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This PDQ summary covers the staging and treatment of ovarian epithelial, fallopian tube, and primary peritoneal cancer.
Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women older than 65 years. Findings from risk-reducing surgeries in healthy women with BRCA1 or BRCA2 mutations have reinforced the hypothesis that many high-grade serous cancers—the most common histologic subtype of ovarian cancer—may arise from precursor lesions that originate in the fimbriae of the fallopian tubes. In addition, histologically similar cancers diagnosed as primary peritoneal carcinomas share molecular findings, such as loss or inactivation of the tumor-suppressors 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, they usually have been included in ovarian cancer clinical trials. On the other hand, 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
Estimated new cases and deaths from ovarian cancer in the United States in 2015:
The most important risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. Approximately 20% of ovarian cancers are familial, and although most of these are linked to mutations in the BRCA1 or BRCA2 genes, several other genes have been implicated in familial ovarian cancers.[6,7] The highest risk appears 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 and one second-degree relative (grandmother or aunt) with ovarian cancer.
In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21.[9,10,11]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.[13,14] Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared with BRCA1 mutation-negative women.[15,16][Level of evidence: 3iiiA] Most women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, these women 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 women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, 2 of them (0.8%) developed subsequent papillary serous peritoneal carcinoma, and 6 of them (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 higher-than-90% reduction in the risk of ovarian cancer (relative risk [RR], 0.04; 95% confidence interval [CI], 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 may influence the estimate of benefit. (Refer to the Description of the Evidence section in the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for more information.)
After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer.
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. In this study, 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. Also, transdiaphragmatic spread to the pleura is common.
For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence, and large-volume ascites. The use of DNA flow cytometric analysis of 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. Stage I tumors have a high proportion of low-grade serous cancers and have a distinctly different derivation than 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 mullerian epithelial origin.
Prognosis for patients with ovarian cancer is influenced by several factors, but multivariate analyses suggest that the most important favorable factors include the following:[25,26,27,28,29]
Although the ovarian cancer-associated antigen, CA-125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease. For patients whose elevated CA-125 normalizes with chemotherapy, more than one subsequent elevated CA-125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.[31,32]
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.[33,34]
Survival and Follow-up
Most patients with ovarian cancer have widespread disease at presentation. This may be partly explained by relatively early spread (and implantation) of high-grade papillary serous cancers to the rest of the peritoneal cavity. Conversely, symptoms such as abdominal pain and swelling, gastrointestinal symptoms, and pelvic pain often go unrecognized, leading to delays in diagnosis. Screening procedures such as gynecologic assessment, vaginal ultrasound, and CA-125 assay have had low predictive value in detecting ovarian cancer in women without special risk factors.[36,37] Efforts have been made to enhance physician and patient awareness of the occurrence of these nonspecific symptoms.[38,39,40,41,42] (Refer to the PDQ summaries on Pain and Gastrointestinal Complications for more information.) As a result of these confounding factors, yearly mortality in ovarian cancer is approximately 65% of the incidence rate.
Long-term follow-up of suboptimally debulked stage III and stage IV patients showed a 5-year survival rate lower than 10% with platinum-based combination therapy prior to the current generation of trials, including taxanes. By contrast, optimally debulked stage III patients treated with a combination of intravenous taxane and intraperitoneal platinum plus taxane achieved a median survival of 66 months in a Gynecologic Oncology Group trial.
Numerous clinical trials are in progress to refine existing therapy 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.[44,45] Information about ongoing clinical trials is available from the NCI Web site.
Other PDQ summaries containing information related to ovarian epithelial, fallopian tube, and primary peritoneal cancer include the following:
The following is a list of ovarian epithelial, fallopian tube, and primary peritoneal cancer histologic classifications.
(Refer to the PDQ summary on Ovarian Low Malignant Potential Tumor Treatment for more information.)
In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires surgery. The role of surgery in patients with stage IV disease 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 examine and biopsy or to obtain cytologic brushings of the diaphragm, both paracolic gutters, the pelvic peritoneum, para-aortic and pelvic nodes, and infracolic omentum, and to obtain peritoneal washings.
