Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

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  • 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • 2 Vanderbilt-Ingram Cancer Center;
  • 3 Mayo Clinic Cancer Center;
  • 4 University of Wisconsin Carbone Cancer Center;
  • 5 University of Colorado Cancer Center;
  • 6 Duke Cancer Institute;
  • 7 UCSF Helen Diller Family Comprehensive Cancer Center;
  • 8 City of Hope National Medical Center;
  • 9 Patient Advocate;
  • 10 Massachusetts General Hospital Cancer Center;
  • 11 The University of Texas MD Anderson Cancer Center;
  • 12 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • 13 Memorial Sloan Kettering Cancer Center;
  • 14 Moffitt Cancer Center;
  • 15 Fox Chase Cancer Center;
  • 16 Stanford Cancer Institute;
  • 17 UCLA Jonsson Comprehensive Cancer Center;
  • 18 O'Neal Comprehensive Cancer Center at UAB;
  • 19 Dana-Farber/Brigham and Women’s Cancer Center;
  • 20 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • 21 Abramson Cancer Center at the University of Pennsylvania;
  • 22 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • 23 UC San Diego Moores Cancer Center;
  • 24 University of Michigan Rogel Cancer Center;
  • 25 UT Southwestern Simmons Comprehensive Cancer Center;
  • 26 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • 27 Yale Cancer Center/Smilow Cancer Hospital;
  • 28 Fred & Pamela Buffett Cancer Center;
  • 29 Huntsman Cancer Institute at the University of Utah;
  • 30 Roswell Park Comprehensive Cancer Center; and
  • 31 National Comprehensive Cancer Network

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Overview

Primary treatment of presumed ovarian, fallopian tube, or primary peritoneal cancer usually consists of appropriate surgical staging and debulking surgery, followed in most (but not all) patients by systemic chemotherapy (OV-1, OV-4, above and 193).15However, for some patients with early-stage disease, surgery alone (followed by observation) may be sufficient as primary treatment. In addition, for certain histologic subtypes, adjuvant therapy with hormonal agents are options that may be considered. Neoadjuvant chemotherapy (NACT) with interval debulking surgery (IDS) should be considered in patients with advanced-stage ovarian cancer who are not good candidates for upfront primary debulking surgery (PDS) due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced.6,7 Emerging data supports an increasing role of PARP inhibitors in the management of ovarian cancer.8 In the primary treatment setting, PARP inhibitors have been incorporated as NCCN recommended maintenance therapy options for select patients after first-line chemotherapy (see OV-5, page 194). Each of these primary treatment options, including maintenance therapy options after first-line chemotherapy, are described in more detail subsequently. For all patients with suspected or confirmed ovarian cancer, a gynecologic oncologist should be involved in assessing whether a patient is a suitable surgical candidate and/or an appropriate candidate for NACT and consideration of laparoscopic evaluation to determine feasibility of debulking surgery. The NCCN Guidelines recommend symptom management and best supportive care for all patients; women should be referred for palliative care assessment if appropriate (see the NCCN Guidelines for Palliative Care, available at NCCN.org).911 This text is written to reflect the recommendations in v1.2020; revisions for the 1.2021 version are underway. For the most recent and complete NCCN Guidelines for Ovarian Cancer, visit NCCN.org.

Primary Surgery

Based on published improved outcomes, it is recommended that a gynecologic oncologist be the provider to determine the best surgical approach and perform the appropriate primary surgery.1214 An open laparotomy is recommended for most patients, but minimally invasive techniques may be appropriate in certain circumstances (see “Open Laparotomy Versus Minimally Invasive Techniques” on page 194). Prior to surgery, patients with advanced disease should be counseled about port placement if intraperitoneal (IP) chemotherapy is being considered. Intraoperative pathologic evaluation with frozen sections may assist in management by providing confirmation of diagnosis and cancer type and providing information about the extent of disease. For all procedures, the surgeon should describe the following in the operative report: (1) the extent of initial disease in the pelvis, mid abdomen, and upper abdomen before debulking; (2) whether a complete or incomplete resection was achieved, and (3) if resection was incomplete, the amount and size of residual disease in the aforementioned areas after debulking.15

For most patients presenting with suspected malignant ovarian, fallopian tube, or primary peritoneal neoplasm, initial surgery should include a hysterectomy (if uterus present) and bilateral salpingo-oophorectomy (BSO) with comprehensive staging and debulking as indicated.5,16,17 This is the recommended approach for stage IA–IV if optimal cytoreduction appears feasible, the patient is a surgical candidate, and fertility is not a concern. It is described in greater detail in “Debulking Surgery for Newly-Diagnosed Disease” (page 195).

For patients with early stage disease who wish to preserve fertility, less-extensive surgery may be an option, as described in “Fertility Sparing Options for Stage I Disease” (page 195).

NACT with IDS should be considered for patients with advanced-stage ovarian cancer who are not good candidates for PDS due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally cytoreduced.6,7 The anticipated benefit from NACT is to allow for medical improvement of the patient and/or clinical response that would increase the likelihood of optimal cytoreduction at IDS. Patients treated with NACT and IDS should also receive postoperative adjuvant chemotherapy. See sections entitled “Neoadjuvant Chemotherapy” and “Interval Debulking Surgery,” in the full NCCN Guidelines for Ovarian Cancer (available online at NCCN.org). As described in “Laparoscopic Evaluation Prior to Resection” (page 195), for certain patients with bulky disease, a minimally invasive procedure may be appropriate for obtaining biopsy material to confirm diagnosis and/or for molecular testing, and for determining whether optimal cytoreduction is possible.

Open Laparotomy Versus Minimally Invasive Techniques

In most cases in which surgery is recommended as part of primary treatment of suspected malignant ovarian, fallopian tube, or primary peritoneal neoplasm, it should be performed by open laparotomy including a vertical midline abdominal incision. The surgical guidelines emphasize that an open laparotomy should be used for most patients undergoing surgical staging, primary debulking, interval debulking, or secondary cytoreduction.

Improvement of minimally invasive methods and selection of appropriate patients are the topics of much study and debate.1848 Minimally invasive techniques are commonly used for early-stage disease (or presumed early-stage disease), and some studies have shown no difference in surgical outcomes, recurrence rates, or survival for those who received minimally invasive versus open surgical staging.19,2123,2628,32,3942,4953 If signs of lymph node metastasis or localized carcinomatosis are found, lymphadenectomy and complete pelvic peritonectomy may be feasible using minimally invasive techniques.36 The NCCN Guidelines indicate that in early-stage disease, minimally invasive techniques to achieve the surgical goals may be considered in selected patients if performed by an experienced gynecologic oncologist.16,29,5456

Studies in patients undergoing PDS for advanced disease have shown that debulking and surgical staging is technically feasible using minimally invasive techniques, and hysterectomy and unilateral salpingo-oophorectomy (USO) or BSO can be achieved using a minimally invasive approach.25,30 Several studies have reported results for patients who received IDS via minimally invasive techniques, following NACT.31,34,35,37,47 These studies have shown that for patients undergoing IDS, minimally invasive approaches are safe, technically feasible, and can achieve optimal cytoreduction, cancer-specific survival may be worse (than with laparotomy) if patients are not carefully selected, and patients with extensive disease will likely need to be converted to open lapartomy.31,34,35,37,47 The NCCN Guidelines recommend that in select patients (who have undergone NACT), minimally invasive procedures may be used for IDS, provided that optimal debulking can be achieved. If the patient cannot be optimally debulked using minimally invasive techniques, either in the PDS or IDS setting, then they should be converted to an open procedure.

Laparoscopic Evaluation Prior To Resection

In select patients with advanced-stage disease, minimally invasive procedures (assessment laparoscopy) may be used to assess whether optimal cytoreduction is likely to be achieved by PDS, to determine whether NACT may be a better initial treatment option.5768 A randomized trial assessed whether laparoscopy would be useful to predict the ability achieve optimal cytoreduction (<1 cm residual disease). Optimal cytoreduction was achieved in 90% (92/102) of patients randomized to the assessment laparoscopy arm compared with 61% (60/99) patients who were randomized to the laparotomy without assessment laparoscopy arm (relative risk, 0.25; 95% CI, 0.13– 0.47; P<.001).63 Assessment laparoscopy to evaluate extent of disease and feasibility of resection was used frequently in the large prospective trials validating NACT and IDS and was required in one of these trials (SCORPION).6872

Fertility Sparing Options for Stage I Disease

Fertility preservation is an evolving field and area of active research, with many approaches being explored, and many patient- and case-specific factors to consider, especially for those with malignancies.7375 Patients who wish to retain fertility options should be referred to a reproductive endocrinologist for preoperative evaluation and consultation. Large retrospective studies and meta-analyses have found that for stage I epithelial ovarian cancer, fertility-sparing surgery did not appear to compromise disease-free survival (DFS) or overall survival (OS) compared with radical surgery.7685 Although clear cell histology is associated with increased risk of poor outcomes,83 some studies have shown that even among patients with stage I clear cell, fertility-sparing surgery does not increase risk of relapse or shorten survival compared with radical surgery.77,78,81,82,85 Large retrospective studies among patients with stage I borderline ovarian tumors have found that recurrence rate and survival is similar for those treated with fertility sparing versus radical surgery.8689 In retrospective studies, including multivariate analyses, fertility sparing surgery does not appear to be associated with poorer outcomes (DFS, PFS, OS) compared with more extensive surgery in patients with stage I germ cell tumors and sex-cord stromal tumors.90105 Fertility-sparing surgery may be considered for patients who wish to preserve fertility and have apparent early-stage disease and/or low-risk tumors, such as early-stage invasive epithelial tumors, LMP lesions, malignant germ cell tumors, or malignant sex cord stromal tumors. Even if the contralateral ovary cannot be spared, uterine preservation can be considered as it allows for potential future assisted reproductive approaches. A USO (preserving the uterus and contralateral ovary/fallopian tube) and comprehensive surgical staging may be adequate for select patients who wish to preserve fertility and appear to have stage IA unilateral tumors.106111 For those with bilateral stage IB tumors who wish to maintain fertility, a BSO (preserving the uterus) and comprehensive surgical staging can be considered. In patients undergoing USO or BSO, comprehensive surgical staging should still be performed in most patients to rule out occult higher-stage disease, because data show that approximately 30% of patients (with presumed early-stage disease) are upstaged after undergoing complete staging surgery.23,27,28,112116 Comprehensive surgical staging may be omitted in pediatric/adolescent patients with clinically apparent early-stage malignant germ cell tumors based on the pediatric surgical literature suggesting that incomplete staging does not result in poorer outcomes (OS).117 For adults with apparent stage I malignant ovarian germ cell tumors, comprehensive staging is recommended based on results from retrospective studies suggesting that incomplete surgical staging may be associated with increased risk of recurrence118,119; although others found no relationship between incomplete staging and DFS.120

