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Home > Health Library > Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
This PDQ summary addresses the staging and treatment of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC).
Regardless of the site of origin, the hallmark of these cancers is their early peritoneal spread of metastases. The inclusion of FTC and PPC within the ovarian epithelial cancer designation is generally accepted because of much evidence that points to a common Müllerian epithelium derivation and similar management of these three neoplasms. The hypothesis that many high-grade serous ovarian cancers (the most common histologic subtype) may arise from precursor lesions that originate in the fimbriae of the fallopian tubes has been supported by findings from risk-reducing surgeries in healthy women with BRCA1 or BRCA2 mutations. In addition, histologically similar cancers diagnosed as primary peritoneal carcinomas share molecular findings, such as loss or inactivation of the tumor-suppressor p53 and BRCA1 or BRCA2 proteins. Therefore, high-grade serous adenocarcinomas arising from the fallopian tube and elsewhere in the peritoneal cavity, together with most ovarian epithelial cancers, represent extrauterine adenocarcinomas of Müllerian epithelial origin and are staged and treated similarly to ovarian cancer. Since 2000, FTC and PPC have usually been included in ovarian cancer clinical trials.
Clear cell and endometrioid ovarian cancers that are linked to endometriosis have different gene-expression signatures, as do mucinous subtypes.
Stromal and germ cell tumors are relatively uncommon and comprise fewer than 10% of cases. (Refer to the PDQ summaries on Ovarian Germ Cell Tumors Treatment and Ovarian Low Malignant Potential Tumors Treatment for more information.)
Incidence and Mortality
Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies, with almost 50% of all cases occurring in women older than 65 years. It is the fifth most frequent cause of cancer death in women.[4,5]
Estimated new cases and deaths from ovarian cancer in the United States in 2021:
The fimbriated ends of the fallopian tubes are in close apposition to the ovaries and in the peritoneal space, as opposed to the corpus uteri (body of the uterus) that is located under a layer of peritoneum.
Normal female reproductive system anatomy.
Increasing age is the most important risk factor for most cancers. Other risk factors for ovarian (epithelial) cancer include the following:
Family history and genetic alterations
The most important risk factor for ovarian cancer is a history of ovarian cancer in a first-degree relative (mother, daughter, or sister). Approximately 20% of ovarian cancers are familial, and although most of these are linked to mutations in either the BRCA1 or BRCA2 gene, several other genes have been implicated.[19,20] The risk is highest in women who have two or more first-degree relatives with ovarian cancer. The risk is somewhat less for women who have one first-degree relative and one second-degree relative (grandmother or aunt) with ovarian cancer.
In most families affected with breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage to the BRCA1 locus on chromosome 17q21 has been identified.[22,23,24]BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.
The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over that of the general population.[26,27] Two retrospective studies of patients with germline mutations in BRCA1 suggest that the women in these studies have improved survival compared with BRCA1 mutation–negative women.[28,29][Level of evidence: 3iiiA] Most women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, the women in these studies may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.
For women at increased risk, prophylactic oophorectomy may be considered after age 35 years if childbearing is complete. In a family-based study among 551 women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, 2 (0.8%) developed subsequent papillary serous peritoneal carcinoma, and 6 (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a reduction in the risk of ovarian cancer that exceeded 90% (relative risk, 0.04; 95% confidence interval, 0.01–0.16), with an average follow-up of 9 years; however, family-based studies may be associated with biases resulting from case selection and other factors that influence the estimate of benefit. After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma that is similar in appearance to ovarian cancer. (Refer to the Description of the Evidence section in the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for more information.)
(Refer to the Clinical Management of Carriers of BRCA Pathogenic Variants section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
Ovarian, fallopian tube, or peritoneal cancer may not cause early signs or symptoms. When signs or symptoms do appear, the cancer is often advanced. Signs and symptoms include the following:
These symptoms often go unrecognized, leading to delays in diagnosis. Efforts have been made to enhance physician and patient awareness of the occurrence of these nonspecific symptoms.[33,34,35,36,37]
Screening procedures such as gynecologic assessment, vaginal ultrasound, and cancer antigen 125 (CA-125) assay have had low predictive value in detecting ovarian cancer in women without special risk factors.[38,39] As a result of these confounding factors, annual mortality in ovarian cancer is approximately 65% of the incidence rate.