The serum CA-125 level is valuable in the follow-up and restaging of patients who have elevated CA-125 levels at the time of diagnosis.[2,3,4] While an elevated CA-125 level indicates a high probability of epithelial ovarian cancer, a negative CA-125 level cannot be used to exclude the presence of residual disease. CA-125 levels can also be elevated in other malignancies and benign gynecologic problems such as endometriosis, and CA-125 levels should be used with a histologic diagnosis of epithelial ovarian cancer.[6,7]
The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define ovarian epithelial cancer. FIGO recently approved a new staging system for ovarian, fallopian tube, and primary peritoneal cancer (see Table 1). The FIGO system is most commonly used.[8,9]
Treatment options for patients with all stages of ovarian epithelial, fallopian tube, and primary peritoneal cancer have consisted of surgery followed by platinum-based chemotherapy. Early stage refers to stages I and II but because of a high recurrence rate for stage II patients in all Gynecologic Oncology Group (GOG) early-stage disease trials, stage II cancers have been included in clinical trials together with the more advanced stages 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.
In two large European trials, European Organization for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm (EORTC-ACTION) and International Collaborative Ovarian Neoplasm (MRC-ICON1 [NCT00002477]), patients with stage IA and stage IB (grades II and III), all stage IC and stage II, and all stage I and stage IIA clear cell carcinoma were randomly assigned to adjuvant chemotherapy or observation. Data were reported individually and in pooled form.[12,13,14]
The EORTC-ACTION trial required at least four cycles of carboplatin or cisplatin-based chemotherapy as treatment. Although surgical staging criteria were monitored, inadequate staging was not an exclusion criterion. Recurrence-free survival (RFS) was improved in the adjuvant chemotherapy arm (hazard ratio [HR], 0.63; P = .02), but overall survival (OS) was not affected (HR, 0.69; 95% confidence interval [CI], 0.44–1.08; P = .10). OS was improved by chemotherapy in the subset of patients with inadequate surgical staging.
The MRC-ICON1 trial randomly assigned patients to six cycles of single-agent carboplatin or cisplatin or platinum-based chemotherapy (usually cyclophosphamide, doxorubicin, and cisplatin) versus observation and had similar entry criteria to the EORTC-ACTION trial; however, the MRC-ICON1 trial did not monitor whether adequate surgical staging was performed. Both RFS and OS were significantly improved; 5-year survival figures were 79% with adjuvant chemotherapy versus 70% without adjuvant chemotherapy.
The pooled data from both studies indicated significant improvement in RFS (HR, 0.64; 95% CI, 0.50–0.82; P = .001) and OS (HR, 0.67; 95% CI, 0.50–0.90; P = .008). These pooled data provided for an OS at 5 years of 82% with chemotherapy and 74% with observation, with a 95% CI in the difference of 2% to 12%. An accompanying editorial emphasized that the focus of subsequent trials must be to identify patients who do not require additional therapy among the early ovarian cancer subset.[Level of evidence: 1iA] Optimal staging is one way to better identify these patients. Except for the most favorable subset (patients with stage IA well-differentiated disease), GOG trials, and the evidence above, which is based on double-blinded, randomized controlled trials with total mortality endpoints, support treatment with cisplatin, carboplatin, and paclitaxel (in the United States).
GOG-0157 evaluated whether six cycles were superior to three cycles of chemotherapy for patients with early stage, high-risk epithelial ovarian cancer after primary surgery. Eligible patients were those with stage IA grade 3 or clear-cell histology, stage IB grade 3 or clear-cell histology, all stage IC, and all stage II. Patients were randomly assigned to either three or six cycles of the combination of paclitaxel (175 mg/m2 administered over 3 hours) and carboplatin dosed (area under the curve, 7.5) over 30 minutes and given every 21 days. The primary endpoint was RFS, and the study was powered to detect a 50% decrease in the recurrence rate at 5 years. A total of 427 patients were eligible. No significant difference was found when three cycles (cumulative incidence of recurrence, 25.4%) were compared with six cycles (cumulative incidence of recurrence, 20.1%) (HR, 0.76; [0.5 – 1.13]) or OS for three cycles (81%) versus six cycles (83%) (HR, 1.02; P = .94).[Level of evidence: 1iiDi]
As expected, the use of six cycles was associated with increased grade 3 or 4 neurologic toxic effects and increased grade 4 hematologic toxic effects. Although surgical staging was required for study entry, an audit revealed that 29% of the study subjects had either incomplete documentation of their surgery or insufficient surgical effort. In a post-hoc analysis of the patients who underwent complete surgical staging, three additional cycles of chemotherapy decreased the risk of recurrence by only 3%. The cumulative incidence of recurrence within 5 years was 18% for women with stage I disease and 33% for women with stage II disease. Given the increased risk of recurrence in patients with stage II disease and combined with an earlier trial, the Ovarian Committee of the GOG has opted to include patients with stage II disease in advanced ovarian cancer trials. The interpretation of this study, including findings on subset analyses, has been the source of controversy.
