NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-19-010-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/86030; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: August 10, 2019; Expiration date: August 10, 2020
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Ovarian Cancer
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Ovarian Cancer
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships: Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Jamie N. Bakkum-Gamez, MD; Lisa Barroilhet, MD; Kian Behbakht, MD; Andrew Berchuck, MD; Heidi J. Gray, MD; Theresa L. Werner, MD; and Emese Zsiros, MD, PhD, (Panel Members) and Jennifer L. Burns (Guidelines Coordinator, NCCN) and Anita M. Engh, PhD (Oncology Scientist/Medical Writer, NCCN) have no conflicts of interest to disclose.
Deborah K. Armstrong, MD, Panel Chair, has disclosed that she receives grant/research support from AstraZeneca Pharamceuticals LP, Advaxis, Clovis Oncology, Syndax, Tesaro, Inc., and Pfizer Inc.
Ronald D. Alvarez, MD, Panel Vice Chair, has disclosed that he receives grant/research support from Inovia, receives consulting fees/honoraria from Unleash and Vaccitech, and is a scientific advisor for Papivax and Tesaro, Inc.
Lee-may Chen, MD, Panel Member, has disclosed that she receives grant/research support from AstraZeneca Pharmaceuticals LP, Clovis Oncology, and Tesaro, Inc.
Mihaela Cristea, MD, Panel Member, has disclosed that she is a scientific advisor for AstraZeneca Pharmaceuticals LP.
Adam C. ElNaggar, MD, Panel Member, has disclosed that he is a scientific advisor for AstraZeneca Pharmaceuticals LP, Clovis Oncology, Tesaro, Inc., and Caris Life Sciences. He also receives grant/research support from Caris Life Sciences.
David M. Gershenson, MD, Panel Member, has disclosed that he has equity interest/stock options in Biogen Iden, Celgene Corporation, and Johnson & Johnson; receives consulting fees/honoraria from Genentech, Inc., and OncLive; receives grant/research support from Novartis Pharmaceuticals Corporation; and receives royalties from Elsevier and UpToDate.
Charles A. Leath III, MD, Panel Member, has disclosed that he is a scientific advisor for AbbVie Inc., and Clovis Oncology.
Joyce Liu, MD, Panel Member, has disclosed that she receives consulting fees/honoraria from Clovis Oncology and Tesaro, Inc.
Haider Mahdi, MD, MPH, Panel Member, has disclosed that he receives grant/research support from Puma Biotechnology, and received consulting fees/honoraria from Tesaro, Inc.
Daniela Matei, MD, Panel Member, has disclosed that she receives consulting fees/honoraria from and is a scientific advisor for Genentech/Roche, AstraZeneca Pharmaceuticals LP, and Radivin.
David M. O'Malley, MD, Panel Member, has disclosed that he receives grant/research support from AbbVie Inc, AstraZeneca Pharmaceuticals LP, Clovis Oncology, Exelixis Inc., Genentech, Inc., GlaxoSmithKline, ImmunoGen, Inc., Janssen Pharmaceutica Products, LP, Novartis Pharmaceuticals Corporation, Novocure, Agenus Inc., Ajinomoto Co, Inc., Array BioPharma Inc., ERGOMED Clinical Research Ltd, INC Research, Inc, Regeneron Pharmaceuticals, Inc., Tesaro, Inc., TRACON Pharmaceuticals, Inc. He receives consulting fees/honoraria from AbbVie Inc., AstraZeneca Pharmaceuticals LP, Clovis Oncology, Genentech, Inc., Ambry Genetics, and Tesaro, Inc. He is a scientific advisor for AbbVie Inc., AstraZeneca Pharmaceuticals LP, Clovis Oncology, Genentech, Inc., ImmunoGen, Inc., Janssen Pharmaceutica Products, LP, Myriad Genetic Laboratories, Inc., Novocure, Agenus Inc., Marker Therapeutics, Inc., OncoQuest Inc., and Regeneron Pharmaceuticals, Inc.
Richard T. Penson, MD, MRCP, Panel Member, has disclosed that he is a scientific advisor for AbbVie, Clovis Oncology, Janssen Oncology, NewLink Genetics, Roche, Inc., and Tesaro Inc.; is a scientific advisor for and received grant/research support from AstraZeneca Pharmaceuticals LP, Eisai Inc., Genentech, Merck & Co., Sutro Biopharma, and Vascular Biogenics Ltd.
Steven W. Remmenga, MD, Panel Member, has disclosed that he is a scientific advisor for TRICARE Humana.