Most patients with ovarian cancer have widespread disease at presentation. Early peritoneal spread of the most common subtype of high-grade serous cancers may relate to serous cancers starting in the fimbriae of the fallopian tubes or in the peritoneum, readily explaining why such cancers are detected at an advanced stage. Conversely, high-grade serous cancers are underrepresented among stage I cancers of the ovary. Other types of ovarian cancers are, in fact, overrepresented in cancers detected in stages I and II. This type of ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported to be as high as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease. The pelvic nodes were involved as often as the para-aortic nodes. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Transdiaphragmatic spread to the pleura is common.
Diagnostic and Staging Evaluation
The following tests and procedures may be used in the diagnosis and staging of ovarian epithelial, fallopian tube, or primary peritoneal cancer:
CA-125 levels can be elevated in other malignancies and benign gynecologic problems such as endometriosis. CA-125 levels and histology are used to diagnose epithelial ovarian cancer.[41,42]
Prognosis for patients with ovarian cancer is influenced by multiple factors. Multivariate analyses suggest that the most important favorable prognostic factors include the following:[43,44,45,46,47]
For patients with stage I disease, the most important prognostic factor associated with relapse is grade, followed by dense adherence and large-volume ascites. Stage I tumors have a high proportion of low-grade serous cancers. These cancers have a derivation distinctly different from that of high-grade serous cancers, which usually present in stages III and IV. Many high-grade serous cancers originate in the fallopian tube and other areas of extrauterine Müllerian epithelial origin.
If the tumor is grade 3, densely adherent, or stage IC, the chance of relapse and death from ovarian cancer is as much as 30%.[48,49,50,51]
The use of DNA flow cytometric analysis of tumors from stage I and stage IIA patients may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.
Case-control studies suggest that BRCA1 and BRCA2 mutation carriers have improved responses to chemotherapy when compared with patients with sporadic epithelial ovarian cancer. This may be the result of a deficient homologous DNA repair mechanism in these tumors, which leads to increased sensitivity to chemotherapy agents.[55,56]
Because of the low specificity and sensitivity of the CA-125 assay, serial CA-125 monitoring of patients undergoing treatment for recurrence may be useful. However, whether that confers a net benefit has not yet been determined. There is little guidance about how patients should be followed up after initial induction therapy, and neither early detection by imaging or by CA-125 elevation has been shown to alter outcomes. (Refer to the Recurrent or Persistent Ovarian Epithelial, FTC, and PPC Treatment section of this summary for more information.)
Other PDQ summaries containing information related to ovarian epithelial, fallopian tube, and primary peritoneal cancer include the following:
Table 1 describes the histologic classification of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC).
In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires surgery. The role of surgery in patients with stage IV ovarian cancer and extra-abdominal disease is yet to be established. If disease appears to be limited to the ovaries or pelvis, it is essential at laparotomy to obtain peritoneal washings and to examine and biopsy or obtain cytologic brushings of the following:
The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) Staging
The FIGO and the American Joint Committee on Cancer (AJCC) have designated staging to define ovarian epithelial cancer. The FIGO-approved new staging system for ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) is the one most commonly used.[2,3]
Treatment options for patients with all stages of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) have consisted of surgery followed by platinum-based chemotherapy.
Early stage refers to stages I and II. However, because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.
Numerous clinical trials are in progress to refine existing therapies and test the value of different approaches to postoperative drug and radiation therapy. Patients with any stage of ovarian cancer are appropriate candidates for clinical trials.[1,2] Information about ongoing clinical trials is available from the NCI website.
The treatment options for ovarian epithelial cancer, FTC, and PPC are presented in Table 6.
Early stage refers to stage I and stage II. However, because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group (GOG) clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.