Patients with stage II ovarian cancer were also enrolled in a Japanese Gynecology Oncology Group study (JGOG-3601 [NCT00226915]) that tested a weekly dosing schedule versus the conventional every-3-week dosing schedule in first-line ovarian cancer.[17,18,19] These results are reviewed in the Advanced-Stage Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment section.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I ovarian epithelial cancer, primary peritoneal cavity cancer, fallopian tube cancer and primary peritoneal cavity cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Treatment options for patients with all stages of ovarian epithelial, fallopian tube, and primary peritoneal cancer have consisted of surgery followed by platinum-based chemotherapy. Because of a high recurrence rate for stage II patients in all Gynecologic Oncology Group (GOG) early-stage disease trials, stage II cancers have been included in clinical trials together with the more advanced stages 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.
Primary surgical cytoreduction
Patients diagnosed with stage III and stage IV disease are treated with surgery and chemotherapy; however, the outcome is generally less favorable for patients with stage IV disease. 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 III disease are applied. The options for intraperitoneal (IP) regimens are also less likely to apply both practically (as far as inserting an IP catheter at the outset) and theoretically (aimed at destroying microscopic disease in the peritoneal cavity) in patients with stage IV disease.
Surgery has been used as a therapeutic modality and also to adequately stage the disease. Surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with omentectomy and debulking of as much gross tumor as can safely be performed. While primary cytoreductive surgery may not correct for biologic characteristics of the tumor, considerable evidence indicates that the volume of disease left at the completion of the primary surgical procedure is related to patient survival. 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]
Results of a retrospective analysis of 349 patients with postoperative residual masses no larger than 1 cm suggested that patients who present at the outset with large-volume disease and achieve small-volume disease by surgical debulking have poorer outcomes than similar patients who present with small-volume disease. Gradual improvement in survival with decreasing residual tumor volume is likely. Although the association may not be causal, retrospective analyses, including a meta-analysis of patients receiving platinum-based chemotherapy, have found cytoreduction to be an independent prognostic variable for survival.[3,4]
For the past three decades, the GOG has conducted separate trials for women whose disease has been optimally cytoreduced (most recently defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum). The extent of residual disease following the initial surgery is a determinant of outcome in most series [1,2,3,4] and has been used in the design of clinical trials, particularly by the GOG.
On the basis of these findings, the standard treatment approaches are subdivided into the following:
However, the extent of cytoreduction is unpredictable, and most current studies do not currently follow clinical trial paths, with the exception of those studies using IP treatment (refer to the Surgery followed by IP chemotherapy section).
Neoadjuvant chemotherapy followed by surgery
A study led by the European Organization for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group (GCG), together with the National Cancer Institute of Canada Clinical Trials Group (EORTC-55971 [NCT00003636]), between 1998 and 2006 included 670 women with stage IIIC and IV ovarian, tubal, and primary peritoneal cancer. The women were randomly assigned to primary debulking surgery followed by at least six courses of platinum-based chemotherapy or to three courses of neoadjuvant platinum-based chemotherapy followed by so-called interval debulking surgery, and at least three more courses of platinum-based chemotherapy. Methods included efforts to ensure accuracy of diagnosis (vis-à-vis 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 were for institution, method of biopsy (i.e., image-guided, laparoscopy, laparotomy, or fine-needle aspiration), and tumor stage (i.e., stages IIIC or IV). The primary endpoint of the study was overall survival (OS), with primary debulking surgery considered the standard.
Median OS for the primary debulking surgery was 29 months, compared with 30 months for patients assigned to neoadjuvant chemotherapy. The hazard ratio (HR) for death in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84–1.13; P = .01 for noninferiority).[Level of evidence: 1iiA] Perioperative and postoperative morbidity and mortality were higher in the primary-surgery group (7.4% severe hemorrhage and 2.5% deaths, contrasting with 4.1% severe hemorrhage and 0.7% deaths in the neoadjuvant group). The strongest independent predictor of prolonged survival was the absence of residual tumor after surgery. The subset of patients achieving optimal cytoreduction (≤1 cm residuum), whether after primary debulking surgery or after neoadjuvant chemotherapy followed by interval debulking surgery, had the best median OS.
Surgery followed by IP chemotherapy
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 platinums 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 intravenous (IV) route. IP cisplatin was the common denominator of these randomized trials.
The use of IP cisplatin as part of the initial up-front approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (SWOG-8501, GOG-0114, and GOG-0172).[7,8,9] These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen. In the three studies, superior progression-free survival (PFS) and OS favoring the IP arm were documented. Specifically, the most recent study, GOG-0172, resulted in a median survival rate of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03).[Level of evidence:1iiA] Toxic effects were greater in the IP arm, contributed to in large part by the cisplatin dose per cycle (100 mg/m2) and by sensory neuropathy from the additional IP as well as from the IV administration of paclitaxel. The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects and catheter-related problems.