Paul Sabbatini, MD, Panel Member, has disclosed that he receives grant/research support from Bristol-Myers Squibb.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca, Celgene Corporation, Clovis Oncology, Eisai, Genentech, Genomic Health, Inc., Novartis, Taiho Oncology, Inc., and TESARO. This activity is supported by an independent educational grant from AbbVie. This activity is supported by educational funding provided by Amgen. This activity is supported by an unrestricted educational grant from Gilead Sciences, Medical Affairs.
Overview
For advanced-stage epithelial ovarian cancer, including fallopian tube and primary peritoneal cancers, the best outcomes have been observed in patients whose primary treatment included complete resection of all visible disease and combination chemotherapy.1 Therefore, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer recommend that primary treatment of presumed advanced-stage ovarian cancer consist of appropriate surgical debulking plus systemic chemotherapy in most patients. For most patients presenting with suspected advanced-stage malignant ovarian cancer, initial surgery should include a total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) with comprehensive staging and debulking as indicated.2–4 Primary debulking surgery (PDS) is the recommended approach for advanced-stage disease if the patient is a surgical candidate, optimal cytoreduction (residual disease <1 cm [R1] and preferably removal of macroscopic disease [R0]) appears feasible, and fertility is not a concern. Neoadjuvant chemotherapy (NACT) with interval debulking surgery (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 disease that is unlikely to be optimally cytoreduced. The anticipated benefit from NACT would be to allow for medical improvement 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. In recent years, new therapies have become available for patients with both newly diagnosed advanced-stage and recurrent ovarian cancer. These NCCN Guidelines Insights focus on recent updates to the recommendations for NACT for advanced-stage ovarian cancer and options for maintenance therapy after completion of primary therapy. These updates to the NCCN Guidelines for Ovarian Cancer are generalized to the more common subtypes and do not necessarily apply to rare ovarian cancer histologies (see full NCCN Guidelines for details).
Neoadjuvant Therapy
Randomized Trials Comparing NACT Versus Conventional Treatment
Several prospective randomized controlled trials have compared a NACT approach (with IDS and postoperative chemotherapy) versus conventional treatment (PDS plus postoperative chemotherapy; Table 1).5–9 These trials focused on patients with FIGO stage IIIC–IV ovarian cancer that was deemed unlikely to be completely resected. As shown in Table 1, the NACT regimens tested in these trials typically consisted of 3 to 4 cycles of upfront chemotherapy followed by IDS with the goal of maximum cytoreduction, followed by 3 to 4 cycles of postoperative chemotherapy. Several of these trials (EORTC 55971,5 SCORPION,7 JCOG06028) allowed IDS in the neoadjuvant arm only for patients experiencing response or stable disease after NACT. The control arms in these trials consisted of PDS (with the goal of maximum cytoreduction) followed by postoperative chemotherapy to a total of 6 to 8 cycles. Specific chemotherapy regimens used in these trials are shown in supplemental eTable 1, available with this article at JNCCN.org.5–9
Randomized Trials Comparing NACT + IDS Versus PDS
Although there was some variability across these trials, results in general demonstrated that patients treated with NACT had improved surgical outcomes (eg, shorter operative time, less blood loss, fewer high-grade surgical complications or surgery-related adverse events [AEs], shorter hospital stay), less extensive and complicated surgeries needed to achieve optimal cytoreduction, and a lower risk of postoperative death (Table 1).5–9 Most of these trials found that NACT increased the likelihood of achieving optimal cytoreduction and/or removal of all macroscopic disease (R0).
Although an NACT approach was associated with improved surgical outcomes and less residual disease after surgery, trials that reported progression-free survival (PFS) and overall survival (OS) found no significant differences when compared with the conventional PDS approach (Table 1). For some of these trials, post hoc analyses were conducted to determine whether there are any subgroups of patients for whom NACT may improve PFS or OS. Although analyses of CHORUS did not identify any subgroups with treatment-dependent differences in PFS or OS, analyses of EORTC 55971 and a pooled analysis of the per protocol populations from EORTC 55971 and CHORUS showed that NACT (with IDS and adjuvant chemotherapy) may improve PFS and/or OS in patients with more extensive disease, but conventional treatment (PDS and postoperative chemotherapy) was associated with better PFS and/or OS in patients with less extensive disease.10,11,13
Importantly, for some of these trials (EORTC 55971, CHORUS) the median PFS and OS for both treatment arms (Table 1) were inferior to those reported in randomized studies of patients undergoing PDS followed by postoperative intravenous chemotherapy for advanced ovarian cancer (OS mean, ∼50 months in the United States).14,15 Although the median OS in the international trial is 20 months lower than that reported in US trials using the customary sequence of therapeutic interventions (ie, PDS followed by chemotherapy), this difference may have been a result of selection of higher risk patients in the NACT trials (which did not include patients with stage IIIB or earlier stages).