Standard Treatment Options for Early-Stage Ovarian Epithelial Cancer, FTC, and PPC
Standard treatment options for early-stage ovarian epithelial, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) include the following:
Surgery with or without chemotherapy
If the tumor is well differentiated or moderately well differentiated, surgery alone may be adequate treatment for patients with stage IA or IB disease. Surgery includes hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. The undersurface of the diaphragm is visualized and biopsied. Biopsies of the pelvic and abdominal peritoneum and the pelvic and para-aortic lymph nodes are also performed. Peritoneal washings are routinely obtained.[1,2] In patients who desire childbearing and have grade 1 tumors, unilateral salpingo-oophorectomy may be associated with a low risk of recurrence.
In the United States, except for the most favorable subset of patients (those with stage IA well-differentiated disease), evidence based on double-blinded, randomized, controlled trials with total mortality endpoints supports adjuvant treatment with cisplatin, carboplatin, and paclitaxel.
Evidence (surgery with or without chemotherapy):
Given the increased risk of recurrence in patients with stage II disease and in those classified as having high-grade serous cancer, the GOG after 2007 opted to include patients with stage II disease in advanced ovarian cancer trials (refer to the Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment section of this summary for more information). Although the routine use of six cycles of chemotherapy is promulgated by guidelines, on subset analyses it is a source of controversy. Platinum-based chemotherapy including paclitaxel for three or six cycles has been evaluated by the GOG in additional trials that included prolonged maintenance paclitaxel, before phasing out early-stage clinical trials.
The following treatments have been largely displaced by the adoption of carboplatin plus paclitaxel for early stages of high-grade ovarian cancers:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for patients with all stages of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) have consisted of surgery followed by platinum-based chemotherapy. Because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group (GOG) clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.
The most common approach to advanced ovarian cancer is surgery followed by adjuvant platinum-based chemotherapy. Published trials, most with primary endpoints of progression-free survival (PFS), are listed in Table 7. A PFS endpoint was endorsed by the Gynecologic Cancer InterGroup (GCIC), but subsequently it was questioned in a systematic review and meta-analysis conducted by the GCIC. After a MEDLINE search of randomized clinical trials of newly-diagnosed patients with ovarian epithelial cancer, FTC, or PPC, all studies with a minimum sample of 60 patients published from 2001 through 2016 were used to extract PFS and overall survival (OS) at an individual level. The PFS was mostly based on measurement of CA-125 levels confirmed by radiological examination or by GCIC criteria. Of 17 trials that were individually assessed, five tested the addition of maintenance therapy, seven tested additional induction drugs, and five tested intensification therapy. No poly (ADP-ribose) polymerase (PARP) inhibitor trials were included in this meta-analysis. The analysis concluded that PFS is not an adequate surrogate for OS, but it was limited by the narrow range of treatment effects observed and by poststudy treatments.
Standard Treatment Options for Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC
Standard treatment options for advanced-stage ovarian epithelial cancer, FTC, and PPC include the following:
Platinum-based chemotherapy is the initial treatment for all patients diagnosed with advanced disease who undergo surgical resection and are staged with cancer that has spread to the pelvic peritoneum (stage II) and beyond (stages III and IV). The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage II and III disease are applied.
Surgery has historically been done by open laparotomy performed by gynecologic oncology surgeons, and has included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and debulking of peritoneal implants (often including resection of the bowel or adjacent organs as needed) to reduce tumor to microscopic, if it can safely be performed.
The volume of disease left at the completion of the primary surgical procedure in GOG studies has been related to patient survival.[2,3,4,5] A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.[Level of evidence: 3iA]
However, in an analysis of 2,655 of the 4,312 patients enrolled in the largest GOG study (GOG-0182 [NCT00011986]) (refer to the Surgery followed by platinum-based chemotherapy section of this summary for more information), only cytoreduction to nonvisible disease that is R0 (i.e., complete surgical resection) had an independent effect on survival. The GOG had conducted separate trials to establish a role for intraperitoneal (IP) therapy for women whose disease has been optimally cytoreduced (defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum) (refer to the Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy section of this summary for a review of these trials).