Debulking Surgery for Newly-Diagnosed Disease

Debulking surgery is widely accepted as an important component of initial treatment of patients with clinical stage II, III, or IV disease, and multiple retrospective studies have contributed to the understanding of the extent of debulking needed to achieve maximal cytoreduction.3,4,14,108,112,121123 Optimal cytoreduction is defined as residual disease less than 1 cm in maximum diameter or thickness17,108,124126; however, maximal effort should be made to remove all gross disease since resection to R0 offers superior survival outcomes.121,127 Although debulking surgery is the standard of care, this recommendation is based on retrospective data (and thus is not a category 1 recommendation).126 In general, the procedures described in this section should be part of the surgical management of patients with ovarian, fallopian tube, or primary peritoneal cancer in an effort to fully stage patients and to achieve maximal debulking preferable to resection of all visible disease in appropriate circumstances and at least to less than 1-cm residual disease if complete cytoreduction is not feasible.128130 These procedures also apply to many of the LCOC.

For patients with newly-diagnosed epithelial ovarian cancer apparently confined to an ovary or to the pelvis, the goal of surgery is to achieve complete cytoreduction of all pelvic disease and to evaluate for occult disease in the upper abdomen or retroperitoneum. For patients with newly diagnosed invasive epithelial ovarian cancer involving the pelvis and upper abdomen, the goal is to achieve optimal cytoreduction of all abdominal, pelvic, and retroperitoneal disease.

On entering the abdomen, aspiration of ascites or peritoneal lavage should be performed for peritoneal cytologic examinations. For obvious disease beyond the ovaries, cytologic assessment of ascites and/or lavage specimens will not alter stage or management. For patients with disease apparently confined to an ovary or to the pelvis, all peritoneal surfaces should be visualized, and any peritoneal surface or adhesion suspicious for harboring metastasis should be selectively excised or biopsied. In the absence of any suspicious areas, random peritoneal biopsies should be taken from the pelvis, paracolic gutters, and undersurfaces of the diaphragm.

Hysterectomy and BSO should be performed. Although hysterectomy is recommended for most patients, USO or BSO with uterine preservation may be considered for selected patients with apparent stage IA/IB disease desiring to preserve fertility (see “Fertility Sparing Options for Stage I Disease,” page 195). Every effort should be made to keep an encapsulated ovarian mass intact during removal.26,131 For young patients who will abruptly enter menopause after surgery, various supportive care measures may be used to help decrease hot flashes and other symptoms, and potentially reduce the risk of other systemic comorbidities that are more likely with surgical menopause.132135 Hormone replacement therapy has not been shown to worsen survival in premenopausal patients with gynecologic cancers, but limited perspective data exist.136,137

For patients with disease apparently confined to an ovary or to the pelvis (presumed stage I/II), omentectomy should be performed to rule out higher-stage disease. For patients with disease involving the pelvis and upper abdomen (stage III/IV), all involved omentum should be removed.

The use of systematic lymphadenectomy is an area of controversy. For patients with presumed early stage, a randomized trial showed that systematic aortic and pelvic lymphadenectomy improved detection of metastatic nodes compared with node sampling (positive nodes found in 9% vs 22%; P=.007), but was not associated with improved PFS or OS.138 Operating time and the proportion of patients requiring blood transfusions was significantly higher for those who underwent systematic lymphadenectomy.138 However, meta-analyses that included retrospective or observational studies have reported that systematic lymphadenectomy improves OS in patients with early stage disease, even though it does not improve PFS.139,140 Similar to this randomized controlled trial, other prospective studies using systematic lymphadenectomy have found 3%–14% of patients had positive lymph nodes.141145

For patients with advanced ovarian cancer, some early prospective studies suggested that systematic lymphadenectomy improved survival.146,147 An early international randomized trial in patients with stage IIIB–IV (optimally debulked) epithelial ovarian cancer found that systematic lymphadenectomy improved PFS compared with resection of bulky nodes only, although OS was not improved, operating times were longer, and more patients required blood transfusions.148 A randomized study of patients with stage IA–IV disease undergoing second look surgery found that although systematic lymphadenectomy increased detection of nodal metastases compared with resection of bulky nodes only (positive nodes found in 24% vs 13%; P=.02), this did not translate into improved PFS or OS in the whole population or in subpopulations based on stage or extent resection.149 As in other studies, systematic lymphadenectomy was associated with longer operating times, more blood loss and transfusions, and longer hospital stays.149 More recently, a large randomized trial (LION, NCT00712218) found that in patients with stage IIB–IV ovarian cancer who had macroscopically complete resection and normal nodes both before and during surgery, lymphadenectomy did not improve PFS or OS, and was associated with increased rates of serious postoperative complications and mortality within 60 days after surgery.150 However, meta-analyses that included data from retrospective and observational studies have found that systematic lymphadenectomy improves OS in patients with advanced disease, even though PFS is not improved.139,140,151153

Pelvic and para-aortic lymph node dissection is recommended for patients with disease confined to affected ovaries or to the pelvis, and for those with more extensive disease who have tumor nodules outside the pelvis that are 2 cm or less (presumed stage IIIB). Para-aortic lymph node dissection should be performed by stripping the nodal tissue from the vena cava and the aorta bilaterally to at least the level of the inferior mesenteric artery and preferably to the level of the renal vessels. The preferred method of dissecting pelvic lymph nodes is removal of lymph nodes overlying and anterolateral to the common iliac vessel, overlying and medial to the external iliac vessel, overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve.154

For those with more extensive disease outside of the pelvis (nodules >2 cm), suspicious and/or enlarged nodes should be resected, if possible.148,155 Systematic lymph node dissection and resection of clinically negative nodes is not required for these patients because results will not change staging and the procedure does not appear to impact OS, based on results from randomized trials (described previously).148150

Some surgeons classify debulking based on the number of procedures. Procedures that may be considered for optimal surgical cytoreduction (in all stages) include: bowel resection and/or appendectomy, stripping of the diaphragm or other peritoneal surfaces, splenectomy, partial cystectomy and/or ureteroneocystostomy, partial hepatectomy, partial gastrectomy, cholecystectomy, and/or distal pancreatectomy.122,127,156

Extensive resection of upper abdominal metastases is recommended as part of debulking for patients who can tolerate this surgery, as it is associated with improved PFS and OS.122,127

Select patients with low-volume residual disease after surgical cytoreduction for stage II or III invasive epithelial ovarian or peritoneal cancer are potential candidates for IP therapy.157,158 In these patients, consideration should be given to placement of an IP catheter with initial surgery.16

Ancillary Palliative Surgical Procedures

Patients presenting with symptoms may benefit from ancillary palliative procedures performed during primary or secondary cytoreductive surgery. Decisions on the use of ancillary procedures should be made in conjunction with a gynecologic oncology surgeon or a practitioner familiar with ovarian cancer patterns of recurrence. Palliative surgical procedures that may be appropriate in select patients include paracentesis or insertion of an indwelling peritoneal catheter, thoracentesis, pleurodesis, video-assisted thorascopy, or insertion of a pleural catheter, nephrostomy or use of ureteral stents, gastrostomy tube, intestinal stents, or surgical relief of intestinal obstruction.

Analysis of Surgical Specimens

As described in the section entitled “Diagnosis, Pathology and Staging” (in these NCCN Guidelines on NCCN.org), surgical specimens should undergo pathology assessment to determine/confirm diagnosis, determine histologic subtype, and stage. Molecular testing is also appropriate for most patients; see the “Molecular Testing” section (available on NCCN.org) for detailed recommendations.

Management After Primary Surgery

In the NCCN Guidelines for Ovarian Cancer, adjuvant therapy is defined as drugs or other forms of supplemental treatment after cancer surgery intended to decrease the risk of disease recurrence or to primarily treat residual disease, whether gross or microscopic, after surgical cytoreduction. Most patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer should receive adjuvant systemic chemotherapy after primary surgery (see OV-4, page 193). Postoperative observation is an option for select patients with stage I disease, depending on cancer histologic type and substage, as shown in Table 1. Observation is considered an option in these select groups of patients with stage I disease either because survival is ˃90% with surgical treatment alone or because for low-risk disease in certain cancer types it has not been demonstrated that adjuvant chemotherapy provides clear clinical benefit compared with observation alone for those who have had complete surgical staging.159165 Furthermore, postoperative observation should generally only be considered for patients who have had resection of all disease and complete surgical staging to rule out the possibility of clinically occult disease that would result in upstaging. For some of the less common epithelial cancer types (mucinous, grade 1 endometrioid, low-grade serous), the benefit of adjuvant systemic therapy has not been demonstrated and observation is an option (Table 1). If analysis of a biopsy or surgical specimen shows a nonepithelial cancer type, such as sex cord stromal or germ cell tumors, a patient should be treated according to separate pathways specific for nonepithelial cancers (See LCOC-10 through LCOC-13 and corresponding Discussion text, in these guidelines, at NCCN.org).

Table 1.

NCCN Recommended Management Options Following Up-Front Primary Surgery for Stage I Disease, Epithelial Cancer Types

Table 1.

