alterations for which FDA-approved tumor-specific or tumor-agnostic targeted therapy options exist and may be beneficial for individual patients.
The ASCO guidelines on tumor testing in epithelial ovarian cancer contain several strong recommendations backed by high-quality evidence.38
First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene mutation or variant should be offered individualized genetic risk evaluation, counseling, and genetic testing.
Women diagnosed with epithelial ovarian cancer with identified germline or somatic pathogenic or likely pathogenic variants in BRCA1 and BRCA2 genes should be offered treatments that are FDA approved under their labeled indication in the upfront and the recurrent setting. BRCA1/2 pathogenic or likely pathogenic variants qualify for and have been associated with higher rates of response to FDA-approved treatments such as PARP inhibitors.
Clinical decisions should not be based on a variant of uncertain significance (VUS; ie, a mutation that has not been verified as a pathogenic variant). Care providers and patients and family members tested should be aware that reclassification of VUS is an ongoing process and it may eventually become possible to definitively determine if a variant is deleterious or benign. Until that time, the patient’s clinical features and family history should inform clinical decision-making.
Women with epithelial ovarian cancer should be offered testing at the time of diagnosis. This has implications for therapeutic decision-making.
Primary treatment for ovarian cancer includes debulking surgery, which is followed by systemic chemotherapy for most patients (Table 3).37 Initial surgery should include a total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO). For select unilateral stage I tumors and/or low-risk ovarian tumors, a unilateral salpingo-oophorectomy may be adequate for a young patient wishing to maintain fertility.
Neoadjuvant chemotherapy may be considered (category 1) for patients with bulky stage III to IV disease who are assessed by a gynecologic oncologist, with histologic confirmation and/or laparoscopic evaluation, and deemed unlikely to be completely cytoreduced to R0, or for patients who are poor surgical candidates.37 Neoadjuvant chemotherapy is not recommended for patients with disease that is confined to the ovary, unless the patient is a poor surgical candidate due to age, frailty, or comorbidities.
The standard intraperitoneal/intravenous (IP/IV) regimen of paclitaxel/cisplatin may be used following intravenous neoadjuvant chemotherapy and IDS.
Based on findings from clinical trials designed to compare neoadjuvant chemotherapy and cytoreduction with primary cytoreductive surgery and adjuvant chemotherapy among women with advanced ovarian cancer, the Society of Gynecologic Oncology guidelines state that women who are determined to be fit for primary cytoreductive surgery, with potentially resectable disease, can be offered either cytoreductive surgery or neoadjuvant chemotherapy.39
Neoadjuvant chemotherapy is noninferior to primary cytoreductive surgery in terms of PFS and OS, and is associated with decreased peri- and postoperative morbidity and mortality, and shorter hospital stays.
Patients with a high likelihood of achieving cytoreduction to less than 1 cm with acceptable mortality are recommended for primary cytoreductive surgery, whereas women with high perioperative risk or a low likelihood of achieving cytoreduction to <1 cm of residual disease are recommended for neoadjuvant chemotherapy.
Following neoadjuvant therapy and IDS, any of the adjuvant therapy options for high-grade serous carcinoma (IV or IP/IV) can be considered.37 A minimum of 6 cycles of neoadjuvant treatment is recommended, including at least 3 cycles of adjuvant therapy following IDS. Patients who have stable disease and are tolerating therapy may continue past 6 cycles of therapy.
For patients with surgically staged IA or IB, grade 1 endometrioid carcinomas, observation is recommended due to survival rates greater than 90% with surgical treatment alone.37
The IP/IV chemotherapy regimen is recommended for patients with stage II-III cancer with optimally debulked disease, who have one of the following ovarian cancer types: high-grade serous, grade 2/3 endometrioid, clear-cell carcinoma, carcinosarcoma. IP chemotherapy is not recommended for stage I or IV disease. For patients with advanced disease (stage II-IV), or stage I high-grade serous, a total of 6 cycles of intravenous chemotherapy are recommended compared with 3 to 6 cycles for stage I with other ovarian cancer types.