Suboptimally debulked stage III and stage IV patients have inferior 5-year survival rates, but the gap has narrowed in trials that included taxanes and other drugs added to platinums. By contrast, optimally debulked stage III patients treated with a combination of intravenous (IV) taxane and IP platinum plus taxane achieved a median survival of 66 months in a GOG trial.[Level of evidence: 1iiA]
Surgery followed by platinum-based chemotherapy
Platinum agents, such as cisplatin or its less-toxic second-generation analog, carboplatin, given either alone or in combination with other drugs, are the foundation of chemotherapy regimens used. Trials by various cooperative groups (conducted from 1999 to 2010) addressed issues of optimal dose intensity [9,10,11] for both cisplatin and carboplatin, schedule, and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.
With the introduction of the taxane paclitaxel, two trials confirmed the superiority of cisplatin combined with paclitaxel when compared with the previous standard treatment of cisplatin plus cyclophosphamide.[15,16] However, two trials that compared single-agent paclitaxel with either cisplatin or carboplatin (ICON3 and GOG-132) failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (refer to Table 7 for a list of these studies).
Based on the evidence, the initial standard treatment for patients with ovarian cancer is the combination of cisplatin or carboplatin with paclitaxel (defined as induction chemotherapy).
Evidence (combination of cisplatin or carboplatin with paclitaxel):
Since the adoption of the standard combination of platinum plus taxane nearly worldwide, clinical trials have demonstrated the following:
Moreover, for the stage III patients who made up 84% to 87% of patients, PFS differences were only noted if surgery achieved R0 resections:
In gynecologic cancer, as opposed to breast cancer, weekly paclitaxel was not explored in phase III trials before 2004. The positive results from the Japanese Gynecologic Oncology Group (JGOG) 3016 study subsequently led to early adoption of divided-dose paclitaxel as the standard treatment, but with only partial confirmation of its superior results.
Evidence (dose-dense [weekly] treatment schedule):
Other than ethnicity, this trial population may have differed from GOG and other studies in that patients were younger (average age, 57 years). Twenty percent of patients had stage II disease and 33% of patients had histologies other than high-grade serous or endometrioid cancer. Also, 11% of patients were entered while receiving neoadjuvant treatment, which was an all-inclusive way of assessing treatments other than chemotherapy in first-line settings. The JGOG-3016 study results demonstrated the following:
Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy
The pharmacologic basis for the delivery of anticancer drugs by the IP route was established in the late 1970s and early 1980s. When several drugs were studied, mostly in the setting of minimal residual disease at reassessment after patients had received their initial chemotherapy, cisplatin alone and in combination received the most attention. Favorable outcomes from IP cisplatin were most often seen when tumors had shown responsiveness to platinum therapy and with small-volume tumors (usually defined as tumors <1 cm).
In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the IV route. IP cisplatin was the common denominator of these randomized trials.
Evidence (surgery followed by IP chemotherapy):
Specifically, the most recent study, GOG-0172, demonstrated the following:[Level of evidence:1iiA]
An updated combined analysis of GOG-0114 and GOG-0172 included 876 patients with a median follow-up of 10.7 years and reported the following results.
In this study, 1,560 patients were randomly assigned to receive six cycles of IV paclitaxel (80 mg/m2 once per week with IV carboplatin [AUC, 6] every 3 weeks) versus IV paclitaxel (80 mg/m2 once per week with IP carboplatin [AUC, 6] [the IP carboplatin arm]) versus once-every-3-weeks IV paclitaxel (135 mg/m2 over 3 hours on day 1, IP cisplatin 75 mg/m2 on day 2, and IP paclitaxel 60 mg/m2 on day 8 [the IP cisplatin arm]). The last regimen was the modified IP superior arm of GOG-0172. All participants received bevacizumab (15 mg/kg IV every 3 weeks in cycles 2−22) and bevacizumab (15 mg/kg every 3 weeks) was added to all three arms.