Notwithstanding these problems, IP therapy for patients with optimally debulked ovarian cancer is receiving wider adoption, and efforts are under way by the GOG to examine some modifications of the IP regimen used in GOG-0172 to improve its tolerability (e.g., to reduce by ≥25% the total 3-hour amount of cisplatin given; a shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration). A Cochrane-sponsored meta-analysis of all randomized IP versus IV trials shows an HR of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms. In another meta-analysis of seven IP versus IV randomized trials that were conducted by Cancer Care of Ontario, the relative ratio (RR) of progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% CI, 0.85–0.98), and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.81–0.95).
For patients unable to undergo surgery, or for those with greater than 1 cm residual disease following surgery, IV chemotherapy is the standard. The foundation is the platinum agents: cisplatin, or its second-generation analog, carboplatin, given either alone or in combination with other drugs. Trials by various cooperative groups in the subsequent two decades addressed issues of optimal dose-intensity [12,13,14] 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 to the previous standard of cisplatin plus cyclophosphamide; however, two trials that compared the agent with either cisplatin or carboplatin as a single agent failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (see Table 2).
Nevertheless, for patients with ovarian cancer, the combination of cisplatin or carboplatin and paclitaxel has been used as the initial treatment (defined as induction chemotherapy) for several reasons:
Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:
In this large study consisting of 84% to 87% of patients with Féderation Internationale de Gynécologie et d'Obstétrique stage III disease, as expected, the extent of cytoreduction was an important prognostic factor in OS. PFS in patients with residuum greater than 1 cm was 13 months, but OS was 33 months; with residuum less than or equal to 1 cm, PFS was 16 months, but OS was 40 months; and with microscopic residuum, PFS was 29 months, but OS was 68 months.
A trial of the Japanese Gynecologic Oncology Group (JGOG-3601 [NCT00226915]) accrued 637 patients and randomly assigned them to a range of six to nine cycles of the weekly (named "dose-dense") 80 mg/m2 of paclitaxel or to the usual every-21-days schedule of paclitaxel at 180 mg/m2. Both regimens were given with carboplatin (AUC, 6) in every-3-weeks cycles. With a primary endpoint of PFS, an increase from 16 to 21 months in the PFS of the weekly paclitaxel-based regimen was sought.
The PFS surpassed expectations at the 1.5-year follow-up after cessation of treatment. The weekly regimen had a median PFS of 28.0 months (95% CI, 22.3–35.4 months), and the intermittent median PFS was 17.2 months (15.7–21.1; HR, 0.71), favoring the weekly regimen (P = .0015). The 3-year OS also favored the weekly regimen (P = .03). The 2013 updated results revealed unexpected median survival results for the weekly regimen (median OS, 8.3 years vs. 5.1 years; P = .040); the intermittent regimen results are also noteworthy relative to other clinical trials of weekly dosing schedules.
Other than ethnicity, this trial population differed from other studies in the following ways:
This trial has stimulated a number of other trials that address weekly dosing schedules versus the conventional every-3-weeks dosing in first-line ovarian epithelial cancer.[25,26,27]
In a phase III trial (MITO-7 [NCT00660842]), the outcomes of 406 patients assigned to weekly paclitaxel (60 mg/m2) administered with a weekly carboplatin (AUC, 2) were compared with those of 404 patients receiving the conventional every-3-weeks regimen of paclitaxel and carboplatin.[Level of evidence: 1iiA] The results failed to confirm the superiority of this particular weekly schedule (PFS, 18.3 months [HR, 0.96; 95% CI, 0.80–1.16]) versus 17.3 months for the standard arm on PFS. However, the treatments did not differ in toxic effects, and in the weekly arm, a decrease in quality of life (FACT-O questionnaire) with the every-3-week cycle was not seen.
Consolidation and/or maintenance therapy
Trials of consolidation and/or maintenance therapy have been carried out with drugs that contribute to the treatment of recurrent ovarian cancer. Presently, none of the treatments that is given after the initial platinum-and-paclitaxel induction has been shown to improve survival; these treatments include the following:
A GOG-178 study of 277 patients compared 3 doses versus 12 doses of monthly paclitaxel given every 4 weeks following a clinically defined complete response at the time of completion of platinum/paclitaxel induction. However, the study was stopped early because of a very significant difference in PFS (28 months vs. 21 months).[Level of evidence: 1iiDiii] Subsequent updates of these data have raised the possibility that a subset of patients with low CA-125 levels might show a survival benefit. A trial to confirm the value of maintenance with taxanes versus observation is being conducted by the GOG.