Some of the recommended intravenous regimens for certain subtypes of stage II-IV ovarian cancer (high-grade serous, grade 2/3 endometrioid, clear-cell carcinoma, or carcinosarcoma) include:
- Paclitaxel, 175 mg/m2 intravenous infusion, followed by carboplatin, dosed at an AUC of 5 to 6 intravenous on day 1, given every 3 weeks for 3 to 6 cycles (stage I-IV disease)
- Dose-dense paclitaxel, 80 mg/m2 intravenous on days 1, 8, and 15 plus carboplatin AUC 5 to 6 intravenous on day 1, every 3 weeks for 6 cycles (stage II-IV disease)
- Paclitaxel 60 mg/m2 followed by carboplatin AUC 2 intravenous, weekly for 18 weeks (stage II-IV disease)
- Docetaxel, 60 to 75 mg/m2 intravenous infusion followed by carboplatin, dosed at AUC of 5 to 6 intravenous on day 1, every 3 weeks for 6 cycles (stage I-IV disease)
- Carboplatin AUC 5 intravenous plus pegylated liposomal doxorubicin 30 mg/m2 intravenous every 4 weeks for 3 to 6 cycles (stage I-IV disease)
The recommended IP chemotherapy regimen is paclitaxel, 135 mg/m2 continuous intravenous infusion on day 1; cisplatin, 75 to 100 mg/m2 IP on day 2 after intravenous paclitaxel; paclitaxel, 60 mg/m2 IP on day 8; repeat every 3 weeks for 6 cycles (for optimally debulked stage II-III disease).
Patients with poor performance status, comorbidities, stage IV disease, or advanced age (>65 years) may not tolerate the IP regimen or the other combination intravenous regimens. Based on clinical judgment and expected tolerance to therapies, alternate dosing (see OV-C, 6 of 10, in the NCCN Guidelines) may be appropriate for elderly patients with epithelial ovarian cancer (including carcinosarcoma, clear-cell, mucinous, and low-grade serous).
Antiangiogenesis Agents as Maintenance Therapy
For stage II-IV disease, NCCN includes as recommended options regimens with bevacizumab added to upfront chemotherapy with carboplatin/paclitaxel followed by bevacizumab as maintenance therapy for those in complete and partial response, with BRCA1/2 wild-type or unknown mutation status.37 Prolonged bevacizumab given upfront with carboplatin/paclitaxel and followed by maintenance bevacizumab is the only recommended GOG-0218 regimen.
Bevacizumab may be continued following primary systemic therapy if a chemotherapy/bevacizumab regimen was used up front, and the patient is in complete or partial response, and has BRCA1/2 wild-type or unknown mutation status; however, no data support the introduction of maintenance bevacizumab if initial chemotherapy did not contain bevacizumab (Figure 2).
Recommendations for Recurrent Disease
Prognosis is poor for patients who progress after 2 consecutive chemotherapy regimens without ever sustaining a clinical benefit (refractory) or for those whose disease recurs in less than 6 months (platinum resistant).40 Typically, progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.37 Secondary cytoreductive surgery can be considered for patients who recur after a long disease-free interval. No single therapeutic agent is currently recommended as the treatment of choice for recurrent ovarian carcinoma.