Surgery before or after platinum-based chemotherapy and the addition of bevacizumab to induction and/or consolidation therapy
Two phase III studies compared the outcome of standard primary cytoreductive surgery with that of neoadjuvant chemotherapy followed by interval cytoreductive surgery; both studies (described below) demonstrated that PFS and OS were noninferior with the use of primary cytoreductive surgery.[41,42]
Evidence (chemotherapy followed by surgery):
Methods included efforts to ensure accuracy of diagnosis (e.g., rule out peritoneal carcinomatosis of gastrointestinal origin) and stratification by largest preoperative tumor size (excluding ovaries) (<5 cm, >5 cm–10 cm, >10 cm–20 cm, or >20 cm). Other stratification factors included institution, method of biopsy (i.e., image-guided, laparoscopy, laparotomy, or fine-needle aspiration), and tumor stage (i.e., stage IIIC or IV). The primary endpoint of the study was OS, with primary debulking surgery considered the standard.[Level of evidence: 1iiA]
A minimization method was used to randomly assign patients in a 1:1 ratio. Participants were stratified by randomizing center, largest radiologic tumor, and prespecified chemotherapy regimen. The primary endpoint was to establish noninferiority, with the upper bound of a one-sided 90% CI for the HRdeath at less than 1.18.
These studies and additional observational and partially published phase III studies have led to the publication of a Clinical Practice Guideline on behalf of the Society of Gynecologic Oncology and the American Society of Clinical Oncology.
Hyperthermic peritoneal chemotherapy (HIPEC) is another pharmacologically based modality to enhance the antitumor effects via direct drug delivery to peritoneal surfaces. It was initially tested against mucinous tumors of gastrointestinal origin. Increasingly, HIPEC is being applied to ovarian cancers, with considerable variation in patient selection, drugs administered, and time at target temperatures (most often 30 minutes at 42°C). The role of HIPEC remains experimental in the treatment of patients with high-grade serous ovarian cancers.
Experience with HIPEC spans more than two decades after initial publications that have since been summarized. Evidence for its use in ovarian cancer includes a randomized study.
In the institutions that have experience performing HIPEC, adverse events were comparable in the two groups. Patients in the HIPEC group had higher incidences of ileus (3% vs. 8%), fever (8% vs. 12%), and thromboembolic events (2% vs. 6%), but in that group, there were smaller differences in electrolyte changes (5% vs. 6%) and neuropathy (27% vs. 31%) than in patients in the surgery group, and both groups of patients had added IV chemotherapy. The use of sodium thiosulfate most likely accounts for this favorable safety profile vis-à-vis cisplatin, which was given as part of HIPEC in a published phase I trial. HIPEC should be considered an option for patients who receive neoadjuvant therapy if they have access to a surgical team who has experience performing HIPEC.
Two phase III trials (GOG-0218 [NCT00262847] and ICON7 [NCT00483782]) have evaluated the role of bevacizumab in first-line therapy for ovarian epithelial cancer, FTC, and PPC after surgical cytoreduction.[50,51] Both trials showed a modest improvement in PFS when bevacizumab was added to initial chemotherapy and continued every 3 weeks for 16 and 12 additional cycles, as a maintenance phase.
Evidence (surgery followed by chemotherapy and bevacizumab):
Results from the trial demonstrated the following:
These two studies supported U.S. Food and Drug Administration (FDA) approval of bevacizumab in the first-line setting, both during induction and as consolidation therapy, after bevacizumab first gained approval in the platinum-resistant setting (AURELIA [NCT00976911] trial).
Surgery before or after platinum-based chemotherapy and the addition of poly (ADP-ribose) polymerase (PARP) inhibitors to induction and/or consolidation therapy
PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, the inhibition of PARP results in the production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene. Cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition,[52,53] has spurred the clinical development of this class of agents. Initially, these agents were tested in women who had been pretreated with chemotherapy. (Refer to the Bevacizumab, other targeted drugs, and poly [ADP-ribose] polymerase [PARP] inhibitors with or without chemotherapy section of this summary for more information.)
Evidence (surgery before or after chemotherapy and PARP inhibitors):
Other consolidation and/or maintenance therapy trials
Phase III trials of consolidation and/or maintenance therapy have been carried out with cytotoxic drugs, small molecules, vaccines, and radioimmunoconjugates  with negative results. Extending duration of paclitaxel has resulted in modest lengthening of PFS in randomized trials.[62,63]
Trials ongoing with antiangiogenic drugs (other than bevacizumab) and PARP inhibitors are described in the Treatment Options under Clinical Evaluation section that follows.