A large variety of regimens and approaches have been tested in prospective randomized trials as postoperative therapy for patients with newly-diagnosed ovarian cancer. Most of these regimens have included intravenous chemotherapy, but IP administration of chemotherapy has also been tested, as have targeted agents and drugs from other classes. Recent trials have shown that maintenance therapy after postoperative platinum-based chemotherapy can have a positive impact on PFS in patients with advanced disease, so integration of maintenance therapy as part of postoperative management is increasing in prevalence and importance.166169 Selection of immediate postoperative treatment should be informed by eligibility criteria for maintenance therapy. This is discussed in greater detail in “Options After First-Line Chemotherapy” (page 209).

Based on results of phase III randomized trials, the NCCN Guidelines include several options for postoperative treatment (within 6 weeks) in patients with advanced epithelial cancers: platinum-based intravenous chemotherapy, platinum-based IV/IP chemotherapy, and platinum-based IP chemotherapy plus bevacizumab, as outlined in Table 2. Specific options and supporting data for each of these categories of treatment are described in greater detail in the sections below. For stage I disease, data are more limited, and while the NCCN Guidelines include some platinum-based intravenous chemotherapy options, IP/intravenous chemotherapy and use of bevacizumab are not recommended approaches for stage I disease (Table 1). Specific options for stage I disease are also discussed below in “Options for Stage I, Epithelial Cancer Types,” (page 202). For certain rarer cancer types, there are additional recommended adjuvant treatment options, including additional chemotherapy options, chemotherapy/bevacizumab regimens (stage II–IV only), and hormonal therapies (Tables 1 and 2). More information on these options can be found in subsequent sections for specific LCOCs.

Table 2.

NCCN Recommended Management Options Following Up-Front Primary Surgery for Stage II–IVa

Table 2.

For all patients, the goals of postoperative therapy and considerations for selection and management during therapy should be discussed prior to the initiation of therapy. As for all aspects of their diagnosis and treatment of ovarian, fallopian tube, or peritoneal cancer, patients should be encouraged to participate in clinical trials. Chemosensitivity/resistance and/or other biomarker assays have been proposed for informing decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available, but the current level of evidence is not sufficient to supplant standard-of-care chemotherapy (category 3). Prior to recommending chemotherapy, requirements for adequate organ function and performance status should be met.

During drug-based therapy, patients should be observed closely and treated for any complications. Appropriate blood chemistry tests should be monitored. Appropriate dose reductions and modifications of chemotherapy should be performed depending on toxicities experienced and goals of therapy. Consider scalp cooling to reduce incidence of alopecia for patients receiving chemotherapy with high rates of alopecia.170

Options for Intravenous Chemotherapy

Comparison of intravenous chemotherapy regimens for postoperative treatment of newly-diagnosed ovarian cancer has been the subject of many prospective randomized trials. Most of these trials have failed to show significant differences between regimens in efficacy outcomes (eg, PFS, OS), but many have shown differences in toxicity profile, ability to complete the planned therapy, and quality of life (QOL). For this reason, the NCCN Guidelines includes a number of recommended options for postoperative intravenous chemotherapy in patients with newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer. The NCCN recommended options for platinum-based intravenous chemotherapy to treat stage II–IV epithelial disease are summarized in Table 3, along with the list of trials that tested these regimens (last column).171179 Supplemental eTable 1 and eTable 2 (available at JNCCN.org) and Table 4 summarize the results of randomized trials that tested these recommended regimens.171175,177196 The most commonly-used regimen, paclitaxel 175/carboplatin, has been considered the standard postoperative chemotherapy for ovarian cancer for many years, so there are many studies in which it has been tested (eTable 1, eTable 2, and Table 4). The history supporting these options is summarized subsequently.

Table 3.

IV Chemotherapy: NCCN Recommended Options for Stage II–IV, All Epithelial Cancer Typesa,b

Table 3.
Table 4.

IV Chemotherapy: Randomized Trials Comparing Paclitaxel 175/Carboplatina With Other Recommended Regimens

Table 4.

Results from multiple early trials suggested that regimens that included a platinum agent resulted in better response rates and PFS (compared with other chemotherapy options).197,198 Subsequent trials aimed at determining which platinum-based combinations are the most effective and safe.

Selecting a Platinum Agent

Multiple randomized trials compared carboplatin versus cisplatin, either alone or in combination with other agents (examples in eTable 1, eTable 2).181184,199204 All these trials showed equivalent efficacy, but differences in toxicity profiles and QOL. Cisplatin was associated with higher rates of neurotoxicity, gastrointestinal toxicities (nausea, emesis), renal toxicity, metabolic toxicities, anemia, and alopecia, while carboplatin was associated with higher rates of thrombocytopenia and granulocytopenia.181184,199204 The AGO-OVAR-3 study found that QOL was significantly better with carboplatin/paclitaxel versus cisplatin/paclitaxel, both in global QOL metrics and on various subscales.183,184 Several randomized studies tested alternating carboplatin and cisplatin every other course, but found that efficacy was similar and toxicity somewhat worse than using carboplatin for every course.188,204 Based on results from all these studies carboplatin is the recommended platinum agent for postoperative intravenous chemotherapy in patients with newly-diagnosed ovarian, fallopian tube, and primary peritoneal cancers.

Selecting A Non-Platinum Agent (for Use in Combination With a Platinum Agent)

Many different chemotherapy agents have been tested in combination with platinum agents as options for intravenous chemotherapy in newly-diagnosed ovarian cancer. Large randomized trials have compared various platinum-based doublet, triplet, and quadruplet combinations with cyclophosphamide, paclitaxel, docetaxel, topotecan, doxorubicin, epirubicin, gemcitabine, topotecan, and melphalan.178,179,187,189191,193196,205211 Trials that compared platinum-based doublets with cyclophosphamide versus paclitaxel showed that paclitaxel was associated with significantly better response rate, PFS, and OS.205207 Thus, paclitaxel is preferred over cyclophosphamide for platinum-based combination therapy in the first-line setting. Based on results from randomized trials showing improved safety and QOL with carboplatin/paclitaxel versus cisplatin/paclitaxel (eTable 1),181184 carboplatin/paclitaxel became the “standard” combination therapy option for postoperative first-line intravenous chemotherapy in patients with ovarian, fallopian tube, or primary peritoneal cancer. Most subsequent trials used this doublet, usually paclitaxel 175 mg/m2 plus carboplatin AUC 5-6, given on day 1 of a 21-day cycle, as the control arm (see examples in eTable 1, eTable 2, and Table 4). This regimen is also a recommended option in the NCCN Guidelines (Table 3).

Two other platinum-based doublets have shown similar efficacy to carboplatin/paclitaxel, but with different safety profiles.178,179 The SCOTROC1 study found that docetaxel/carboplatin resulted in similar PFS, OS, and global QOL scores as paclitaxel/carboplatin, and was associated with lower rates of neurotoxicity, arthralgia, myalgia, alopecia, and abdominal pain, but higher rates of other adverse events (AEs; gastrointestinal, peripheral edema, allergic reactions, and nail changes; Table 4).179 The MITO-2 trial found that pegylated liposomal doxorubicin [PLD]/carboplatin was associated with a higher response rate but similar PFS and OS as paclitaxel/carboplatin (Table 4).178 PLD/carboplatin was associated with higher rates of certain hematologic toxicities, skin toxicity, and stomatitis, but lower rates of neurotoxicity and alopecia than the paclitaxel/carboplatin control.178 Global QOL and most functional domains and symptom scales were the same across treatment arms, PLD/carboplatin was associated with worse scores for certain patient-reported toxicities.178 Therefore, this regimen may be useful in select patients at high risk for neurotoxicity or those who would like to avoid alopecia. The docetaxel/carboplatin and liposomal doxorubicin/carboplatin regimens are both recommended options in the NCCN Guidelines (Table 3), and may be considered for patients who are at high risk for neuropathy (eg, patients with diabetes).212

Randomized trials testing platinum-based triplet or quadruplet regimens have generally found that these do not improve efficacy but are associated with worse toxicity when compared with platinum-based doublets187,189191,193196 or single-agent platinum regimens.208,209 Examples of platinum-based triplet and quadruplet regimens that have been compared with the standard paclitaxel/carboplatin regimen are in eTable 2. One study showed that adding gemcitabine to carboplatin/paclitaxel actually resulted in worse PFS compared with carboplatin/paclitaxel alone (eTable 2).194

Carboplatin/Paclitaxel Dosing Options

As noted above, for postoperative first-line treatment of ovarian cancer, the most commonly used dosing for intravenous carboplatin/paclitaxel combination therapy is Paclitaxel 175 mg/m2 + carboplatin AUC 5-6, both given on day 1 of a 3-week cycle. As summarized in Table 4, multiple randomized studies have compared different dosing schedules for intravenous carboplatin and paclitaxel regimens as first-line postoperative therapy for ovarian cancer.171175,177,213,214 Three different randomized trials (JGOG-3016, GOG-0262, and ICON8) tested “dose-dense” weekly paclitaxel dosing of 80 mg/m2 combined with the standard carboplatin dosing (AUC 6, day 1, every 3 weeks).172,174,175,177 JGOG-3016 results showed that this regimen improved PFS and OS, GOG-0262 showed that this regimen improved PFS (in the subset of patients who were not receiving concurrent bevacizumab), and ICON8 found no significant improvements in PFS or OS (Table 4). All 3 trials reported increased rates of neutropenia and signs of worse QOL among patients treated with the dose dense regimen.

