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Ovarian Epithelial Cancer Treatment (Professional) (cont.)

Stage III and Stage IV Ovarian Epithelial Cancer Treatment

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.[1] 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.[1][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.[2] 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 [NCT00003636]) between 1998 and 2006 included 670 women with stage IIIC and IV ovarian, tubal, and primary peritoneal cancers.[5] 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--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).[5][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:

  1. Treatment options for patients with optimally cytoreduced stage III disease.
  2. Treatment options for patients with suboptimally cytoreduced stage III and stage IV disease.

Treatment Options for Patients With Optimally Cytoreduced Stage III Disease

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).[6] 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).[9][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.[10]

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.[11] 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).[10]

Treatment Options for Patients With Suboptimally Cytoreduced Stage III and Stage IV Disease

Cytoreductive surgery

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.[12][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.[13] 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.

Systemic chemotherapy

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,[17] schedule,[18] and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.[19] 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).

Table 2. Paclitaxel/Platinum Combinations Versus Comparator Arms in Trials

TrialTreatment RegimensNo. of Patients% Early CrossoverProgression-free Survival (mo)Overall Survival (mo)
AUC = area under the curve.
a Statistically inferior result (P< .001–< .05).
GOG-132Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)20122%14.226.6
Cisplatin (100 mg/m2)20040%16.430.2
Paclitaxel (200 mg/m2, 24 h)21323%11.2a26
MRC-ICON3[20]Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 647823%17.336.1
Carboplatin AUC 694325%16.135.4
Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 623223%1740
Cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) and cisplatin (50 mg/m2)42120%1740
GOG-111[21]Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)184None1838
Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)202None13a24a
EORTC-55931[22]Paclitaxel (175 mg/m2, 3 h) and cisplatin (75 mg/m2)162None15.535.6
Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)1614%11.5a25.8a

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:

  • GOG-132 was regarded by many as showing that sequential treatment with cisplatin and paclitaxel was equivalent to the combination because many patients crossed over before progression; moreover, the cisplatin only arm was more toxic because it utilized a 100 mg/m2 dose.
  • The Medical Research Council (MRC-ICON3) study, while having fewer early crossovers, could be interpreted similarly in regard to the impact on survival of sequential treatment.
  • Data from MRC-ICON4 have shown a survival advantage for patients treated with the combination treatment regimen versus those treated with single-agent carboplatin upon recurrence (see Table 3).
  • In past trials, single-agent platinums were not superior to platinum combined with an alkylating agent; therefore, the explanation of a detrimental effect of cyclophosphamide is unlikely.

Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:

  • Noninferiority for carboplatin plus paclitaxel versus cisplatin plus paclitaxel.[21,22,23]
  • Noninferiority for carboplatin plus paclitaxel versus carboplatin plus docetaxel.[24]
  • No advantage but increased toxic effects by adding epirubicin to the carboplatin plus paclitaxel doublet.[25]
  • Noninferiority for carboplatin plus paclitaxel versus sequential carboplatin-containing doublets with either gemcitabine or topotecan; or, triplets with the addition of gemcitabine or pegylated liposomal doxorubicin to the reference doublet as shown below:[26,27]
    • From February 2001 to September 2004, the Gynecologic Cancer InterGroup trial GOG-0182 randomly assigned 4,312 women with stage III or stage IV epithelial ovarian or primary peritoneal cancer to four different experimental arms and to a reference treatment consisting of carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 3 weeks for eight cycles.[26] Stratification factors were residual-disease status and the intention to perform interval debulking surgery. Lethal events attributable to treatment occurred in less than 1% of patients without clustering to any one regimen. None of the experimental regimens were inferior. With a median duration of follow-up of 3.7 years, the adjusted relative risk of death ranged from 0.952 to 1.114, with the control arm achieving a PFS of 16.0 months and a median OS of 44.1 months.

      In this large study consisting of 84% to 87% of patients with the Féderation Internationale de Gynécologie et d'Obstétrique stage III disease, as expected, the extent of cytoreduction was an important prognostic factor in OS. Results of PFS in patients with residuum greater than 1cm, less than or equal to 1 cm, or microscopic were 13, 16, and 29 months, respectively; whereas for OS, the results were 33, 40, and 68 months, respectively.[26]

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, not one of the treatments given after the initial platinum/paclitaxel induction has been shown to improve survival; these treatments include the following:

  • IP cisplatin (four cycles).[28]
  • Yttrium-labeled radioimmunoconjugate plus IP chemotherapy.[29]
  • IV topotecan (four cycles).[30]
  • Oregovomab vaccination (randomized trial vs. placebo).[31]
  • High-dose chemotherapy with hematopoietic support.[32]
  • Monthly paclitaxel (12 cycles).[33,34]
  • Olaparib, an oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (phase II trial).[35]

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).[33][Level of evidence: 1iiDiii] Subsequent updates of this data have raised the possibility that a subset of patients with low CA 125 levels might show a survival benefit.[36] 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.[34] 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.[34]

An accompanying editorial points out the weaknesses of both studies in order to draw conclusions (both stopped early and were noninformative for survival endpoint).[37] 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.


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 cancers following surgical cytoreduction.[38,39] 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, respectively, as a maintenance phase.

GOG-0218 was a double blind, 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 six cycles).[38] Participants were randomly assigned to receive:

  • Chemotherapy plus placebo (cycles 2 through 22) (i.e., control).
  • Chemotherapy plus bevacizumab (15 mg/kg cycles 2 through 6), followed by placebo (cycles 7 through 22) (i.e., bevacizumab initiation).
  • Chemotherapy plus bevacizumab (15mg/kg cycles 2 through 22) (i.e., bevacizumab throughout).

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 a 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, 38.7, and 39.7 months for the control group, bevacizumab-initiation group, and the bevacizumab-throughout group, respectively. Quality of life was not different between the three groups. Hypertension grade 2 or greater 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%).[38][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 greater adverse events were more common in the bevacizumab group. Quality of life was not different between the two groups.[39][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.[40] 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).[40][Level of evidence: 1iiDiii]

These three 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. Without additional data, a statement about how bevacizumab should be used in ovarian cancer treatment is not possible because of the uncertain impact on OS, lack of clear delineation of who derives the greatest benefit, and prominent, associated toxicities.[41]

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

  • Additional IP radioimmunoconjugates, vaccines, and targeted drugs are under clinical evaluation, primarily as consolidation therapy.

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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