Selection of Patients for NACT
NCCN recommendations for workup and selection of patients for NACT are aligned with the eligibility criteria and protocols used in the randomized controlled trials shown in Table 1. For these trials, preoperative evaluations and debulking surgeries were performed by gynecologic oncologists; some trials included additional requirements to ensure that the surgeons had sufficient experience performing the procedures.5–9 The NCCN Ovarian Cancer Panel emphasizes that evaluation by a gynecologic oncologist is important for determining the most appropriate method of obtaining tissue for histologic confirmation and of determining the extent of disease. This recommendation is consistent with those from Society of Gynecologic Oncology and ASCO.16
Most of the trials in Table 1 required confirmation of staging and diagnosis based on imaging plus histology of a biopsy specimen or cytology of ascites or pleural effusion. Some trials had additional entry criteria based on serum cancer antigen 125 (CA-125) and carcinoembryonic antigen (CEA) levels, and some required additional diagnostic tests to rule out other types of malignancies. Laparoscopy to evaluate extent of disease and feasibility of resection was required in one of the trials (SCORPION) and also frequently used in the other trials. Reports from several of these trials noted that for some patients, the assignment of histologic type and disease stage was revised after biopsy or laparoscopic evaluation, and sometimes revised after debulking surgery.5–8 The NCCN Guidelines recommend pathologic confirmation of diagnosis and histologic subtype based on analysis of tumor tissue. If biopsy is not feasible, cytopathology from ascites or pleural effusion combined with a CA-125:CEA ratio of >25 can be used.6,17–19 Although biopsy can be obtained through a variety of methods, and minimally invasive techniques can be used, laparoscopic evaluation should be considered for determining the feasibility of resection, because it may allow for a more accurate evaluation of whether optimal cytoreduction can be achieved. Because germline and/or somatic BRCA1 and BRCA2 mutation status may inform future options for maintenance therapy, all patients with histologically confirmed ovarian cancer should undergo genetic risk evaluation and BRCA1 and BRCA2 testing, if not previously performed. However, treatment should not be delayed for genetic counseling referral, because delay in treatment is associated with poorer outcomes.20,21
Regimen Options for Patients Treated With NACT
A wide variety of platinum-based regimens have been used in clinical trials testing NACT plus IDS and postoperative chemotherapy. All of the randomized trials in Table 1 used platinum-based combination chemotherapy or monotherapy (supplemental eTable 1). Other chemotherapy regimens that have been tested in prospective trials in patients with ovarian cancer are shown in supplemental eTable 2.22–27 For most of the trials in supplemental eTables 1 and 2, patients received the same chemotherapy regimen for both NACT and postoperative therapy. For the prospective trials comparing different chemotherapy regimens in patients treated with a NACT approach (PRIMOVAR-1, GEICO 1205/NOVA, ANTHALYA, OV21/PETROC), none has yet demonstrated the superiority of any regimen based on surgical outcomes, PFS, or OS (supplemental eTable 2).23,25–27 Given that a wide variety of regimens have been successfully used in prospective trials, and in the absence of data indicating that specific regimens should be excluded or favored, the NCCN Guidelines provide a list of options that can be used before and/or after surgery in patients treated with an NACT approach (supplemental eTable 3), including all of the intravenous regimens recommended for conventional treatment of stage II–IV disease (ie, PDS followed by chemotherapy).
Bevacizumab-Containing Regimens for Patients Treated With NACT
Several prospective trials have explored whether adding bevacizumab to platinum-based regimens improves outcomes for patients treated with NACT. Preliminary results from GEICO 1205/NOVA found that adding bevacizumab to a standard carboplatin/paclitaxel regimen did not significantly change the rate of complete response (CR) on NACT (prior to IDS), rate of “optimal surgery”, or PFS, but did show a lower rate of grade 3–4 AEs in the arm that included bevacizumab (70% vs 42%, P=.026).25 The ALTHALYA trial used a similar carboplatin/paclitaxel regimen, but did not find a significant difference in the rate of grade 3–5 AEs for patients treated without versus with bevacizumab (63% vs 62%).26 Results from ALTHALYA also showed no difference between treatment arms for CR rate prior to IDS, percent of patients with no macroscopic residual disease after IDS, or surgical outcomes (operative time, length of hospital stay, length of stay in intensive care unit, frequency of blood transfusions, and rate of postoperative complications).26 Taken together, results from these trials indicate that although platinum-based regimens that include bevacizumab have acceptable safety for patients treated with an NACT approach, more data are needed to determine whether the addition of bevacizumab impacts PFS. It is important to note that all of the prospective trials in supplemental eTables 1 and 2 that allowed use of bevacizumab in the NACT setting used a washout period before (and sometimes after) IDS, usually of at least 28 days.7,24–26 The NCCN Guidelines include 2 bevacizumab-containing regimens as options for NACT and post-IDS chemotherapy (supplemental eTable 3).
