Ovarian Epithelial Cancer Treatment (Professional) (cont.)
IN THIS ARTICLE
Stage III and Stage IV Ovarian Epithelial Cancer Treatment
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Treatment options for patients with all stages of ovarian epithelial cancer have consisted of surgery followed by chemotherapy.
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]
A study led by the European Organization for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada (NCIC) Clinical Trials Group (EORTC-55971) between 1998 and 2006 included 670 women with stage IIIC and IV ovarian, tubal, and primary peritoneal cancers. 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-Ó-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.
For the past 3 decades, the Gynecologic Oncology Group (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:
Treatment Options for Patients With Optimally Cytoreduced Stage III Disease
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 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 was 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).
Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease
The value of interval cytoreductive surgery has been the subject of two large phase III trials. In the first study, performed by the EORTC, patients subjected to debulking after four cycles of cyclophosphamide and cisplatin (with additional cycles given later) had an improved survival rate compared with patients who completed six cycles of this chemotherapy without surgery.[Level of evidence: 1iiB] The GOG-0162 trial was designed to answer a very similar question but used the then-standard paclitaxel-plus-cisplatin regimen as the chemotherapy. This trial did not demonstrate any advantage from the use of interval cytoreductive surgery. The divergence of results may be caused by the efficacy of the chemotherapy obscuring any effects of interval cytoreduction, the wider use of maximal surgical effort at the time of diagnosis by U.S. gynecologic oncologists, or unknown factors. Although many patients with stage IV disease also undergo cytoreductive surgery at diagnosis, whether this improves survival has not been established.
First-line treatment of ovarian cancer is cisplatin, given IV, or its second-generation analog, carboplatin, given either alone or in combination with other drugs. Clinical response rates from these drugs regularly exceed 60%, and median time-to-recurrence usually exceeds 1 year in this subset of suboptimally debulked women. Trials by various cooperative groups in the subsequent 2 decades addressed issues of optimal dose-intensity [14,15,16] 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 6).
Table 6. Paclitaxel/Platinum Combinations Versus Comparator Arms in Trials
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 a number of reasons:
Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:
Consolidation and/or maintenance therapy
In an effort to improve on the modest results achieved in suboptimally debulked patients (in contrast to those achieved after optimal cytoreduction and IP therapy), trials of consolidation and/or maintenance therapy have been carried out with drugs that contribute to the treatment of recurrent ovarian cancer. Presently, not one of the treatments given after the initial platinum/paclitaxel induction has been shown to improve survival; these treatments include the following:
A GOG-178 study of 277 patients compared three doses versus twelve 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 this data have raised the possibility that a subset with low CA 125s 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) complete response 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 ongoing and larger GOG-178 study cited above.
Treatment options under clinical evaluation:
Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III ovarian epithelial cancer and stage IV ovarian epithelial 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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