Two randomized trials (MITO-7, ICON8) compared standard paclitaxel/carboplatin dosing with weekly paclitaxel (60 or 80 mg/m2) plus weekly carboplatin (AUC 2), and found no significant differences in efficacy outcomes.171173 MITO-7, which tested 60 mg/m2 paclitaxel, showed higher rates of pulmonary toxicity, but lower rates of neutropenia, febrile neutropenia, thrombocytopenia, neuropathy, hair loss, and vomiting, and significant improvement in QOL.171 ICON8, which tested 80 mg/m2 paclitaxel, showed higher rates of neutropenia and carboplatin hypersensitivity reaction, and worse global QOL compared with standard carboplatin/paclitaxel dosing.172,173 Based on these results, if a weekly regimen is used, the paclitaxel weekly/carboplatin weekly regimen using 60 mg/m2 paclitaxel is the recommended option (for stage II–IV disease; Table 3).

Options for Stage I, Epithelial Cancer Types

Most of the patients had stage III–IV disease in randomized trials testing intravenous chemotherapy as postoperative first-line treatment of ovarian cancer. More recent trials allowed patients with stage II–IV disease, but only some included patients with select stage I disease (eTable 1, eTable 2, and Table 4). Therefore, the list of recommended options is much shorter for patients with stage I disease, as summarized in Table 5, which also shows trials that tested the recommended regimens (last column).171173,178,179,187,194,215,216 Patients with stage I disease were included in randomized trials comparing intravenous paclitaxel/carboplatin (standard dosing) with single-agent carboplatin (ICON3),187 docetaxel/carboplatin (SCOTROC1),179 PLD/carboplatin (MITO-2),178 and weekly paclitaxel/weekly carboplatin (MITO-7, ICON8).171173 Of these, the first three are recommended options for stage I disease in epithelial cancer types. Paclitaxel weekly/carboplatin weekly is more logistically challenging to administer and is therefore not often used in the setting of stage I disease, given the lower risk of recurrence (compared with more advanced disease). Patients with stage I disease have also been included in some randomized trials testing triplet or quadruplet regimens,187,194,209,210 but the added toxicity of these regimens with no clear impact on efficacy makes options inappropriate for stage I.

Table 5.

IV Chemotherapy: Regimens Recommended for Stage I, All Epithelial Cancer Typesa,b

Table 5.

Number of Cycles

Recommendations for the number of cycles of treatment vary with the stage of the disease. Panel members had an extensive discussion about the number of cycles of chemotherapy that should be recommended for patients with advanced-stage disease. There is no evidence confirming that more than 6 cycles of combination chemotherapy are required for initial chemotherapy. Early randomized studies showed that patients treated with 8 or 10 cycles of adjuvant first-line platinum-based intravenous chemotherapy had similar survival but experienced worse toxicity than those treated with only 5 cycles.217,218 For the regimens recommended in the NCCN Guidelines (for postoperative first-line intravenous chemotherapy), most of the supporting phase III randomized trials tested 6 cycles of therapy (see eTable 1, eTable 2, and Table 4). Although cross-trial comparisons should be interpreted with caution, the few trials that used >6 cycles,190,191,195,196 did not appear to show better outcomes than those that used 6 cycles. Also, it has been noted that among the 2 trials showing improved efficacy with first-line cisplatin/paclitaxel versus cisplatin/cyclophosphamide in patients with advanced ovarian cancer, the later trial that allowed continuation beyond 6 cycles, up to 9 cycles reported a smaller treatment effect (on PFS, OS) and had higher rates of neurotoxicity, suggesting that treatment beyond 6 cycles is unlikely to provide additional clinical benefit.205,206 One randomized trial (NCT00102375) showed that adding 4 cycles of topotecan after 6 cycles of carboplatin/paclitaxel did not improve PFS or OS, or even response among those with measurable disease (eTable 2).190 The phase III randomized trial GOG-157 compared 3 versus 6 cycles of paclitaxel/carboplatin as postoperative first-line intravenous chemotherapy for patients with stage I–II epithelial ovarian cancer at high risk, defined as stage IA/IB with grade 3 or clear cell, or stage IC/II with any grade.215,216 For the ITT population, the number of cycles did not have a significant impact on RFS or OS, whereas 6 cycles was associated with higher rates of grade 3-4 neurotoxicity, grade 4 granulocytopenia, and grade 2–4 anemia.215,216 After a median of 91 months of follow-up, exploratory analysis by cancer type showed that 6 cycles (versus 3) was associated with significant improvement in RFS for patients with serous histology (hazard ratio [HR], 0.30 [95% CI, 0.13-0.72]; P=.007), but this effect was not seen for any other cancer subtypes (endometrioid, clear cell, mucinous), and the number of cycles did not significantly impact OS for any subgroup.216 Based on these data the NCCN Guidelines recommend 6 cycles adjuvant intravenous chemotherapy for stage I high-grade serous carcinoma, 3 cycle for other stage I epithelial cancers, and 6 cycles for stage II–IV epithelial disease (regardless of tumor type).

Targeted Agents

Bevacizumab in the First-Line Setting

Two phase 3 randomized trials, GOG-0218 and ICON7, tested the effects of adding bevacizumab during first-line platinum-based combination chemotherapy and as single-agent maintenance therapy after first-line chemotherapy (for patients who had not progressed during initial treatment with chemotherapy + bevacizumab).219221 The study design and results from these trials are summarized in Table 6.219223

Table 6.

Bevacizumab in the First-Line Setting: Phase III Randomized Controlled Trials

Table 6.

Bevacizumab in the First-line Setting: Efficacy

In GOG-0218, although PFS was similar for patients treated with carboplatin/paclitaxel (Arm 1, control) versus those who also had bevacizumab during initial treatment (Arm 2, carboplatin/paclitaxel/bevacizumab), patients treated with carboplatin/paclitaxel/bevacizumab followed by maintenance with single-agent bevacizumab (Arm 3) had a 3-month improvement in median PFS compared with the control arm (See Table 6).219,222 OS was not significantly different across all 3 arms (Table 6), even after long-term follow-up.219,222,223 The effects of treatment on PFS and OS were nonproportional over time, however, with the greatest difference between arms around 15 months, and the Kaplan-Meier curves converging again about 9 months later. Results from ICON7 were similar, with results from the primary analysis (median follow-up 19.4 months) showing longer PFS with carboplatin/paclitaxel/bevacizumab, followed by single-agent bevacizumab maintenance therapy (Arm 2) compared with carboplatin/paclitaxel along (Arm 1).220 Analyses after longer follow-up (median 48.9 months), however, showed no significant treatment-dependent differences in PFS or OS (Table 6).221 Again the effects were nonproportional over time, with the treatment-dependent differences in PFS and OS increasing to a peak between 12–18 months, and the Kaplan-Meier curves subsequently converging.221

For both GOG-0218 and ICON7, outcomes with upfront paclitaxel/carboplatin/bevacizumab plus single-agent bevacizumab maintenance (Arm 3 in GOG-0218, Arm 2 in ICON7) were compared with control (paclitaxel/carboplatin alone, Arm 1) for a variety of patient subgroups to determine whether there are particular groups of patients that benefit from bevacizumab. Results across both studies showed that patients with features associated with poor prognosis tend to derive a greater benefit from the addition of bevacizumab.219 Analyses of data from GOG 0218 showed that bevacizumab improved OS in patients with stage IV disease and in patients with ascites, another high-risk group (more likely to have poor performance score, high-grade serous histology, higher median pretreatment CA-125 level, suboptimal surgical cytoreduction).222224 For ICON7, although after long-term follow up (median 48.9 months) there were no significant effects of bevacizumab on PFS or OS for the total population, subgroup analyses identified a high-risk group for which bevacizumab improved both PFS (median PFS for Arm 1 vs Arm 2: 10.5 vs 16.0 months; HR, 0.73 [95% CI, 0.61-0.88]; P=.001) and OS (median OS for Arm 1 vs Arm 2: 30.2 vs 39.7 months; HR, 0.78 [95% CI, 0.63–0.97]; P=.03).221 This high-risk group included those with either stage IV, inoperable stage III, or suboptimally debulked (residual disease >1 cm) stage III. Exploratory analyses suggest that stage may be more important than the extent of residual disease for identifying patients who may benefit from bevacizumab.225 Although sample sizes were small, analyses found no significant impact of bevacizumab on OS for the following subgroups: clear cell carcinoma, low stage high-grade disease, low grade serous.221

An exploratory analysis of GOG-0218, including 1,195 patients with DNA samples that could be sequenced, showed that the presence of mutations in BRCA1, BRCA2, or nonBRCA homologous recombination repair (HRR) genes was associated with longer PFS and OS relative to patients with no mutations in these genes, even after adjusting for treatment, stage, size of residual disease, and performance status at baseline.226 For patients without mutations in any of these genes, the addition of bevacizumab (to up-front chemotherapy and as maintenance) was associated with improved PFS (median PFS for Arm 1 vs Arm 3: 10.6 vs 15.4 months; HR, 0.71 [95% CI, 0.60–0.85]; P=.0001). This treatment effect on PFS was not observed in the group of patients with mutations in BRCA1/2 or a nonBRCA HRR gene. These findings are consistent with those from other exploratory analyses suggesting that patients with poorer prognosis may derive the most benefit from bevacizumab.226 Nonetheless, mutation status did not significantly modify the effect of bevacizumab on PFS, so these data are insufficient to support using mutation status to identify patients who may benefit from first-line and maintenance bevacizumab.

Bevacizumab Safety and QOL

Based on earlier studies, toxicities that may occur in patients treated with bevacizumab and are of particular concern, may require intervention and often lead to treatment discontinuation include the following: pain (grade ≥2), neutropenia (grade ≥4), febrile neutropenia, thrombocytopenia, bleeding (grade ≥2; various types), hypertension (grade ≥2), thromboembolism (grade ≥3, various types), gastrointestinal events (perforations, abscesses, and fistulas), reversible posterior leukoencephalopathy syndrome, renal injury and proteinuria (grade ≥3), and wound disruption.227 In both GOG-0218 and ICON7, the following types of toxicities were more common in the bevacizumab arm: bleeding, hypertension, proteinuria, thromboembolic events (grade ≥3), gastrointestinal perforation (grade ≥3) and wound healing complications.219,220 For some of these the difference between arms was smaller than expected. Neutropenia occurred with similar rates across arms, and reversible posterior leukoencephalopathy syndrome occurred in GOG-0218 in only the bevacizumab arms.