Intraperitoneal/Intravenous Regimens for Patients Treated With NACT
Several trials have explored the use of intraperitoneal/intravenous regimens in patients treated with an NACT approach. Both SWOG S0009 and OV21/PETROC tested postoperative intraperitoneal/intravenous regimens for patients who had platinum-based NACT followed by optimal cytoreduction by IDS.22,27 In SWOG S0009, among patients with a ≥50% decrease in CA-125 level during NACT, optimal debulking by IDS (<1 cm and malignant pleural effusions resolved), and postoperative intraperitoneal/intravenous chemotherapy, median PFS (29 months) and OS (34 months) compared favorably with results from other trials using intravenous regimens (supplemental eTable 2).22 To determine whether postoperative intraperitoneal/intravenous chemotherapy improves outcomes compared with intravenous regimens among patients treated with NACT, the OV21/PETROC trial compared 3 different postoperative regimens (supplemental eTable 2) in patients previously treated with platinum-based intravenous NACT (3–4 cycles) and optimal cytoreduction by IDS.27 Although trends in the rate of progression or death in the first 9 months (from randomization) favored the carboplatin/paclitaxel intraperitoneal/intravenous regimen (Arm 3, 24.5%) over the cisplatin/paclitaxel intraperitoneal/intravenous regimen (Arm 2, 34.7%) or the carboplatin/paclitaxel intravenous regimen (Arm 1, 38.6%), later results (median follow-up 33 months) showed no difference in median PFS between the intraperitoneal/intravenous and the intravenous regimens (supplemental eTable 2). OS rate at 2 years was also not significantly different (74% vs 81% for Arm 1 vs Arm 3).27 Based on these results, the NCCN Guidelines include both the cisplatin/paclitaxel and carboplatin/paclitaxel intraperitoneal/intravenous regimens as options for postoperative therapy in patients who have received NACT and IDS (supplemental eTable 3). Given the lack of survival improvement in OV21/PETROC, more data are needed to establish whether postoperative intraperitoneal chemotherapy provides clinical benefit in patients who have received intravenous NACT and IDS. Recent results from the phase III randomized controlled GOG-0252 trial have also called into question the value of postoperative intraperitoneal chemotherapy for patients with advanced-stage ovarian cancer treated with PDS.28 Although earlier trials showed improved PFS and/or OS with intraperitoneal vs intravenous chemotherapy,1,14,29,30 results from GOG-0252 showed no improvement.28 However, unlike previous trials, all regimens used in GOG-0252 contained bevacizumab, which may have compensated for the effect of intraperitoneal chemotherapy administration.
Number of Chemotherapy Cycles Before and After IDS
As shown in supplemental eTable 2, results from the PRIMOVAR-1 phase II randomized trial showed that treatment with 3 versus 2 cycles of NACT did not impact response rate, extent of cytoreduction achieved in IDS, operative time, extent of surgery needed, or PFS or OS.23 Nonetheless, because most of the randomized trials testing NACT protocols used 3 to 4 cycles before IDS (Table 1 and supplemental eTables 1 and 2), the NCCN Guidelines indicate that 3 cycles of NACT before IDS is preferred, although surgery after 4 to 6 cycles may be used based on the clinical judgement of the treating gynecologic oncologist.
After 3 cycles of NACT, patients should be evaluated by a gynecologic oncologist to determine the likelihood of optimal cytoreduction. For patients who responded to NACT and are likely to have optimal cytoreduction, IDS should be performed. Those with stable disease after 3 cycles of NACT can consider IDS, but also should consider either (1) switching to treatment of persistent/recurrent disease or (2) treatment with additional cycles of NACT (to a total of ≥6 cycles) prior to IDS. Patients who experience disease progression during NACT should switch to therapy for persistent/recurrent disease.
Most of the trials testing NACT regimens used at least 3 cycles of chemotherapy after IDS, or indicated that the total number of cycles should be 6 to 8 (Table 1 and supplemental eTables 1 and 2). The NCCN guidelines recommend that regardless of the number of cycles of NACT received, IDS should always be followed by adjuvant chemotherapy. For all patients who undergo NACT plus IDS, a minimum of 6 cycles of treatment is recommended, including at least 3 cycles of adjuvant therapy after IDS.