Treatment Options Under Clinical Evaluation
Trials are ongoing with antiangiogenic drugs (other than bevacizumab) and with PARP inhibitors. PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, inhibition of PARP results in production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene; cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition [52,53] has spurred the clinical development of this class of agents. Sensitivity to platinum compounds is a feature of homologous recombination deficiency, and a population of platinum-sensitive patients is expected to be homologous recombination deficiency enriched and most likely to benefit from PARP inhibition. Several of these drugs have been studied in ovarian cancer as monotherapy or drug combinations and have demonstrated activity in the recurrent setting, with olaparib, rucaparib, and niraparib achieving FDA approval with varying indications. (Refer to the Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC Treatment section of this summary for more information.) Phase III studies are ongoing with these three agents after first-line treatments, and also with a fourth drug, veliparib, which is not otherwise commercially available.
Information about ongoing clinical trials is available from the NCI website.
Approximately 80% of patients diagnosed with ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) will relapse after first-line platinum-based and taxane-based chemotherapy and may benefit from subsequent therapies. Early detection of persistent disease by second-look laparotomies after completion of first-line treatment is no longer practiced. When the outcomes in institutions practicing such procedures (50% of institutions) were informally compared with the outcomes in institutions not using such procedures, lack of support for second-look laparotomies grew. This was confirmed in the Gynecologic Oncology Group (GOG) GOG-0158 trial.
However, the practice of close follow-up of patients completing treatment by measuring cancer antigen 125 (CA-125) levels at intervals of 1 to 3 months was nearly universally adopted. In patients who are in clinical complete remission, increases in CA-125 from their initial treatment represent the most common method to detect disease that will eventually relapse clinically.
Treatment based on abnormal increases in CA-125 in the absence of symptoms or imaging evidence of disease has been addressed in a clinical trial.
Evidence (early vs. delayed initiation of treatment):
A quality-of-life assessment accompanying this study found a detrimental effect in the early treatment when it was compared with waiting for the development of signs and symptoms.
The impact of these findings on CA-125 surveillance patterns over a decade in five U.S. Cancer Centers was disappointingly low.[4,5] Monitoring CA-125 levels in follow-up was used to separate platinum-sensitive from platinum-resistant recurrences and plays a role in identifying appropriate candidates for secondary cytoreduction, although this strategy awaits confirmation with a randomized trial.
Treatment Options for Patients with Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC
Drug treatment options for patients with recurrent disease are subdivided as follows:
Other agents that have shown activity in phase II trials are listed in Table 10 and may also be used alone or in combination with other drugs, but such treatments are best done in prospective trials.
Cytoreduction may be used; this intervention has been studied in the setting of randomized clinical trials (e.g., GOG-0213 [NCT00565851], DESKTOP III [NCT01166737], and SOC 1 [NCT01611766]). The SOC 1 trial was published with immature survival data. Eligibility criteria differed between each of the trials. Only 67% of patients achieved complete gross resections in the GOG-0213 trial, compared with 77% of patients in the SOC 1 trial and 75% of patients in the DESKTOP III trial. The Dutch SOCcer trial was closed prematurely in 2015 because only 27 of 230 planned patients (12%) were accrued in 5 years.[9,10] In order for the GOG trial to study the role of surgery, the target enrollment was 485 patients which took almost 10 years to achieve.
The role of radiation therapy in patients with recurrent ovarian cancer has not been defined.
Platinum-containing chemotherapy regimens
Table 8 shows the chemotherapy regimens used in first relapse for the treatment of platinum-sensitive recurrent ovarian cancer.
On the basis of improved survival with etoposide or fluorouracil, carboplatin was approved in 1987 for the treatment of patients with ovarian cancer whose disease recurred after treatment with cisplatin. In a randomized phase II trial of paclitaxel, a currently used second-line drug, the cisplatin-containing combination of cisplatin plus doxorubicin plus cyclophosphamide, yielded a superior survival outcome. This study and subsequent studies (see Table 8) have reinforced the use of carboplatin as the treatment core for patients with platinum-sensitive recurrences. Cisplatin is occasionally used, particularly in combination with other drugs, because of its lesser myelosuppression, but this advantage over carboplatin is counterbalanced by greater patient intolerance.
