Early-Stage Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment
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.
- If the tumor is well differentiated or moderately well differentiated, surgery alone may be adequate treatment for patients with stage IA and IB disease. Surgery should include hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Additionally, the undersurface of the diaphragm should be visualized and biopsied; pelvic and abdominal peritoneal biopsies and pelvic and para-aortic lymph node biopsies are required and peritoneal washings should be obtained routinely. In selected patients who desire childbearing and have grade I tumors, unilateral salpingo-oophorectomy may be associated with a low risk of recurrence.
- If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and death from ovarian cancer is as much as 30%.[3-6] Clinical trials evaluating the following treatment approaches have been performed:
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.[12-14]
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.[17-19] 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.
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