Interval Debulking Surgery
Analyses of data from multiple prospective trials found that the extent of residual disease after NACT plus IDS was prognostic for PFS and OS.5,6,9,23 As shown in Table 1 and supplemental eTables 1 and 2, these trials reported optimal cytoreduction in 45% to 91% of patients, with complete removal of all macroscopic disease in 30% to 59%. Therefore, the goal of IDS is to achieve complete removal of macroscopic disease (R0) whenever possible. NCCN-recommended procedures for IDS, described in detail in supplemental eTable 4, are similar to those used in these trials,5–8,22–24,26 and similar to those recommended for PDS. As mentioned earlier, these trials required experienced gynecologic oncologists for preoperative evaluation and IDS.5–7,26 Minimally invasive techniques can be used for IDS in select patients. Patients whose disease is unable to be optimally debulked using minimally invasive techniques should be converted to an open procedure (supplemental eTable 4).
Hyperthermic Intraperitoneal Chemotherapy at the Time of IDS
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a technique in which chemotherapy is delivered in a heated solution perfused throughout the peritoneal space. The rationale for hyperthermic delivery is that heat can increase penetration of the chemotherapy at the peritoneal surface and enhance the sensitivity of cancer cells to chemotherapy by inhibiting DNA repair.31–33 Concerns about the inconvenience of delivery and toxicities associated with postoperative intraperitoneal/intravenous chemotherapy motivated researchers to determine whether HIPEC could improve safety and quality of life. Although raising body temperature carries substantial risks, methods have been developed for raising the temperature of the intraperitoneal space with minimal increase in the temperature of the rest of the body.
Over the past several decades, a few prospective comparative trials (supplemental eTable 5)34–37 and numerous prospective noncomparative trials (supplemental eTable 6)38–51 have reported on the use of HIPEC in patients with ovarian cancer. HIPEC methods have evolved over the years to reduce intraoperative and postoperative complications. Both “open” and “closed” abdominal techniques have been developed and tested in prospective studies (supplemental eTables 5 and 6).34,35,37–51 HIPEC protocols used in prospective studies usually perfused chemotherapy for 60 or 90 minutes (depending on agent and dose used) with solution heated to achieve an intraperitoneal temperature of 41°C to 43°C.34–51 The duration and safety of cytoreductive surgery plus HIPEC procedures varied across trials, with median procedure time ranging from 300 to 600 minutes and median hospital stay ranging from 8 to 24 days.34–44,46–51 Excessive blood loss was common, and in some studies, more than half of the patients required transfusions. Intraoperative and postoperative mortality (<30 days from surgery) ranged from 0% to 7%,38–45,47 although the most recent trials all report no deaths related to the procedure.49–51 The rate of complications from surgery vary across trials, with major/severe complications (<30 days from surgery) occurring in 9% to 40% of patients.38–47,49,50 Studies from one center reported that complication rates decreased in more recent years compared with when their center first started performing debulking and HIPEC procedures.40,52 Common major/severe complications observed across trials include various types of fistulas, abscesses, and infections (wound infection, sepsis, pneumonia, central line–associated infection, intra-abdominal infection), surgical wound dehiscence, bowel perforation, ileus, hemorrhages, venous thromboembolism, myocardial infarction, pleural effusions, pneumothorax, and renal failure/insufficiency.34,39–43,45,47,48,50,53 Many studies reported that additional procedures were needed to manage complications.34,40,41,44,46,47,49,50,53,54
Given the risks associated with HIPEC, prospective studies have focused on using HIPEC immediately after debulking (as part of the same procedure) in patients with high-volume intraperitoneal disease (FIGO stage III–IV at diagnosis or recurrence), particularly those with peritoneal carcinomatosis, who are at risk for widespread residual microscopic disease even after resection to no visible disease. Compared with postoperative intraperitoneal therapy, intraoperative intraperitoneal administration may enable better perfusion of the peritoneal space because adhesions will not yet have formed. Patients with less extensive disease were excluded because they are less likely to have widespread microscopic disease after debulking, and therefore the potential benefit is unlikely to outweigh risks of the procedure. Patients with distant extra-abdominal metastases were often excluded from HIPEC studies because of concerns that intraperitoneal therapy would not be effective treatment of extraperitoneal disease.