Oxaliplatin, initially introduced with the hope that it would overcome platinum resistance, has activity mostly in platinum-sensitive patients  but has not been compared with carboplatin alone or in combinations.
With all platinum agents, outcome is generally better the longer the initial interval without recurrence from the initial platinum-containing regimens. Therefore, on occasion, patients with platinum-sensitive recurrences relapsing within 1 year have been included in trials of nonplatinum drugs. In one such trial, comparing the pegylated liposomal doxorubicin to topotecan, the subset of patients who were platinum sensitive had better outcomes with either drug (and in particular with pegylated liposomal doxorubicin) relative to the platinum-resistant cohort.
Several randomized trials have addressed whether the use of a platinum in combination with other chemotherapy agents is superior to single agents (see Table 8).
Evidence (platinum in combination with other chemotherapy agents):
Given its toxicity profile and noninferiority to the standard regimen, carboplatin plus pegylated liposomal doxorubicin is an important option for patients with platinum-sensitive recurrence.
Carboplatin plus paclitaxel has been considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurological toxic effects. The GOG-0213 trial is comparing this regimen with the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.
Bevacizumab, other targeted drugs, and poly (ADP-ribose) polymerase (PARP) inhibitors with or without chemotherapy
Evidence (bevacizumab with gemcitabine/carboplatin):
Evidence (bevacizumab added to carboplatin or carboplatin doublets):
The study demonstrated that the addition of bevacizumab improved PFS but did not result in any OS benefit and was associated with increased toxicity. This study preceded incorporation of PARP inhibitors in phase III trials for patients with platinum-sensitive recurrence. In a subset analysis of patients with BRCA mutations in this study, only 23 patients in the standard arm and 30 patients in the chemotherapy-plus-bevacizumab arm had documented deleterious mutations. These details underscore the evolution of targeted treatment that has occurred during and after this study.
Evidence (bevacizumab plus pegylated liposomal doxorubicin/carboplatin vs. bevacizumab plus gemcitabine/carboplatin):
Refer to Table 8 for results of clinical trials that used gemcitabine/carboplatin.[16,24] Adverse events differed among the two comparators but serious adverse events were 10% with pegylated liposomal doxorubicin/carboplatin and 9% with gemcitabine/carboplatin. Specifically, hypertensive crisis, presumably related to bevacizumab, occurred in five patients after receiving pegylated liposomal doxorubicin/carboplatin and in three patients after receiving gemcitabine/carboplatin.
Evidence (PARP inhibitors with or without antiangiogenic agents):
PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, inhibition of PARP results in production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene; cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition [25,26] has spurred the clinical development of this class of agents. Sensitivity to platinum compounds is a feature of homologous recombination deficiency, and a population of platinum-sensitive patients is expected to be homologous recombination deficiency-enriched and most likely to benefit from PARP inhibition. Clinical studies with olaparib have been ongoing since 2005 when a phase I study enrolled women with ovarian cancer who were known BRCA mutation carriers. Because of objective responses in this initial trial, olaparib, and subsequently rucaparib and niraparib, have been studied after several lines of treatment for recurrence; these studies lead to an initial approval for olaparib, and then rucaparib and niraparib, as listed in Table 9.
The data from this trial were used by the U.S. Food and Drug Administration (FDA) to approve olaparib for patients with ovarian cancer who have known BRCA1 or BRCA2 mutations and have failed three previous regimens.
Platinum-refractory or platinum-resistant recurrence
Clinical recurrences that take place within 6 months of completion of a platinum-containing regimen are considered platinum-refractory or platinum-resistant recurrences. Anthracyclines (particularly when formulated as pegylated liposomal doxorubicin), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences on the basis of activity and their favorable therapeutic indices relative to agents listed in Table 10. The long list underscores the marginal benefit, if any, of these agents. Clinical trials should be considered for patients with platinum-resistant disease.