Data from both GOG-0218 and ICON7 showed that most toxicities developed during the chemotherapy phase of treatment, although there were a few AEs of concern that continued to develop during the bevacizumab maintenance phase, including hypertension, high-grade pain, proteinuria, and thromboembolism.219 Exploratory analyses tried to identify factors that might be associated with increased risk bevacizumab-associated adverse events.228,229 Analysis of GI-related adverse events in GOG-0218 identified inflammatory bowel disease, bowel resection at primary surgery as being associated with increased risk of grade ≥2 perforation, fistula, necrosis, or hemorrhage.228 Another analysis of GOG-0218 reported that patients treated with bevacizumab had higher rates of readmission, and noted that most readmissions occur within the first 40 days after surgery but after the first cycle of chemotherapy was delivered.229 Other factors associated with increased rates of readmission (across treatment arms) include baseline CA-125 level, disease stage, surgery involving bowel resection, residual disease, ascites, high body mass index and poor performance score. Whereas shorter time to start of chemotherapy after surgery was associated with increased rates of readmission,229 time to initiation longer than 25 days was associated with poorer OS (across treatment arms).230

Both GOG-0218 and ICON7 reported some small but statistically significant differences between treatment arms in the global measures of QOL. Analyses of GOG-0218 showed that QOL improved somewhat during the course of the study across all arms (FACT-O TOI scores improved from ∼67-68 to ∼76-68).219,231 Results showed slightly worse QOL for patients treated with bevacizumab during the chemotherapy phase (FACT-O TOI scores ≤3 points lower than for placebo; P<.001), but this difference did not persist in the maintenance phase.219,231 There were no statistically significant differences in QOL scores for patients treated with bevacizumab during chemotherapy only (Arm 2) versus bevacizumab during chemotherapy plus maintenance (Arm 3),231 which further supports the idea that bevacizumab maintenance did not impact QOL. For FACT-O TOI scores, the threshold for clinically meaningful differences has been suggested to be 5–7 points. Results from ICON7 showed that for both arms QOL improved somewhat over the course of the trial, during both the chemotherapy phase and the maintenance phase.220,232 However, these increases were smaller in bevacizumab arm (Arm 2), such that QOL scores were better in the control arm (Arm 1) versus the bevacizumab arm (Arm 2) at the end of chemotherapy (week 18; mean QLQ-C30 score difference of 6.1 points; P<.0001) and at the end of the maintenance phase (week 54; 6.4 points; P<.0001).232 Although differences between the two arms (favoring placebo) were consistently present and statistically significant, it is unclear whether they are clinically meaningful, as the threshold for clinical significance is a matter of debate, and some have argued that it should be 10 points.

NCCN Recommendations

Based on results from GOG-0218 and ICON7, the NCCN Guidelines include bevacizumab-containing regimens as options for first-line chemotherapy following cytoreductive surgery (Table 7).219221,223 The regimens recommended are those used in these trials that consist of upfront carboplatin/paclitaxel/bevacizumab, followed by bevacizumab maintenance (shown in Table 6, footnote h and Table 7). In both of these trials, treatment was discontinued upon disease progression, so the guidelines recommend single-agent bevacizumab maintenance only for those who have not progressed during the 6 cycles of upfront carboplatin/paclitaxel/bevacizumab (OV-5). Given that GOG-0218 found that patients treated with upfront carboplatin/paclitaxel/bevacizumab without single-agent bevacizumab maintenance did not have improved outcomes compare with control (carboplatin/paclitaxel), observation is not a recommended option for patients with response or stable disease following completion of a first-line regimen containing bevacizumab (OV-5, bottom two pathways). Currently there are no data to support introducing bevacizumab as maintenance therapy if bevacizumab was not included in the initial primary regimens used (see OV-5, top pathways).

Table 7.

NCCN Recommended IV Bevacizumab/Chemotherapy Options for Stage II–IV, All Epithelial Cancer Typesa,b

Table 7.

GOG-0218 did not include patients with stage I–II disease, and ICON7 included patients with stage I–IIA disease only if they were considered “high risk” because of poor differentiation (high grade) or clear cell histology (Table 6). Due to these entry criteria and the results of subgroup analysis suggesting that bevacizumab may only be beneficial in patients with more advanced disease, the NCCN Guidelines do not include the bevacizumab-containing regimens (including bevacizumab maintenance) as options for stage I disease, but only recommend them for patients with stage II or higher.

GOG-0218 and ICON7 included patients primarily with ovarian cancer, but also some with primary peritoneal or fallopian tube cancer.219,220 These trials mostly included patients with serous histology, but did include patients with other cancer types (mucinous, clear cell, endometrioid). Therefore, the NCCN recommendations regarding use of bevacizumab as part of first-line chemotherapy and maintenance apply to patients with any of these epithelial cancer types.

Intraperitoneal/Intravenous Regimen

IP chemotherapy has been explored as an option for ovarian cancer based on the idea that localized delivery could improve efficacy, particularly against microscopic spread and peritoneal carcinomatosis, with an acceptable safety profile. Although results from smaller randomized trials (n<120) suggested no clinical benefit (response rate, PFS, OS) with IP/intravenous compared with intravenous regimens,233,234 three larger randomized trials (n>400) in newly diagnosed chemotherapy naïve patients with stage III disease and residual disease ≤1 cm after primary surgery compared intravenous regimens with IP/intravenous regimens using similar agents, and found that IP/intravenous chemotherapy resulted in improved PFS and/or OS, with at least borderline statistical significance (See Table 8).158,235,236 One phase II randomized trial (n=218) in patients with stage IIIC–IV epithelial ovarian cancer with optimal debulking also showed that IP/intravenous administration improved PFS and OS compared with intravenous only.237,238 Results from these trials suggest that IP/intravenous administration significantly increases risk of certain high-grade hematologic toxicities (eg, granulocytopenia, leukopenia, neutropenia, thrombocytopenia), and certain nonhematologic toxicities (eg, gastrointestinal and metabolic toxicities, renal toxicity, abdominal pain, neurologic toxicities, infection, fatigue).158,235237,239 The increased risk of toxicity was considered acceptable given the improvement in OS, which was greater than a year (16 months) in one of the trials (Table 8).158,235,236 Pooled analyses of GOG-114 and GOG-172 data showed that the IP/intravenous regimen was associated with lower risk of relapse in the peritoneal space,240 and long-term follow-up (>10 years) showed significant PFS benefit (P=.01) and OS benefit (P=.042), especially after adjusting for other prognostic factors (P=.003 for PFS, P=.002 for OS).241 This analysis also showed that survival improves with each cycle of IP chemotherapy.241 Although the extent of residual disease was prognostic for outcome, IP/intravenous chemotherapy still provided PFS benefit even among those with some gross residual disease (>0-≤1 cm).241 Based on these results, an IP/intravenous option similar to the regimen used in GOG-172 was added to the NCCN Guidelines (Table 9) for patients with optimally debulked (<1 cm residual) stage III disease.158 Women with optimally debulked stage II disease may also receive IP chemotherapy, as the NCCN Panel has decided that many of the regimens tested in stage III–IV should also be offered to patients with stage II disease. Patients with stage II were allowed in GOG-0252 and another (small) randomized trial, although in both of these studies the IP/intravenous regimens did not significantly improve PFS or OS compared with intravenous regimens.234,242 IP chemotherapy is not recommended for stage I or IV disease.

Table 8.

IP/IV Versus IV Platinum-Based Chemotherapy: Randomized Trials

Table 8.
Table 9.

NCCN Recommended IP/IV Platinum-Based Chemotherapy Option for Optimally Debulkeda Stage II–III, Selected Epithelial Cancer Typesb

Table 9.

In the large randomized trials that showed that IP/intravenous benefit, most of the patients had serous or endometrioid disease, and high-grade tumor histology (Table 8), so it is unclear whether patients with LCOCs will benefit from IP/intravenous chemotherapy. In the NCCN Guidelines, the clear cell carcinoma and carcinosarcoma are the only LCOCs for which IP/intravenous chemotherapy is a recommended option, as these cancer types are associated with higher risk of poor outcomes.243246 Patients with carcinosarcoma were not included in the randomized trials testing IP/intravenous chemotherapy, but 2%–6% of patients had clear cell carcinoma.158,235,236,242 These trials included mostly patients with ovarian cancer, but in GOG-172, 12% of patients had primary peritoneal cancer. In the NCCN Guidelines the recommended IP/intravenous regimen is an option regardless of primary site (ovarian, fallopian, or primary peritoneal). All women should be counseled about the clinical benefit associated with combined IP/intravenous chemotherapy administration before undergoing surgery.

Enthusiasm for IP/intravenous chemotherapy has waned considerably due to the results of GOG-0252, a large randomized trial in patients with stage II/III optimally resected (≤1 cm), or stage III/IV suboptimally resected (>1 cm) disease (Table 8).242 Results showed that for combination therapy with paclitaxel/carboplatin/bevacizumab, IP administration of the carboplatin did not improve PFS or OS compared with intravenous administration (Table 8).242 An intravenous/IP paclitaxel/cisplatin/bevacizumab regimen also did not improve PFS for OS relative to the control intravenous paclitaxel/carboplatin/bevacizumab regimen (Table 8).242 These results suggest that given the PFS benefit of adding bevacizumab (during chemotherapy and maintenance), IP administration does not further improve outcomes.

For the recommended IP chemotherapy regimen (Table 9), the IP paclitaxel was infused over 24 hours in the clinical trial (GOG-172).158 A 3-hour infusion of paclitaxel has not been proven to be equivalent to a 24-hour infusion, although a 3-hour infusion has been reported to be more convenient, easier to tolerate, and less toxic.247 Note that in all the supporting trials and in the NCCN Guidelines, IP regimens include intravenous regimens so that systemic disease can also be treated.