Only a few phase III prospective comparative studies have tested whether HIPEC improves outcomes for patients with advanced ovarian cancer (summarized in supplemental eTable 5). The most recent and largest (n=245) of these, M06OVH-OVHIPEC, showed that HIPEC improved recurrence-free survival and OS in patients with FIGO stage III primary epithelial ovarian, fallopian tube, or peritoneal cancer who underwent NACT due to extensive abdominal disease or suboptimal PDS.37 Although the total procedure time for debulking + HIPEC was longer than for debulking alone, HIPEC did not appear to have any major effects on hospital stay (median, 10 vs 8 days) or administration of postoperative intravenous chemotherapy (ie, time to initiation, rate of completion of all 3 cycles). Most important, no differences in rates of toxicity were seen between arms (grade 3–4 toxicities: 27% vs 25%) or in any of the health-related quality-of-life metrics evaluated.
Because of these positive results, the NCCN Guidelines now include an option to consider HIPEC at the time of IDS in patients with stage III disease treated with NACT (see OV-2 [footnote n], page 903). Similar to the trial, which required patients to have response or stable disease after 3 cycles of NACT and which treated patients with postoperative chemotherapy (3 cycles), the NCCN Guidelines recommend HIPEC as an option for patients who have response or stable disease after NACT (3 cycles preferred, but 4–6 allowed) and that all patients treated with NACT and IDS (± HIPEC) receive postoperative chemotherapy. Analyses of M06OVH-OVHIPEC showed that the effect of HIPEC was consistent across a wide variety of subgroups (age, histologic type, prior surgery, extent of disease, laparoscopy before surgery). Therefore, the NCCN Guidelines indicate that HIPEC can be considered for all patients with stage III disease for which NACT and IDS is performed, without any further requirements for selection of patients. Importantly, HIPEC is not recommended for patients treated with PDS (no NACT) based on initial results from a randomized controlled trial showing that HIPEC did not improve PFS or OS in a population of patients with optimal cytoreduction (<1 cm residual) after PDS or after NACT + IDS (supplemental eTable 5).36 In the subset of patients who underwent NACT and IDS, however, long-term follow-up showed a trend toward improved PFS and OS with HIPEC.36
In most prospective studies testing HIPEC, the surgery prior to HIPEC was conducted with the goal of maximal cytoreduction (R0 resection) and involved TAH/BSO, omentectomy, and a variety of other procedures, depending on the extent of disease. Optimal cytoreduction (residual disease <1 cm) was achieved in most patients in these trials, and, in some studies, was a requirement for receiving subsequent HIPEC (supplemental eTables 5 and 6). Rates of complete cytoreduction (R0 resection) varied from 50% to 100% in these trials,38–40,42–48,50,51 and univariable and multivariable analyses showed that residual disease after debulking was the strongest predictor of OS.38,39,43–45,53,55 Therefore, NCCN recommends maximum effort to achieve complete cytoreduction during IDS, regardless of whether HIPEC is planned.
The NCCN-recommended HIPEC agent is cisplatin, 100 mg/m2, as was used in M06OVH-OVHIPEC.37 Although this trial tested only one regimen for NACT and postoperative chemotherapy (carboplatin, area under the curve [AUC] 5–6 + paclitaxel, 175 mg/m2 body surface area), other studies have used a variety agents, and the optimal pairing of pre/postoperative regimens with HIPEC agent has not been determined. The NCCN Guidelines currently do not restrict the HIPEC recommendation based on the regimen selected for NACT or postoperative chemotherapy.
Options After First-Line Chemotherapy
There are now increasing options for patients with advanced-stage ovarian cancer who have a partial response or a CR after primary therapy (some combination of surgery + chemotherapy; see OV-5, page 904). NCCN recommendations have been revised several times recently due to emerging data from clinical trials; these recent data and their impact on the recommendations are discussed herein.
Bevacizumab Maintenance Therapy
As described in detail in the complete version of the NCCN Guidelines for Ovarian Cancer (available at NCCN.org), bevacizumab maintenance therapy is recommended for patients with stage II–IV disease who experience response or stable disease after postoperative chemotherapy with one of the recommended carboplatin/paclitaxel/bevacizumab regimens.
Olaparib Maintenance Therapy After Primary Chemotherapy
Olaparib is a PARP inhibitor shown to be active in recurrent ovarian cancer,56–63 and has been FDA-approved for multiple indications,64 summarized in Table 2 (the corresponding recommendations can be found on OV-7 and OV-C 6 and 7 of 9 in the NCCN Guidelines at NCCN.org).