Combination platinum-based chemotherapy for a total of 6 cycles is preferred for first recurrence in patients with platinum-sensitive disease (Table 3).37 For patients with platinum-sensitive disease, preferred combinations include (see OV-C, 7 of 10):
- Carboplatin/paclitaxel ± bevacizumab
- Carboplatin/liposomal doxorubicin ± bevacizumab
For platinum-resistant disease, nonplatinum-based agents or regimens are the preferred cytotoxic therapy options (ie, cyclophosphamide [oral]/bevacizumab, docetaxel, oral etoposide, gemcitabine, weekly paclitaxel, liposomal doxorubicin with or without bevacizumab, weekly paclitaxel/bevacizumab, topotecan with or without bevacizumab; see OV-C, 8 of 10).37
Some of the other recommended cytotoxic therapy options include, capecitabine, cyclophosphamide, doxorubicin, ifosfamide irinotecan, melphalan, oxaliplatin, paclitaxel, albumin-bound paclitaxel, pemetrexed, and vinorelbine. Response rates with these therapies range from 12% to 64%. Pazopanib monotherapy (category 2B) may also be used in patients with recurrent disease.37
The NCCN Ovarian Cancer Panel recommends single-agent olaparib as a preferred recurrence therapy option for patients with advanced ovarian cancer (platinum sensitive or resistant) who have received ≥2 lines of chemotherapy and who have a deleterious germline BRCA mutation that has been detected using an FDA-approved test or another validated test performed in a CLIA-approved facility. Bevacizumab monotherapy (contraindicated in patients who are at increased risk for gastrointestinal perforation) and niraparib monotherapy (for patients who have received ≥3 lines of chemotherapy and whose cancer is associated with HRD defined by either: (1) a deleterious or suspected deleterious BRCA mutation; or (2) genomic instability and progression >6 months after response to the last platinum-based chemotherapy) are other preferred options for recurrence therapy (see OV-C 7 and 8 of 10).37
Niraparib, olaparib, and rucaparib are all single-agent options recommended as maintenance therapy for patients with platinum-sensitive recurrent disease who are in complete or partial response after ≥2 lines of platinum-based chemotherapy, including the most recent line.
Single-agent rucaparib is a recurrence therapy option for patients with platinum-sensitive or platinum-resistant advanced ovarian cancer who have been treated with ≥2 lines of chemotherapy and have a deleterious germline or somatic BRCA mutation. Rucaparib is a preferred recurrence therapy option due to a lack of good treatment options for this setting.
Integrating Ovarian Cancer Guideline Updates into Practice
Updates to the Guidelines
There have been several updates to the current version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).37 First, niraparib monotherapy has been added as a maintenance therapy option for patients in complete or partial remission after platinum-based first-line chemotherapy for advanced ovarian cancer in the following situations: (1) BRCA1/2 wild-type or unknown and no bevacizumab used during primary therapy; and (2) germline or somatic BRCA1/2 mutation.
Bevacizumab plus olaparib was added as a maintenance therapy option for patients with advanced ovarian cancer who are in complete or partial remission after platinum-based first-line chemotherapy if bevacizumab was used as part of primary therapy.37 Olaparib monotherapy has been added as a maintenance therapy option for patients with advanced ovarian cancer who are in complete or partial remission after platinum-based first-line chemotherapy and have germline or somatic BRCA1/2 mutations.
The indications have been modified for postremission bevacizumab.37 It is a single-agent option for those with advanced ovarian cancer who are in complete or partial remission following first-line platinum-based chemotherapy with a bevacizumab-containing regimen, if BRCA1/2 wild-type or unknown. Postremission bevacizumab monotherapy is not recommended for patients with a BRCA1/2 mutation.
After first-line therapy with bevacizumab, data are limited on maintenance therapy with a single-agent PARP inhibitor (olaparib or niraparib) for patients with a germline or somatic BRCA1/2 mutation.37 However, single-agent PARP inhibitors can be considered based on the magnitude of benefit of PARP inhibitor maintenance therapy for other subgroups. Data are limited for maintenance therapy with a PARP inhibitor for patients with stage II disease.
Niraparib, olaparib, or rucaparib can be considered as maintenance therapy options for patients with platinum-sensitive disease who are in complete or partial response after 2 or more lines of platinum-based therapy, including the most recent line (preferred options for those with a BRCA mutation).37 There are limited data on the use of a maintenance PARP inhibitor in patients who previously received a PARP inhibitor or after recurrence on therapy with bevacizumab. Combination bevacizumab/PARP inhibitor is not recommended at this time for maintenance after recurrence therapy.
Using the Guidelines
“NCCN Guidelines® are treatment guidelines agreed upon by experts in the field,” explained Amina Ahmed, MD, MS, assistant professor in the Division of Gynecologic Oncology and Associate Chief Medical Officer for Rush University Cancer Center and Cancer Service Line, Rush University Medical Center, Chicago, IL. “In regards to ovarian cancer, the NCCN Guidelines outline all recommended treatment modalities for all stages in the primary setting. The guidelines are also comprehensive in the recurrent setting.”