A smaller Italian study entered 200 patients over 7 years who were randomly assigned to either 12 similar courses of monthly paclitaxel or observation; patients were in clinical complete response (n = 95) or pathologic complete response (n = 105) after induction therapy at the time of their random assignment. Sensory neuropathy was the most prominent toxicity and was grade 2 in 21.3% of the patients and grade 3 in 6.7% of the patients. The median PFS for the maintenance paclitaxel arm was 34 months (95% CI, 20–43 months) and 30 months (95% CI, 17–53 months) for the observation arm. Neither PFS nor OS differences were significant.
An accompanying editorial points out the weaknesses of both studies in order to draw conclusions (both stopped early and were noninformative for survival endpoint). Also, although both studies addressed the issue of maintenance paclitaxel administered monthly, the patient populations differed. This was reflected by the considerably better outcome in both arms of the Italian study. Taken together, paclitaxel maintenance is of unproven value and requires validation by the completed and larger GOG-178 study cited above.
Two phase III trials (GOG-0218 [NCT00262847] and ICON 7 [NCT00483782]) have evaluated the role of bevacizumab in first-line therapy for ovarian, fallopian tube, and primary peritoneal cancer following surgical cytoreduction.[41,42] 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.
GOG-0218 was a double-blinded, randomized controlled trial that included 1,873 women with stage III or IV disease, all of whom received chemotherapy—carboplatin (AUC 6) and paclitaxel (175 mg/m2 for 6 cycles). Participants were randomly assigned to receive:
The women were enrolled with a primary endpoint of PFS; 40% of the patients had suboptimally resected stage III disease, and 26% had stage IV disease. There was no difference in PFS between the control group and the bevacizumab-initiation group. There was a statistically significant increase in PFS in the bevacizumab-throughout group when compared with the control group (14.1 vs. 10.3 months), with an HR of progression or death of 0.717 in the bevacizumab-throughout group (95% CI, 0.625–0.824; P < .001). Median OS was 39.3 months for the control group, 38.7 months for the bevacizumab-initiation group, and 39.7 months for the bevacizumab-throughout group. Quality of life was not different between the three groups. Hypertension grade 2 or higher was more common with bevacizumab than with the placebo. There were more treatment-related deaths in the bevacizumab-throughout arm (10 of 607, 2.3%) than in the control arm (6 of 601, 1.0%).[Level of evidence: 1iDiii]
ICON 7 randomly assigned 1,528 women after initial surgery to chemotherapy—carboplatin (AUC 5 or 6) plus paclitaxel (175 mg/m2 for six cycles)—or to chemotherapy plus bevacizumab (7.5 mg/kg for six cycles), followed by bevacizumab alone for an additional 12 cycles. The women were randomly assigned, and PFS was the main outcome measure; 9% of patients had early-stage, high-grade tumors, and 70% had stage IIIC or IV disease. Twenty-six percent had more than 1 cm of residual tumor prior to initiating chemotherapy. Median PFS was 17.3 months in the control group and 19 months in the bevacizumab group. HR for progression or death in the bevacizumab group was 0.81 (95% CI, 0.70–0.94; P = .004). Bevacizumab was associated with an increase in bleeding, hypertension (grade 2 or higher), thromboembolic events (grade 3 or higher), and gastrointestinal perforations. Grade 3 or higher adverse events were more common in the bevacizumab group. Quality of life was not different between the two groups.[Level of evidence: 1iiDiii]
A third trial, OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases [NCT00434642]), assessed the role of bevacizumab in the treatment of platinum-sensitive recurrences (see Table 3 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine + carboplatin) with or without bevacizumab for recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer, 242 patients were randomly assigned per arm. Median PFS for patients receiving bevacizumab was 12.4 months versus 8.4 months for those receiving a placebo. The effect of bevacizumab on HR to progression in patients assigned to the bevacizumab arm compared with placebo was 0.484 (95% CI, 0.388–0.605; P <.0001). Objective responses to chemotherapy were increased when combined with bevacizumab (78.5% vs. 57.4%; P < .0001).