FDA-Approved Indications for Bevacizumab and PARP Inhibitors in Ovarian Cancer
More recently, the phase III, double-blind, randomized 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 were in a CR or PR after first-line platinum-based chemotherapy for advanced ovarian cancer (supplemental eTable 7).68 The risk of progression or death was 70% lower, and whereas the median PFS (from randomization) was 13.8 months for placebo, the median PFS for olaparib had not been reached after a median follow-up of 41 months; OS data are immature. Rates of serious AEs (21% vs 12% for olaparib vs placebo) and study-drug discontinuation due to toxicity were higher in the olaparib arm (supplemental eTable 7). Anemia and neutropenia were among the grade 3–4 AEs that were more frequent with olaparib versus placebo, and sometimes led to study-drug discontinuation. Health-related quality-of-life scores were stable during study treatment with olaparib, and decreased slightly with placebo; this difference was not clinically significant. 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 ovarian cancer, olaparib is currently the only one that is FDA-approved for maintenance treatment after response to first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation (Table 2). The other agents are also being actively studied for this same indication, with results forthcoming.
Selection of Patients for Olaparib Maintenance Therapy
Disease Type, Histology, and Mutation Status
SOLO-1 enrolled patients with newly diagnosed, histologically confirmed high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer, although most had high-grade serous histology (96%) and ovarian cancer (85%).68 Patients were required to have a deleterious or suspected deleterious BRCA1 or BRCA2 mutation. Most patients had germline BRCA mutations (n=388/391); only 2 had wild-type germline BRCA1 and BRCA2, and were included in the study based on somatic mutations. For this reason, the recommendation for olaparib maintenance in the first-line setting is category 1 for patients with germline BRCA1/2 mutations and category 2A for patients with somatic BRCA1/2 mutations (and wild-type or unknown germline BRCA1/2 mutation status).
Because BRCA1/2 mutation status is important for selection of maintenance therapy in patients whose disease responds to primary treatment, the NCCN Guidelines have been updated to 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,20,69 and olaparib maintenance would not be initiated until completion of platinum-based first-line chemotherapy. The NCCN Guidelines recommend that BRCA testing be performed using an FDA-approved test or other validated test performed in a CLIA-approved facility.
Disease Stage and Primary Treatment
SOLO-1 enrolled patients with stage III–IV disease, most with PDS (62%) or IDS (35%).68 Patients with stage IV were allowed to have (chemotherapy +) biopsy only, but only a small percentage of the study population had no debulking surgery (2%). At least 75% had no residual macroscopic disease after surgery. After completion of primary chemotherapy, 82% experienced CR (no evidence of disease based on imaging and normal CA-125 level). The NCCN recommendation for maintenance olaparib applies to patients who are in a CR or PR after debulking surgery and chemotherapy, including those treated with PDS + adjuvant chemotherapy, and those treated with NACT, IDS, and adjuvant chemotherapy (OV-2 and OV-5, pages 903 and 904, respectively). Maintenance olaparib is not a recommended option 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 in the complete version of these guidelines at NCCN.org).
In SOLO-1, all patients were required to have had first-line platinum-based chemotherapy, without bevacizumab, for 6 to 9 cycles. Both intravenous regimens and intraperitoneal/intravenous regimens were allowed. Most patients in the trial were treated with carboplatin/paclitaxel or cisplatin/paclitaxel, and most received 6 cycles (supplemental eTable 7).68 In the NCCN Guidelines, all the intravenous and intraperitoneal/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 (supplemental eTable 3). As discussed earlier, 2 bevacizumab-containing regimens are included among these recommended options. Although SOLO-1 does not provide data to indicate whether maintenance olaparib provides benefit to patients treated with bevacizumab-containing chemotherapy regimens, it is important to note that the effect of maintenance olaparib on PFS (70% improvement; supplemental eTable 7)68 was far greater than the effects on PFS reported with the addition of bevacizumab to both upfront and maintenance therapy (<30% improvement).70–72 PFS curves from SOLO-1 show large separation between olaparib versus placebo throughout the time course of the study (median follow-up, 41 months),68 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.71,72 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.73 The NCCN panel voted to include olaparib as a maintenance therapy option for patients who were treated with primary chemotherapy regimens containing bevacizumab, provided that they are in a CR or PR after completion of chemotherapy (OV-5, page 904). Combination maintenance therapy with both bevacizumab and olaparib is not currently recommended because of insufficient safety and efficacy data.