The IP paclitaxel/cisplatin regimen is associated with leukopenia, infection, fatigue, renal toxicity, abdominal discomfort, and neurotoxicity.158,235237,239 In GOG-172, only 42% of women were able to complete all 6 treatment cycles of the IP regimen158; with more experience, this percentage has improved in the major cancer centers.248 It has been suggested that a lower IP cisplatin dose of 75 mg/m2 may help to decrease toxicity.247,248 However, the chemotherapy portion of the intravenous/IP paclitaxel/cisplatin/bevacizumab regimen used in GOG-0252 was very similar to the intravenous/IP paclitaxel/cisplatin regimen used in GOG-172, but with a lower dose of cisplatin (75 mg/m2 vs 100 mg/m2), and did not improve PFS/OS relative to control (Table 8),158,242 so it is unclear whether the intravenous/IP chemotherapy regimen with the lower cisplatin dose provides any benefit compared with intravenous administration.

Prior to the administration of the combined IP and intravenous regimen, patients must be apprised of the increased toxicities with the combined regimen when compared with using intravenous chemotherapy alone (increased myelosuppression, renal toxicities, abdominal pain, neuropathy, gastrointestinal toxicities, metabolic toxicities, and hepatic toxicities). Patients who are candidates for the IP cisplatin and IP/intravenous paclitaxel regimen should have normal renal function before starting, a medically appropriate PS based on the future toxicities of the IP/intravenous regimen, and no previous evidence of medical problems that could significantly worsen during chemotherapy, such as preexisting neuropathy. Reasons for discontinuing the IP regimen included catheter complications, nausea/vomiting/dehydration, and abdominal pain.249 Women unable to complete IP therapy should receive intravenous therapy. Expert nursing care may help to decrease complications.250 Giving intravenous hydration before and after IP chemotherapy is a useful strategy to prevent certain toxicities (nausea, vomiting, electrolyte imbalances, and metabolic toxicities).248 Prior to receiving and after receiving each cycle of IP cisplatin, adequate amounts of intravenous fluids need to be administered to prevent renal toxicity. After each cycle has been completed, patients need to be monitored carefully for myelosuppression, dehydration, electrolyte loss, end-organ toxicities (such as renal and hepatic damage), and all other toxicities. After chemotherapy, patients often require intravenous fluids (5–7 days) in the outpatient setting to prevent or help treat dehydration.

Options After First-Line Chemotherapy

After initial treatment (eg, surgery followed by chemotherapy), patients should undergo regular clinical re-evaluation. Observation with follow-up is recommended for patients who had stage I disease at presentation and have no signs of new disease (OV-4, page 193). Recommendations for surveillance during observation are in the monitoring/follow-up section (OV-6; available at NCCN.org).

For patients who had stage II–IV disease at presentation, options following surgery and chemotherapy depend on the success of these interventions. These patients should be evaluated with imaging as clinically indicated to determine the extent of residual disease or progression and screen for new metastases. Imaging should include chest/abdominal/pelvic CT, MRI, PET/CT or PET (skull base to midthigh).

Patients with persistent disease or progression during initial treatment should be treated with second-line approaches (see “Therapy for Resistant Disease or Recurrence” on OV-7 and “Recurrent Disease,” available at NCCN.org).251,252

For patients with advanced-stage (stages II–IV) disease who, after primary therapy (surgery plus chemotherapy), are in complete clinical remission (ie, complete response [CR], defined as no definitive evidence of disease251,252), partial remission (ie, partial response [PR]), or stable disease, recommended options depend on the extent of their response and the type of primary chemotherapy they received (see OV-5, page 194). These recommendations have been revised several times recently due to emerging data from clinical trials,166169 summarized in Tables 10, 11, and 12. These recent data and their impact on the recommendations are discussed in the subsequent sections.

Table 10.

Phase III RCTs Testing PARP Inhibitors for Maintenance After First-Line Chemotherapy: Efficacy

Table 10.
Table 11.

Phase III RCTs Testing PARP Inhibitors for Maintenance After First-Line Chemotherapy: Patient Characteristicsa

Table 11.
Table 12.

Adverse Events Associated With PARP Inhibitor Maintenance After First-Line Systemic Therapya

Table 12.

Bevacizumab Maintenance Therapy

As described in detail in “Bevacizumab in the First-Line Setting” (page 202), results from the phase III GOG-0218 and ICON7 trials support the use of single-agent bevacizumab maintenance therapy for patients with stage II–IV disease who experience response or stable disease after postoperative chemotherapy with one of the carboplatin/paclitaxel/bevacizumab regimens used in these trials (and recommended by NCCN).219221 Based on these results, bevacizumab monotherapy was a recommended option for maintenance for patients with stage II–IV disease who were in CR/PR after a primary treatment with surgery and one of the bevacizumab-containing regimens recommended in the first-line setting. However, due to results from subsequent trials showing benefit from PARP inhibitors, as described subsequently, bevacizumab monotherapy is no longer recommended for patients with BRCA1/2 mutations, but is still recommended as an option for patients who have wild-type or unknown BRCA1/2 mutation status (in CR/PR after a recommended bevacizumab-containing first-line chemotherapy regimen), as these patients have fewer PARP inhibitor options (see OV-5, page 194).

PARP Inhibitor Maintenance Therapy After Primary Chemotherapy

Several PARP (poly ADP ribose polymerase) inhibitors have been shown to be active in recurrent ovarian cancer,253260 and have been FDA approved for multiple indications in ovarian cancer (summarized in Table 13)261263; the corresponding recommendations can be found in the NCCN Guidelines algorithm for “Post-Primary Treatment: Maintenance Therapy” (OV-5, page 194), “Therapy for Persistent Disease or Recurrence” (OV-7, available at NCCN.org) and “Principles of Systemic Therapy: Acceptable Recurrence Therapies for Epithelial Ovarian (including LCOC)/Fallopian Tube/Primary Peritoneal Cancer” (OV-C 7 and 8 of 10, available at NCCN.org).

Table 13.

FDA-Approved Indications for Bevacizumab and PARP Inhibitors in Ovarian Cancer

Table 13.

More recently, several phase III double-blind, randomized trials have tested PARP inhibitors as maintenance therapy for patients with newly-diagnosed, histologically confirmed, FIGO stage III–IV ovarian, fallopian tube, or primary peritoneal cancer who have completed first-line chemotherapy.166169 Characteristics of the patient populations in these trials are summarized in Table 11, and efficacy and safety results are summarized in Tables 10 and 12.

Olaparib Monotherapy

The SOLO-1 trial demonstrated a remarkable improvement in PFS with single-agent olaparib versus placebo as maintenance therapy for patients with a germline or somatic BRCA1/2 mutation who had a CR or PR after first-line platinum-based chemotherapy (Table 10).166 The risk of progression or death was 70% lower, with the median PFS (from randomization) of 13.8 months for placebo, and the median PFS for olaparib had not been reached after a median follow-up of 41 months; OS data are also immature. A subsequent subgroup analysis showed that the PFS benefit was significant regardless of BRCA mutation type (BRCA1 vs BRCA2).264 Based on results from SOLO-1, the NCCN Guidelines include olaparib monotherapy as a maintenance therapy option for patients who have a BRCA1/2 mutation and have a CR or PR after completion of primary therapy including surgery and platinum-based chemotherapy (Table 14).

Table 14.

NCCN Recommended Options for Maintenance After First-Line Chemotherapya

Table 14.

SOLO-1 excluded patients who received bevacizumab as part of primary systemic therapy, so the efficacy of single-agent olaparib in after chemotherapy/bevacizumab primary therapy is unknown. Nonetheless, the benefit from olaparib was sizeable and significant across many subgroups analyzed.166,264 It is important to note that the effects of maintenance olaparib on PFS (70% improvement; Table 10)166 are far greater than the effects on PFS reported for the addition of bevacizumab to both upfront and maintenance therapy (<30% improvement).219,221,222 PFS curves from SOLO-1 show large separation between olaparib versus placebo throughout the time course of the study (median follow-up, 41 months),166 in contrast to results from GOG-0218 and ICON7 showing PFS curves converging well before 40 months, even for the high-risk groups shown to benefit most from bevacizumab.221,222 In addition, the exploratory analysis of GOG-0218 based on BRCA mutation status suggests that bevacizumab may not improve PFS in patients with BRCA1/2 mutations.226 The PAOLA-1 trial (described in the next section) suggested that maintenance olaparib could provide PFS benefit in patients who had bevacizumab during first-line chemotherapy.167 For these reasons single-agent olaparib is a category 1 option only for patients who did not have bevacizumab as part or primary therapy, but is a category 2A option for patients who received prior bevacizumab, provided that they were in a CR or PR after completion of chemotherapy (Table 14). The NCCN Panel included a footnote to make it clear that data are limited on the use of single-agent olaparib after first-line platinum-based chemotherapy plus bevacizumab, but that evidence from other subgroups suggests that it should be considered as an option for these patients.

Olaparib + Bevacizumab

The phase III double-blind, randomized PAOLA-1 trial demonstrated a remarkable improvement in PFS (HR, 0.59) when olaparib (vs placebo) was added to maintenance bevacizumab in patients who have a CR or PR after first-line platinum-taxane chemotherapy plus bevacizumab for advanced disease (Table 10).167 Unlike SOLO-1, PAOLA-1 included both patients with and without BRCA1/2 mutations. Subgroup analyses showed that similar to the SOLO-1 trial, for patients with BRCA1/2 mutations, maintenance olaparib reduced the risk of progression or death by approximately 70% (Table 10).167 A subsequent subanalysis found that the PFS benefit of adding olaparib to bevacizumab maintenance was similar and significant regardless of BRCA mutation type (BRCA1 vs BRCA2).265 Based on these results, maintenance with bevacizumab + olaparib is a category 1 option for patients who have a CR/PR after completing bevacizumab-containing first-line therapy, and single-agent bevacizumab was removed as a maintenance therapy option in this setting.