In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance. A subsequent analysis will appear when additional survival data become mature; however, at the time of publication, differences in median survival were not apparent, and crossover from a placebo to bevacizumab had occurred in 31% of the patients. Bevacizumab-associated toxicities such as hypertension and proteinuria were more prominent than in the first-line trials, but feared safety issues, such as gastrointestinal perforations, did not occur during the study. Discontinuing treatment because of adverse events was more common with bevacizumab (n = 55 vs. n = 12 for placebo), but fewer patients discontinued treatment because of disease progression (n = 104 vs. n = 160 for placebo).[Level of evidence: 1iiDiii]
The AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) (NCT00976911) trial was an open-label randomized trial designed to evaluate the effect of adding bevacizumab to standard chemotherapy in patients with platinum-resistant recurrent ovarian cancer. Eligible patients had platinum-resistant disease (progression within 6 months of finishing a platinum-containing regimen), and no more than two prior regimens. Patients with platinum-refractory disease (those with progression during receipt of a platinum-containing regimen), and those with clinical and radiological signs of bowel involvement were ineligible. Patients were prescribed one of three chemotherapy regimens, based on physician preference:
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. Patients in the bevacizumab arm exhibited longer PFS (HR, 0.48; 95% CI, 0.38 to 0.60); median PFS was 3.4 months in the chemotherapy-alone arm versus 6.7 months in the chemotherapy plus bevacizumab arm. The objective response rate was 12.6% in the chemotherapy-alone arm versus 30.9% in the chemotherapy plus bevacizumab arm. There was no statistically significant difference in OS between the regimens (13.3 months chemotherapy-alone vs. 16.6 months chemotherapy plus bevacizumab). Patients in the chemotherapy plus bevacizumab arm had an increased incidence of hypertension and proteinuria, when compared with patients in the chemotherapy-only arm. Gastrointestinal (GI) perforation was only 2% in those receiving chemotherapy plus bevacizumab, which reflects the study's stringent exclusion criteria.
The primary endpoint for the quality-of-life portion of the study was a 15% or greater absolute improvement in the abdominal-GI–symptom portion of the assessment modules at week 8 to week 9 of the protocol for patients in the chemotherapy plus bevacizumab arm. The study used patient-reported outcomes from the EORTC Ovarian Cancer Module 28 and the Functional Assessment of Cancer Therapy-Ovarian Cancer symptom index (FOSI) at baseline and every 8 to 9 weeks until disease progression. 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% to 27.6%; P = .002).
The U.S. Food and Drug Administration has approved the use of bevacizumab in combination with PLD, paclitaxel, or topotecan as a result of these trials.
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 and chemotherapy combination was extended beyond six cycles until progression.
In summary, consistent effects of bevacizumab have been shown to improve relative risk and PFS rates in platinum-sensitive and platinum-resistant recurrences more than the improvement that is achieved with chemotherapy alone; however, there is the cost of anticipated bevacizumab-related toxic effects. At this time, the evidence does not support the use of bevacizumab as front-line therapy, because the gain in PFS comes with increased toxicity without improvement in OS or quality of life.
Treatment Options Under Clinical Evaluation
Information about ongoing clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II ovarian epithelial cancer, stage III ovarian epithelial cancer, stage IV ovarian epithelial cancer, fallopian tube cancer and primary peritoneal cavity cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Overall, approximately 80% of patients diagnosed with ovarian epithelial, fallopian tube, and primary peritoneal cancer 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 the 50% of institutions practicing such procedures were informally compared with the outcomes in institutions not using such procedures, additional lack of support for them grew, as was found in the case for patients entered in GOG-0158. However, the practice of close follow-up of patients completing treatment by serial CA-125s 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.
A trial by the Medical Research Council and European Organization for Research and Treatment of Cancer (MRC-OV05, which is now closed) examined the consequences of early institution of treatment for recurrence versus treatment delayed until clinical symptoms appeared. Patients in clinical complete remission after platinum-based chemotherapy were registered and followed with CA-125s only and clinical visits. Upon detection of a twofold elevation over the normal range, patients were randomly assigned to disclosure of the result (and early treatment for recurrence) versus continued blinding and treatment upon development of signs and symptoms indicative of clinical relapse. The number of randomly assigned patients was to exceed 500 in order to yield a superior survival outcome at 2 years with early institution of therapy; this required 1,400 registrations, which were accrued between May 1996 and August 2005. Among 1,442 registrants, 29% continued to show no evidence of relapse, 19% relapsed without evidence of CA-125 doubling beyond normal or at the same time, and another 4% died before becoming eligible for random assignment. Registrants had stage III and stage IV disease in 67% of the cases, whereas these stages represented 80% of the randomly assigned patients. The median survival of all patients registered was 70.8 months.