Drugs used to treat platinum-refractory or platinum-resistant recurrences include the following:
Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[43,44,45,46,47] Patients generally received paclitaxel in front-line induction regimens. Re-treatment with paclitaxel, particularly in weekly schedules, had activity comparable with that of other drugs. Residual neuropathy upon recurrence may shift the choice of treatment towards other agents.
Randomized studies have indicated that the use of topotecan achieved results that were comparable with those achieved with paclitaxel.
Evidence (pegylated liposomal doxorubicin):
This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.
Gemcitabine is an antimetabolite that was developed and approved in combination with platinum-based chemotherapy drugs and has shown activity as a single agent. Gemcitabine combined with cell cycle−targeted drugs and other drug combinations used in indications such as pancreatic and lung cancers are being explored.[56,57,58,59]
Pemetrexed combined with gemcitabine has had unconvincing results compared with either agent alone.[60,61] More studies are forthcoming that target cell cycle derangements common in certain genomic subtypes of ovarian cancer. Specifically, gemcitabine is presumed to be more active when there is loss of G1/S checkpoint from TP53 mutations, CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation.
Chemotherapy and/or bevacizumab
The FDA has approved the use of bevacizumab in combination with pegylated liposomal doxorubicin, paclitaxel, or topotecan as a result of the OCEANS and AURELIA trials.
OCEANS (NCT00434642) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrences. (Refer to the Bevacizumab with chemotherapy in platinum-sensitive recurrence section of this summary for more information.)
Evidence (bevacizumab with chemotherapy):
Patients were then randomly assigned to receive either chemotherapy alone or chemotherapy with bevacizumab (10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks if on the 3-week-dosing schedule). Crossover to a bevacizumab-containing regimen was allowed at progression for those patients in the chemotherapy-only arm. PFS was the primary outcome, with response rate, OS, safety, and quality of life used as secondary endpoints. The enrollment included 361 patients with a median follow-up of 13.9 months in the chemotherapy-only arm and 13.0 months in the chemotherapy-plus-bevacizumab arm.
Although there were some limitations in study design, more patients on the chemotherapy-plus-bevacizumab arm had 15% or greater improvement in their GI scores when compared with baseline. For the chemotherapy-plus-bevacizumab arm, 34 of 115 patients (29.6%) showed improvement versus 15 of 118 (12.7%) patients who showed improvement on the chemotherapy-alone arm (difference, 16.9%; 95% CI, 6.1%–27.6%; P = .002).
These studies confirm the effect of improving PFS when bevacizumab is added to chemotherapy for ovarian cancer. In the OCEANS trial, the HR for progression was even more prominent than in the first-line trials, and a significant effect was seen when the bevacizumab-chemotherapy combination was extended beyond six cycles until progression.
In summary, the improvement achieved by bevacizumab in relative risk and PFS rates in platinum-sensitive and platinum-resistant recurrences has been consistently more than the improvement achieved with chemotherapy alone; however, bevacizumab-related toxic effects must be considered.
Three phase II studies have shown activity for this antibody to vascular endothelial growth factor.
Other drugs used to treat platinum-refractory or platinum-resistant recurrence (efficacy not well defined)
The drugs shown in Table 10 are not fully confirmed to have activity in a platinum-resistant setting, have a less desirable therapeutic index, and have a level of evidence lower than 3iiiDiv.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Ovarian Epithelial Cancer, Fallopian Tube Cancer (FTC), and Primary Peritoneal Cancer (PPC)
Added National Cancer Institute as reference 4.
Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC Treatment
Revised text to state that cytoreduction has been studied in the setting of randomized clinical trials. Also added text about the differing eligibility requirements, the percentages of patients who achieved gross total resections, and the slow accrual rates for these trials (cited Shi et al., Du Bois et al., 2014 van de Laar et al., and 2017 van de Laar et al. as references 6, 8, 9, and 10, respectively).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of ovarian epithelial, fallopian tube, and primary peritoneal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
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PDQ® Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389443]
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Last Revised: 2021-05-20
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