Dr Ahmed explained that the NCCN Guidelines can be used as a quality metric to assess how standard practice is applied for patients. “I use the guidelines as a quality and safety metric in my division to see if all of the practitioners are practicing consistently and to standardize treatment approaches for patients,” she said.
According to Dr Ahmed, a benefit of the NCCN Guidelines is that they are general enough so that practitioners can apply their own thought processes and results from the literature. Dr Ahmed also explained that many community physicians support their practice pattern by following the NCCN Guidelines.
Integrating Guideline Updates into Practice
According to Dr Ahmed, the most recent updates include the FDA approval of the PARP inhibitors used as maintenance treatment in the upfront and recurrent setting after platinum-based chemotherapy, and the approval of bevacizumab in the upfront and maintenance settings. A recent update includes use of PARP inhibitors for all patients who are treated with primary chemotherapy with advanced-stage ovarian cancer who are either BRCA-positive or who do not have a genomic or somatic mutation.
“The data were based on the PRIMA study of the usage of PARP inhibitors maintenance after upfront chemotherapy in advanced-stage ovarian cancer, which was published last year and we now have recent FDA approval,” Dr Ahmed explained.
The PRIMA study has shown that the PFS is prolonged for all patients irrespective of BRCA status with the use of PARP inhibitors. “I think all practitioners are moving in the direction of giving maintenance PARP inhibitors to patients with advanced-stage ovarian cancer after completion of primary treatment,” Dr Ahmed noted.
How to Stay Up to Date with the Guidelines
There is a downloadable NCCN Guidelines application that provides practice guidelines for all disease states. “The algorithms are very easy to use and they are updated frequently,” Dr Ahmed noted.
Another way to stay up to date is by signing up to receive alerts from various journals and societies. “This helps to stay current of newly published studies and treatment modalities,” she said.
The NCCN Guidelines are also there to keep community physicians up to date on the most recent information. “We have access to various lectures and speakers and information that just flows into an academic center differently than it does in the community,” Dr Ahmed explained. “The NCCN Guidelines are really where experts put these guidelines together based on the literature and opinion that are then available for treating physicians.”
Overall, the NCCN Guidelines provide guidance for practitioners treating ovarian cancer of all stages, including both primary and recurrent disease. “For physicians looking at the guidelines, if you need greater clinical support, I would go back to the randomized clinical trials that support the treatment modality that you are prescribing for your patient,” Dr Ahmed concluded.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
- Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2017, based on November 2019 SEER data submission, posted to the SEER website, April 2020. Bethesda, MD: National Cancer Institute. https://seer.cancer.gov/csr/1975_2017.
- Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol. 2018;81(1):17-38.
- du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009;115(6):1234-1244.
- European Society of Gynaecological Oncology. Advanced (stage III-IV) ovarian cancer surgery. Quality indicators. Complete report. Accessed July 31, 2020. www.esgo.org/media/2016/10/Advanced-stage-III-IV-ovarian-cancer-surgery-Quality-indicators-Complete-report-1.pdf.
- Basta A, Bidziński M, Bieńkiewicz A, et al. Recommendation of the Polish Society of Oncological Gynaecology on the diagnosis and treatment of epithelial ovarian cancer. Oncol Clin Pract. 2015;11(5):233-243.
- FDA approves Genentech’s Avastin® (Bevacizumab) plus chemotherapy as a treatment for women with advanced ovarian cancer following initial surgery. News release. Genentech. June 13, 2018. Accessed July 8, 2020. http://ovarian.org/about-ovarian-cancer/treatment/493-2018-06-13-21-09-18.
- Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019;37(26):2317-2328.
- Clamp AR, James EC, McNeish IA, et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. Lancet. 2019;394(10214):2084-2095.
- Lopez-Guerrero JA, Romero I, Poveda A. Trabectedin therapy as an emerging treatment strategy for recurrent platinum-sensitive ovarian cancer. Chin J Cancer. 2015;34(1):41-49.
- Monk BJ, Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer. 2012;48(15):2361-2368.