Median survival for patients randomly assigned to early treatment (n = 265) was 25.7 months compared with 27.1 months for patients in the delayed-treatment group (n = 264) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.8–1.2). The median delay in instituting second-line chemotherapy was 4.8 months, and the median delay in instituting third-line chemotherapy was 4.6 months. Treatments for second-line chemotherapy were comparable among the two groups (mostly platinum- and taxane-based), whereas third-line treatments were less often applied to the delayed-treatment group. The study concluded that there was no benefit in the detection of early presence of disease by CA-125; this is consistent with the failure of second-look surgeries to provide improved outcomes after early detection of persistent disease. Monitoring CA-125 levels in follow-up may play a role in identifying appropriate candidates for secondary cytoreduction, although this strategy awaits confirmation with a randomized trial.
Local Modalities: Surgery and Radiation Therapy
Cytoreduction is often employed, but such intervention is only now being studied in the setting of a randomized clinical trial (GOG-0213). The role of radiation therapy in patients with recurrent ovarian cancer has not been defined.
Systemic treatment options for patients with recurrent disease are subdivided as follows:
Carboplatin was approved in 1987 for the treatment of patients with ovarian cancer whose disease recurred after treatment with cisplatin, based on improved survival with etoposide or 5-fluorouracil. In a randomized phase II trial of paclitaxel, a currently used second-line drug, the cisplatin-containing combination of cisplatin plus doxorubicin plus cyclophosphamide (CAP), yielded a superior survival outcome. This, and subsequent studies (see Table 3), have reinforced using 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 platinums, 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 (PLD) to topotecan, the subset of patients who were platinum sensitive had better outcomes with either drug (and in particular with PLD) 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 3). In an analysis of data examining jointly the results of three trials performed by the Medical Research Council/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and ICON investigators (known as ICON-4), a platinum-plus-paclitaxel combination yielded a superior outcome, in terms of response rates, progression-free survival (PFS), and overall survival (OS), compared with carboplatin as a single agent or other platinum-containing combinations as controls. Platinum plus paclitaxel was compared with several control regimens, although 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (HR, 0.76; 95% CI, 0.66–0.89; P = .004) and OS (HR, 0.82; 95% CI, 0.69–0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.; [Level of evidence: 1iiA] The AGO had previously compared the combination of epirubicin plus carboplatin with carboplatin alone and had not found significant differences in outcome.
Another trial by European and Canadian groups compared gemcitabine plus carboplatin to carboplatin. The PFS of 8.6 months with the combination was significantly superior to 5.8 months for the carboplatin alone (HR, 0.72; 95% CI, 0.58–0.90; P = .003). The study was not powered to detect significant differences in OS, and the median survival for both arms was 18 months (HR, 0.96; CI, 0.75–1.23; P = .73).
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.
In a phase III trial, carboplatin plus PLD (CD) was compared with carboplatin plus paclitaxel (CP) in patients with platinum-sensitive recurrence (>6 months). The primary endpoint was PFS with a median PFS for the CD arm of 11.3 months versus 9.4 months for the CP arm (HR, 0.823; 95% CI, 0.72–0.94; P = .005).[Level of evidence: 1iiDiii] Long-term follow-up revealed no difference in OS rates between the two arms (30.7 months for CD vs. 33.0 months for CP). The CP arm was associated with increased severe neutropenia, alopecia, neuropathy, and allergic reaction; the CD arm was associated with increased severe thrombocytopenia, nausea, and hand-foot syndrome. Given its toxicity profile and noninferiority to the standard regimen, CD is an important option for patients with platinum-sensitive recurrence.
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 PLD), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences based on activity and their favorable therapeutic indices relative to agents listed in Table 4. The long list underscores the marginal benefit, if any, generally conveyed by these agents. Patients with platinum-resistant disease should be encouraged to enter clinical trials.
Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[15,16,17,18,19] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable with those achieved with paclitaxel. Topotecan was compared with PLD in a randomized trial of 474 patients and demonstrated similar response rates, PFS, and OS at the time of the initial report, which was contributed primarily by the platinum-resistant subsets.
Drugs used to treat platinum-refractory or platinum-resistant recurrence:
The combination of weekly topotecan and biweekly bevacizumab was evaluated in a phase II study that showed an objective response rate of 25% (all partial responses) in a platinum-resistant patient population. The most common grade 3 and grade 4 toxicities were hypertension, neutropenia, and gastrointestinal (GI) toxicity, though no bowel perforations occurred.
Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer. Response rates (19.7% vs. 17.0%; P = .390), PFS (16.1 wk vs. 17.0 wk; P = .095), and OS (60 wk vs. 56.7 wk; P = .341) did not differ significantly between the liposomal doxorubicin and topotecan arms.[Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.