PAOLA-1 also showed that adding olaparib to maintenance bevacizumab resulted in a smaller but still significant improvement in PFS for those with BRCA1/2 wild-type or unknown (Table 10).167 Due to the smaller magnitude of this effect, the NCCN Guidelines include olaparib + bevacizumab combination and bevacizumab monotherapy both as a category 2A maintenance therapy options for patients with BRCA1/2 wild-type or unknown mutation status who are in a CR or PR after completion of first-line platinum-based chemotherapy/bevacizumab combination (Table 14).

In PAOLA-1, the population without BRCA1/2 mutations was further subdivided based on results of MyChoice CDx (Myriad Genetic Laboratories), a proprietary tumor tissue assay that uses multiple molecular tests and combines several metrics (loss of heterozygosity [LOH],266 telomeric allelic imbalance,267 and large scale state transitions268 to determine the genomic instability score (GIS), a proxy measure for the presence of homologous recombination deficiency.269,270 GIS cutoff of 42 was used to define homologous recombination deficiency status based on a prior analyses of a population of breast and ovarian cancer cases showing that this cutoff identified 95% of patients who had BRCA1/2 deficiency, defined as either (1) one deleterious mutation in BRCA1 or BRCA2, with LOH in the wild-type copy, (2) two deleterious mutations in the same gene, or (3) promoter methylation of BRCA1 with LOH in the wild-type copy.271 Among those without BRCA1/2 mutations, the PFS benefit of maintenance olaparib was significant for those with homologous recombination deficiency (as defined by the proprietary assay) but was not significant for those who did not have homologous recombination deficiency (Table 10). For this reason, the NCCN Panel included the following footnote relating to the use of maintenance bevacizumab + olaparib: in the absence of a BRCA1/2 mutation, homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor therapy (category 2B). OS results from PAOLA-1 were not mature.

Niraparib Monotherapy

Similar to the SOLO-1 results for olaparib monotherapy, the PRIMA trial demonstrated a remarkable improvement in PFS with single-agent niraparib (versus placebo) as maintenance therapy for patients with a BRCA1/2 mutation who were in a CR/PR after first-line platinum-based chemotherapy (Table 10).168 Based on these results, the NCCN Guidelines include single-agent niraparib as a maintenance therapy option for patients with BRCA1/2 mutations who have completed primary treatment including surgery and platinum-based first-line therapy (Table 14). PRIMA likely did not include many patients who had prior bevacizumab as part of primary systemic therapy, so for patients with a BRCA1/2 mutation maintenance niraparib is a category 1 option for those who had first-line platinum-based chemotherapy without bevacizumab, and a category 2A option for those who had bevacizumab in conjunction with first-line platinum-based chemotherapy (Table 14).

Unlike SOLO-1, the presence of a BRCA1/2 mutation was not part of the entry criteria for the PRIMA trial. PRIMA included patients who did not have deleterious mutations in BRCA1/2, and results showed significant PFS improvement with niraparib (versus placebo) for the overall population. Subgroup analyses showed that the effect of maintenance niraparib on PFS was still significant among patients without a BRCA1/2 mutation (HR, 0.71 [95% CI, 0.58–0.88]), although the size of the effect appears smaller than that seen in patients with BRCA1/2 mutations (Table 10). Based on these results, the NCCN Guidelines include single-agent niraparib as an option for maintenance therapy for patients with BRCA1/2 wild-type or unknown, provided they are in a CR or PR after completion of primary platinum-based chemotherapy (without bevacizumab) (Table 14). Given the smaller magnitude of the PFS effect in patients without BRCA1/2 mutation, and that PRIMA likely included very few patients who had bevacizumab as part of primary therapy, single-agent niraparib is not a recommended maintenance therapy option for those who have BRCA1/2 wild-type or unknown and received bevacizumab as part of primary therapy (Table 14).

As in PAOLA-1, in PRIMA the patient group without BRCA1/2 mutation was further subdivided into homologous recombination deficient and proficient based on a GIS cutoff of 42 using the MyChoice CDx (Myriad Genetic Laboratories).168 Results showed that the PFS effect of niraparib (versus placebo) remained significant for the smaller subgroup of patients with homologous recombination deficiency but no BRCA1/2 mutation, and was significant, with a trend toward smaller magnitude, for the homologous recombination proficient subgroup (Table 10).168 Because of these results, the NCCN Panel chose to include the following footnote relating to the use of maintenance niraparib: in the absence of a BRCA1/2 mutation, homologous recombination deficiency status may provide information on the magnitude of benefit of PARP inhibitor therapy (category 2B).

OS data from the interim analysis was reported (Table 10), but it is premature to draw conclusions from those results.

Veliparib

The phase III VELIA study design was similar to GOG-0218 and ICON7 bevacizumab trials in that it tested the effect of adding veliparib during first-line chemotherapy and as subsequent single-agent maintenance after completion of chemotherapy.169 VELIA did not require that patients have CR/PR before receiving maintenance therapy; they only needed to have absence of progression during first-line systemic therapy (6 cycles) and no limiting toxicities. Results showed that whereas adding veliparib during first-line chemotherapy did not significantly improve PFS compared with chemotherapy alone, those who received veliparib during first-line chemotherapy and maintenance therapy had significantly improved PFS compared with those who received chemotherapy alone (with placebo during first-line systemic therapy and maintenance; Table 10). Subgroup analyses showed that whereas the PFS benefit from veliparib appeared to be the greatest for those with a BRCA1/2 mutation, and was significant for those with homologous recombination deficiency (BRCA1/2 mutation or a GIS ≥33 on myChoice CDx assay), the effect was smaller and not significant for the subgroup without BRCA1/2 mutation and the subgroup that was homologous recombination proficient (no BRCA1/2 mutation and GIS <33; Table 10). OS results were not mature.169 Veliparib is not recommended in the NCCN Guidelines because it is not FDA approved for any indications. Nonetheless the consistency of the results observed in VELIA support the use of PARP inhibitors as maintenance therapy after first-line platinum-based chemotherapy, and suggest that adding PARP inhibitors during primary chemotherapy may not provide substantial clinical benefit.

PARP Inhibitor Safety

Table 12 summarizes key safety data for the four phase III trials testing PARP inhibitor therapy as maintenance following first-line systemic therapy. Across trials, PARP inhibitor maintenance was associated with higher rates of a number of common nonhematologic AEs, such as fatigue/asthenia, nausea and vomiting (Table 12). These nonhematologic AEs tended to be low-grade and rarely led to study-drug discontinuation.166169 PARP inhibitor therapy was also associated with increased risk for a number of hematologic AEs, such as anemia, neutropenia, and thrombocytopenia (Table 12). Hematologic AEs were the most common high grade AEs (grade ≥3), and the most common cause of study drug discontinuation due to toxicity.166169 Although rare (≤2%), PARP inhibitor therapy was also associated with risk of myelodysplastic syndrome or acute myeloid leukemia,166169 and is mentioned in the FDA labels.261,262 Bevacizumab is associated with risk of hypertension; in the PAOLA-1 trial, hypertension was a common AE and a common high-grade AE in both arms, although it did not lead to discontinuation.167 Across trials, rates of high-grade AEs (grade ≥3) were higher for single-agent PARP inhibitor maintenance therapy compared with placebo. In PAOLA-1, however, there was only a small difference between arms in the rate grade ≥3 adverse events (Table 12), and serious AEs occurred in 31% in each arm,167 showing that risk of high-grade/serous AEs was similar for maintenance bevacizumab with versus without olaparib. Rates of study-drug discontinuation due to toxicity were higher with PARP inhibitor maintenance therapy across all trials, including PAOLA-1, largely due to hematologic AEs.

In the SOLO-1, PAOLA-1, PRIMA, and VELIA trials, there were no statistically significant differences between treatment arms in the heath-related QOL metrics evaluated.166169

FDA-Approved Indications for Maintenance Therapy After First-line Systemic Therapy

Although 3 PARP inhibitors (olaparib, rucaparib, and niraparib) are approved for single-agent maintenance therapy in select patients who are in CR or PR after platinum-based chemotherapy for recurrent disease, olaparib, niraparib, and olaparib + bevacizumab are currently the only PARP inhibitor regimens that are FDA approved for maintenance treatment after response to first-line chemotherapy in patients with newly diagnosed advanced disease (Table 13). The FDA approved indications are for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy (Table 13). The FDA indication for single-agent olaparib in this setting is limited to those with a deleterious or suspected deleterious BRCA mutation, and the FDA indication for bevacizumab plus olaparib in this setting is limited to those with homologous recombination deficiency, as defined by a deleterious or suspected deleterious BRCA mutation and/or genetic instability, as measured using an FDA-approved companion diagnostic. Veliparib is not currently FDA approved.

Maintenance with single-agent bevacizumab is FDA approved in this setting for patients with stage III–IV epithelial ovarian, fallopian tube, or primary peritoneal cancer that has been treated with surgical resection and combination carboplatin/paclitaxel/bevacizumab (Table 13).

NCCN Recommendations for Maintenance After Primary Chemotherapy

For patients who have completed primary surgery and systemic therapy, the NCCN recommended options for management of patients who have completed primary therapy are summarized in Table 14, including maintenance therapy options. The recommended options depend on disease stage, agents used for primary systemic therapy, response to primary treatment, and BRCA1/2 mutation status. For the maintenance therapy options, Table 14 also shows which NCCN recommended options are consistent with an FDA-approved indication, as well as options consistent with an FDA-approved indication that are not recommended in the NCCN Guidelines. Discrepancies between the NCCN recommendations and FDA-approved indications are highlighted in yellow. Table 14 shows the trials that provided data that supports the maintenance therapy options. As illustrated in Table 14, there are several key discrepancies between the FDA labels and NCCN Guidelines recommendations.