NCCN Recommendations
Olaparib has been added to the NCCN Guidelines as an option for maintenance therapy for patients with stage II–IV disease and germline or somatic BRCA1/2 mutations who are in CR or PR after completing primary treatment with surgery and chemotherapy (OV-5, page 904). When determining whether a patient is a candidate for olaparib maintenance after first-line therapy, it is important to consider the eligibility criteria and characteristics of the patient population enrolled in the SOLO-1 trial.68
Options No Longer Recommended
Paclitaxel Maintenance Therapy
Based on results from the randomized GOG-178 trial, paclitaxel used to be a postremission therapy option for patients with stages II–IV and CR after first-line therapy. In patients with CR after initial 5 to 6 cycles of platinum/paclitaxel combination, those receiving 12 versus 3 additional cycles of paclitaxel sustained a PFS advantage (22 vs 14 months; P=.006), although no significant improvement in OS.74,75 Longer maintenance with paclitaxel was associated with higher rates of grade 2–3 neuropathy and grade 3 pain.75 More recent results from phase III randomized trials have shown that for patients with CR after first-line platinum/taxane-based chemotherapy, maintenance treatment with paclitaxel (versus observation) did not improve PFS or OS, and was associated with higher rates of gastrointestinal toxicity and neurotoxicity.76,77 For these reasons, the NCCN Guidelines no longer include paclitaxel as an option for maintenance therapy after primary chemotherapy.
Pazopanib Maintenance Therapy
Pazopanib used to be a recommended postremission therapy option for patients with stages II–IV disease who are in a clinical CR after first-line chemotherapy. This recommendation was based on the AGO-OVAR 16 phase III randomized trial showing improved PFS with pazopanib versus placebo (17.9 vs 12.3 months; HR, 0.77; 95% CI, 0.64–0.91; P=.0021) in patients with FIGO stage II–IV and no evidence of progression or persistent disease (>2 cm) after surgery plus platinum-taxane chemotherapy (≥5 cycles).78 Pazopanib was a category 2B recommendation for postremission therapy because the FDA has not approved this indication,79 there was no increase in OS, and the safety profile was concerning. Safety results from AGO-OVAR 16 showed that pazopanib was associated with significantly increased rates of certain grade 3–4 toxicities, including hypertension, neutropenia, liver-related toxicity, diarrhea, fatigue, thrombocytopenia, and palmar-plantar erythrodysesthesia, and that many of these toxicities were contributing to an increased rate of treatment discontinuation (discontinuation rate due to AEs for pazopanib vs control: 33.3% vs 5.6%).78 A recent analysis of AGO-OVAR 16 showed that maintenance pazopanib was associated poorer quality of life, often due to persistent diarrhea.69 At NCCN Member Institutions, pazopanib is rarely or never used for maintenance after primary chemotherapy for ovarian cancer. The NCCN panel consensus supported the removal of postremission pazopanib as an option for maintenance therapy after first-line chemotherapy.
NCCN Recommendations
For patients with advanced disease (stages II–IV) who have completed primary treatment with surgery and a recommended platinum-based chemotherapy regimen (supplemental eTable 3) and have no signs of progression, options depend on the primary chemotherapy regimen used, response to treatment, and BRCA1/2 mutation status (OV-5, page 904). Patients who are in CR, defined as no evidence of disease, after primary chemotherapy without bevacizumab have several options: (1) maintenance therapy in the context of a clinical trial, (2) observation, or (3) maintenance olaparib for those with a BRCA1 or BRCA2 mutation. Patients who are in PR after chemotherapy without bevacizumab can consider options recommended for persistent disease (OV-7, available in the complete version of these guidelines at NCCN.org), and those with a BRCA1/2 mutation also have maintenance olaparib as an alternative. Patients who are in a CR or PR after a bevacizumab-containing regimen can be treated with maintenance bevacizumab as per the protocol selected for primary therapy (GOG-0218 or ICON7); maintenance with single-agent olaparib is an alternative for those who have BRCA1/2 mutations. Patients with stable disease after primary treatment with a bevacizumab-containing regimen should receive bevacizumab therapy according to the protocol used for primary treatment (GOG-0218 or ICON7). In each of the above settings in which maintenance olaparib is an option, it is a category 1 option for patients with a germline mutation in BRCA1/2, and a category 2A option for those with a somatic mutation in BRCA1/2. Further research is needed to determine the effect of maintenance olaparib in patients with somatic BRCA1/2 mutations (wild-type germline) and in those without BRCA1 or BRCA2 mutations.
Summary and Conclusions
These NCCN Guidelines Insights highlight updates to the recommendations for primary treatment of patients diagnosed with advanced ovarian cancer. The NCCN Guidelines are in continuous evolution. They are updated annually, and sometimes more often if new high-quality clinical data become available in the interim. Recommendations in the NCCN Guidelines, with few exceptions, are based on the evidence from clinical trials. Expert medical clinical judgment is required when applying these guidelines in the context of individual clinical circumstances to provide optimal care. The physician and patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the panel strongly encourages patient/physician participation in prospective clinical trials.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2019. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