A randomized trial of gemcitabine versus PLD showed noninferiority and no advantage in therapeutic index of one drug over the other.
In a phase III study, 235 patients who did not respond to initial treatment with a platinum-based regimen, but who had not previously received paclitaxel or topotecan, were randomly assigned to receive either topotecan as a 30-minute infusion daily for 5 days every 21 days or paclitaxel as a 3-hour infusion every 21 days. The overall objective response rate was 20.5% for patients who were randomly assigned to treatment with topotecan and 13.2% for patients who were randomly assigned to treatment with paclitaxel (P = .138). Both groups experienced myelosuppression and GI toxic effects. Nausea and vomiting, fatigue, and infection were observed more commonly following treatment with topotecan, whereas alopecia, arthralgia, myalgia, and neuropathy were observed more commonly following paclitaxel. (Refer to the PDQ summary on Gastrointestinal Complications for information on gastrointestinal toxic effects; refer to the PDQ summary on Nausea and Vomiting and the PDQ summary on Fatigue; and refer to the PDQ summary on Pain for information on arthralgia, myalgia, and neuropathy.)
The AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) (NCT00976911) trial was an open-label randomized trial designed to evaluate the effect of adding bevacizumab to standard chemotherapy in patients with platinum-resistant recurrent ovarian cancer. Eligible patients had platinum-resistant disease (progression within 6 months of finishing a platinum-containing regimen), and no more than two prior regimens. Patients with platinum-refractory disease (those with progression during receipt of a platinum-containing regimen), and those with clinical or radiological signs of bowel involvement were ineligible. Patients were prescribed one of three chemotherapy regimens, based on physician preference:
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. 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. Patients in the bevacizumab arm exhibited longer PFS (HR, 0.48; 95% CI, 0.38 to 0.60); median PFS was 3.4 months in the chemotherapy-alone arm versus 6.7 months in the chemotherapy-plus-bevacizumab arm. The objective response rate was 12.6% in the chemotherapy-alone arm versus 30.9% in the chemotherapy-plus-bevacizumab arm. There was no statistically significant difference in OS between the regimens (13.3 months for the chemotherapy-alone regimen vs. 16.6 months for the chemothearpy-plus-bevacizumab regimen). Patients in the chemotherapy-plus-bevacizumab arm had an increased incidence of hypertension and proteinuria, when compared with patients in the chemotherapy-only arm. Gastrointestinal (GI) perforation was only 2% in those receiving chemotherapy plus bevacizumab, which reflects the study's stringent exclusion criteria. Quality of life, as measured by improvement in the GI-symptom subscale, was also improved in the patients on the bevacizumab-plus-chemotherapy arm.
The first study (GOG-0170D) included 62 patients who had received only 1 or 2 previous treatments (these last patients had received 1 additional platinum-based regimen because of an initial interval of 12 months or longer after first-line regimens and also had to have a performance status of 0 or 1). Patients received a dose of 15 mg/kg every 21 days; there were 2 complete responses and 11 partial responses, a median PFS of 4.7 months, and an OS of 17 months. This activity was noted in both platinum-sensitive and platinum-resistant subsets.
The second study only included patients with platinum-resistant disease using an identical dose schedule, but the study was stopped because 5 of 44 patients experienced bowel perforations, 1 of them fatal; 7 partial responses had been observed. This increased risk of bowel perforations was associated with three or more previous treatments.[35,36,37][Level of evidence: 3iiiDii]
The third study (CCC-PHII-45) included 70 patients who received 50 mg of oral cyclophosphamide daily, in addition to bevacizumab (10 mg/kg every 2 wk); 17 partial responses were observed and 4 patients had intestinal perforations.
A phase II study by the Gynecologic Oncology Group utilized pemetrexed (900 mg/m2) IV every 3 weeks in 51 patients with platinum-resistant recurrent disease. The response rate was 21% in a heavily pretreated population in which 39% of the patients had received 5 or more regimens previously. Myelosuppression and fatigue were the most common severe toxicities.
Other drugs used to treat platinum-refractory or platinum-resistant recurrence
This group includes drugs that 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.
Treatment Options for Patients with Recurrent or Persistent Disease
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent ovarian epithelial cancer, fallopian tube cancer and primary peritoneal cavity cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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.
The name of this summary and the major section titles and subtitles throughout were changed to include fallopian tube cancers and peritoneal cancer treatment.
General Information About Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer
Editorial changes were made to this section.
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
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment are:
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National Cancer Institute: PDQ® Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq. Accessed <MM/DD/YYYY>.
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