  1. The FDA-approved indication for maintenance bevacizumab is limited to patients with stage III-IV disease, whereas the NCCN Guidelines include this as an option for stage II disease. The rationale for this is discussed in “Selecting Patients for Maintenance Therapy, Disease Stage”(page 217).
  2. The FDA-approved indication for maintenance bevacizumab is not qualified based on BRCA1/2 mutation status. In contrast, the NCCN Guidelines single-agent bevacizumab maintenance is limited to those without a BRCA1/2 mutation. The rationale for this is discussed in “Olaparib + Bevacizumab” (page 212).
  3. The FDA-approved indication for olaparib/bevacizumab combination maintenance therapy does not specify that patients must have had prior bevacizumab, whereas the NCCN Guidelines restrict this option to those with prior bevacizumab, as there are no prospective randomized trial data to suggest that maintenance bevacizumab provides any clinical benefit to those who did not receive prior bevacizumab in combination with platinum-based chemotherapy.
  4. The FDA-approved indication for olaparib/bevacizumab combination maintenance therapy is restricted to patients with BRCA1/2 mutations or genomic instability, presumably based on the results of the subgroup analysis in PAOLA-1 showing no PFS benefit for those without homologous recombination deficiency. The NCCN Guidelines include olaparib/bevacizumab combination maintenance therapy as an option regardless of homologous recombination deficiency status, choosing instead to focus on the PFS benefit observed for the larger subgroup of patients without BRCA1/2 mutation (not further subdivided by homologous recombination deficiency status).
  5. The FDA approved indication for niraparib maintenance is not restricted by BRCA1/2 mutation status or whether bevacizumab was given in combination with platinum-based chemotherapy. In the NCCN Guidelines, however, for patients who received bevacizumab as part of primary therapy, niraparib is a maintenance option only for those with a BRCA1/2 mutation. The rationale for this is described in “Niraparib Monotherapy” (page 214).
When determining whether a patient is a candidate for maintenance after first-line therapy, and selecting among recommended maintenance therapy options, it is important to consider the eligibility criteria and characteristics of the patient population enrolled in the trials supporting the maintenance therapy options. The following sections describe considerations for selecting maintenance therapy.

Selecting Patients for Maintenance Therapy

Diagnosis and Cancer Type

As shown in Table 11, the trials testing PARP inhibitors as maintenance therapy after first-line systemic therapy enrolled patients with newly-diagnosed, histologically confirmed ovarian, primary peritoneal, or fallopian tube cancer. The FDA indications in this setting for olaparib, olaparib + bevacizumab, and niraparib all apply to cancers originating in any of these primary sites (Table 13).

Although most patients in the trials testing PARP inhibitor maintenance after primary therapy had high-grade serous histology (95%–100%), several of these trials (SOLO-1, PAOLA-1, PRIMA), included a small percentage of patients with high-grade endometrioid (2.3%–2.7%), and a small percentage with other cancer types (1.5%–2.3%; Table 11). The NCCN Guidelines recommendations for maintenance options apply to patients with high-grade serous or grade 2/3 endometrioid cancer types. It is not clear whether these maintenance therapies are appropriate for patients with less common epithelial ovarian cancer types (carcinosarcoma, clear cell carcinoma, mucinous carcinoma, grade 1 endometrioid, low grade serous). The FDA indications for PARP inhibitors in this setting are all for “epithelial” cancer (Table 13).

Disease Stage

The trials testing PARP inhibitor maintenance therapy after first-line treatment all required patients to have FIGO stage III-IV, and most patients had stage III disease (65%–83%; see Table 11). Cases of stage II disease at initial diagnosis are rare, especially among patients who have undergone complete surgical staging, so there is little data and low probability of future trials that will address the question of whether it is appropriate to use PARP inhibitors as maintenance after completing primary therapy for stage II disease. For this reason, the NCCN Panel decided that the PARP inhibitor maintenance therapy options (olaparib, niraparib, olaparib + bevacizumab) for patients who have completed first-line chemotherapy are recommended for stage III-IV disease, and should also be considered for patients who have stage II disease, noting that supporting data are limited for stage II. These maintenance therapy options are not recommended for patients with stage I disease (Table 14). The FDA indications for olaparib, olaparib + bevacizumab, and niraparib as maintenance therapy options after first-line chemotherapy are for patients with “advanced” disease, which is not clearly defined (Table 13).

The GOG-0218 and ICON7 regimens for first-line platinum-based chemotherapy with concurrent bevacizumab followed by single-agent maintenance bevacizumab are recommended in the NCCN Guidelines as options for stage III-IV disease, and the NCCN panel recommends that these can be considered for patients with stage II disease. They are not recommended for stage I disease. Use in stage II should take into consideration that GOG-0218 included only stage III-IV,219 and although ICON7 included patients with high-risk stage I/II, subanalyses showed that the greatest benefit from bevacizumab among patients with more advanced disease, with no significant impact of bevacizumab on OS for patients with earlier stage disease.221 The corresponding FDA-approved indication for carboplatin/paclitaxel/bevacizumab followed by single-agent bevacizumab is limited to stage III-IV disease (Table 13).

BRCA1/2 Mutation Status

Because BRCA1/2 mutation status is important for selection of maintenance therapy in patients with stage II-IV disease that responds to primary treatment, the NCCN Guidelines recommend screening for BRCA1 and BRCA2 mutations earlier in the course of workup and primary treatment. Genetic risk evaluation and BRCA1/2 testing should be initiated as soon as the diagnosis has been confirmed histologically by evaluation of tumor tissue. Primary chemotherapy should not be delayed for a genetic counseling referral, because delay between surgery and start of chemotherapy is associated with poorer outcomes,230,272 and maintenance would not be initiated until completion of platinum-based first-line chemotherapy, which takes (at least) 18 weeks. The NCCN Guidelines recommend that BRCA testing be performed using an FDA-approved test or other validated test performed in a CLIA-approved facility.

Homologous Recombination Deficiency

There is consensus that the presence of a deleterious germline or somatic mutation in BRCA1 or BRCA2 confers a level of homologous recombination deficiency that is clinically relevant to the selection of therapy for patients with ovarian cancer. However, for patients with ovarian cancer who do not have a deleterious or suspected deleterious mutation in BRCA1 or BRCA2, various molecular markers and metrics have been proposed to determine whether the cancer is associated with a clinically relevant level of homologous recombination deficiency. Different methods and cutoffs were used in the PAOLA-1, PRIMA, and VELIA trials.167169 Because in PRIMA the study regimen being tested improved PFS (compared with control) even among the homologous recombination “proficient” subgroups, but the same was not true in PAOLA-1 or VELIA (Table 10), it is not clear whether the assays and cutoffs used to assign homologous recombination deficiency in those studies should be used to inform selection of maintenance therapy after first-line treatment. This is an area of ongoing investigation and as such, the NCCN Panel is not ready to recommend any particular approach for determining homologous recombination deficiency in patients with ovarian cancer who do not have a BRCA1/2 mutation.

Primary Treatment

All four trials testing PARP inhibitor maintenance after primary treatment included both patients who had received upfront PDS followed by adjuvant chemotherapy, as well as patients who had received NACT with IDS and adjuvant chemotherapy (Table 11). For trials with reported data regarding the types of primary surgery received (SOLO-1, PAOLA-1, VELIA), more than half of the patients had upfront PDS, most of the remainder had NACT and IDS, and very few did not have any primary surgery (≤7%; Table 11). In these three trials, more than half of the population had surgery resulting in no macroscopic residual disease after surgery (Table 11). In SOLO-1 and PAOLA-1, subgroup analyses showed significant PFS benefit from PARP inhibitor maintenance regardless of the type of primary surgery (PDS vs IDS) and presence vs absence of macroscopic residual disease after primary surgery.167,264 Subgroup analyses of VELIA showed PFS benefit from veliparib regardless of the type of primary surgery (PDS vs IDS).169

In contrast to the other 3 trials, the PRIMA trial required that patients with stage III have either unresectable disease or visible residual disease after primary surgery, and likely included more patients treated with IDS (versus PDS), such that a much smaller proportion of the population had a surgery that resulted in no macroscopic disease. For PRIMA the data on primary surgeries received and extent of residual disease after surgery were not reported clearly. The PRIMA report did not include subgroup analyses based on type of surgery or residual disease after surgery, but did show that the PFS benefit associated with maintenance niraparib was significant for both those with and those without prior NACT.168

In SOLO-1, PAOLA-1 and PRIMA, most patients had at least 6 cycles of platinum-based chemotherapy as part of primary treatment (Table 11). Both intravenous regimens and IP/intravenous regimens were allowed in SOLO-1 and PAOLA-1.166,167 In the NCCN Guidelines, all the intravenous and IP/intravenous regimens recommended for neoadjuvant/adjuvant primary chemotherapy in patients with stage II–IV high-grade serous or endometrioid disease include 6 cycles of platinum-based combination chemotherapy (see Table 3 and “Principles of Systemic Therapy, Primary Systemic Therapy Regimens,” OV-C 4 of 10, available at NCCN.org).

SOLO-1, PAOLA-1 and PRIMA required patients to have CR or PR before initiation of maintenance therapy, and most had complete response after primary systemic therapy, although the definitions of CR and PR varied (Table 11). Subgroup analyses in SOLO-1 and PRIMA showed that PFS benefit from single agent PARP inhibitor maintenance was significant regardless of depth of response (CR vs PR) after first-line systemic therapy.166,168 VELIA did not require that patients have CR or PR after primary chemotherapy as a criteria for receiving veliparib maintenance therapy, and did not report response rate for the overall population.169

The NCCN recommendations for maintenance bevacizumab and PARP inhibitors apply to patients with a CR (no evidence of disease) or PR after debulking surgery and chemotherapy, including those treated with PDS followed by adjuvant chemotherapy, and those treated with NACT, IDS, and adjuvant chemotherapy (see OV-2 [available at NCCN.org] and OV-5 [page 194]). Maintenance therapy is not recommended for patients who have progressive or stable disease on primary treatment; these patients should be treated with recurrence therapy options as shown on OV-7 (available at NCCN.org).

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