- Aravantinos G, Pectasides D. Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review. J Ovarian Res. 2014;7:57. doi: 10.1186/1757-2215-7-57.
- Marchetti C, De Felice F, Palaia I, et al. Efficacy and toxicity of bevacizumab in recurrent ovarian disease: an update meta-analysis on phase III trials. Oncotarget. 2016;7(11):13221-13227.
- Yi S, Zeng LO, Kuang Y, et al. Anti-angiogenic drugs used with chemotherapy for patients with recurrent ovarian cancer: a meta-analysis. Onco Targets Ther. 2017;10:973-984.
- Rouzier R, Gouy S, Selle F, et al. Efficacy and safety of bevacizumab-containing neoadjuvant therapy followed by interval debulking surgery in advanced ovarian cancer: results from the ANTHALYA trial. Eur J Cancer. 2017;70:133-142.
- Chan JK, Herzog TJ, Hu LL, et al. Bevacizumab in treatment of high-risk ovarian cancer: a cost-effectiveness analysis. Oncologist. 2014;19(5):523-527.
- Duong M, Wright E, Yin L, et al. The cost-effectiveness of bevacizumab for the treatment of advanced ovarian cancer in Canada. Curr Oncol. 2016;23(5):E461-E467.
- Hinde S, Epstein D, Cook A, et al. The cost-effectiveness of bevacizumab in advanced ovarian cancer using evidence from the ICON7 trial. Value Health. 2016;19(4):431-439.
- Raja FA, Griffin CL, Qian W, et al. Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer. Br J Cancer. 2011;105(7):884-889.
- Ledermann JA, Embleton AC, Raja F, et al. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;387(10023):1066-1074.
- Pignata S, Lorusso D, Scambia G, et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial. Lancet Oncol. 2015;16(5):561-568.
- du Bois A, Floquet A, Kim JW, et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol. 2014;32(30):3374-3382.
- Floquet A, Vergote I, Colombo N, et al. Progression-free survival by local investigator versus independent central review: comparative analysis of the AGO-OVAR16 Trial. Gynecol Oncol. 2015;136(1):37-42.
- Du Bois A, Kristensen G, Ray-Coquard I, et al. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2016;17(1):78-89.
- FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. News release. US Food and Drug Administration. May 8, 2020. Accessed May 23, 2020. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-plus-bevacizumab-maintenance-treatment-ovarian-fallopian-tube-or-primary.
- Balasubramaniam S, Beaver JA, Horton S, et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer. Clin Cancer Res. 2017;23(23):7165-7170.
- Swisher EM, Lin KK, Oza AM, 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):75-87.
- Scott LJ. Niraparib: first global approval. Drugs. 2017;77(9):1029-1034.
- Suh DH, Lee KH, Kim K, Kang S, Kim JW. Major clinical research advances in gynecologic cancer in 2014. J Gynecol Oncol. 2015;26(2):156-167.
- Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852-861.
- Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512-2519.
- Pujade-Lauraine E, Ledermann JA, Selle F, 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):1274-1284.
- FDA approves olaparib tablets for maintenance treatment of ovarian cancer. News release. US Food and Drug Administration. August 17, 2017. Accessed August 4, 2020. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-tablets-maintenance-treatment-ovarian-cancer.
- Friedlander M, Shannon C, Goh J, Scott C, Mileshkin L. Practical considerations for clinicians for transitioning patients on maintenance therapy with olaparib capsules to the tablet formation of olaparib. Asia Pac J Clin Oncol. 2018;14(6):459-464.
- González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
- FDA approves niraparib for first-line maintenance of advanced ovarian cancer. News release. US Food and Drug Administration. April 29, 2020. Accessed April 30, 2020. www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer.
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer V.1.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed [April 23, 2020]. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
- Konstantinopoulos PA, Norquist B, Lacchetti C, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(11):1222-1245.
- Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(28):3460-3473.
- Griffiths RW, Zee YK, Evans S, et al. Outcomes after multiple lines of chemotherapy for platinum-resistant epithelial cancers of the ovary, peritoneum, and fallopian tube. Int J Gynecol Cancer. 2011;21(1):58-65.