Clinical Obstetrics and Gynecology

Evidence supports the current paradigm for the management of patients with recurrent or persistent ovarian carcinoma. The paradigm requires that patients be classified as platinum-sensitive or platinum-resistant. Patients who achieve a complete response with platinum-based therapy and experience at least 6 months free from recurrence should be categorized as having chemosensitive disease and should be retreated with carboplatin-based doublets. Patients who progress while receiving treatment, whose best response is stable disease, or who experience a complete response of <6 months duration should be categorized as having chemoresistant disease and should be treated with a nonplatinum single agent.

Ovarian cancer is the second most common invasive malignancy of the female genital tract in the United States. In 2011, ovarian cancer accounted for an estimated 22,280 new cases.1 More importantly, an estimated 15,500 deaths as a result of ovarian cancer accounted for over half of all deaths from gynecologic cancers.1 The lethal nature of ovarian cancer results from the fact that >70% of cases present as advanced (stage III or IV) disease because of the lack of an effective early-diagnostic test. Because of this, most patients require systemic therapy as the mainstay of treatment. Although the success rate with initial therapy has increased over the last 3 decades, a majority of patients develop recurrent or persistent disease and require treatment beyond initial therapy. This review will present a brief summary of current management for newly diagnosed disease and then will focus on the management of patients with recurrent or persistent disease with systemic therapy.

The approach to patients with newly diagnosed disease must take into account key characteristics of ovarian cancer. The first of these key characteristics is histology. Essentially 90% of ovarian cancer has been thought previously to arise from celomic epithelium, which surrounds the ovary during development and lines the entire peritoneal cavity. More recent data, however, bring this into question.2 Recent proposals have suggested categorizing epithelial ovarian cancer into type I lesions (low-grade serous, low-grade endometrioid, clear cell, mucinous, and transitional carcinoma) that generally are genetically stable, are confined to the ovary at presentation, and behave in an indolent manner and type II lesions (high-grade serous/endometrioid and undifferentiated carcinomas and carcinosarcomas) that behave in a highly aggressive manner, evolve rapidly, and present at an advanced stage. The most common histology is high-grade serous carcinoma, the cell of origin for which is thought to be of nonovarian origin (eg, fallopian tube).3,4

For clinical purposes, epithelial cancers should be reported as falling into either type I or type II. Type I lesions are substantially less frequent (<25% of all lesions), present as earlier stage disease, and exhibit a substantially better survival. Among these, mucinous, clear cell, and low-grade serous carcinomas are being studied by the Gynecologic Oncology Group (GOG) as individual entities separate from the rest of the ovarian carcinomas.5 Optimal treatment for these lesions is not yet known. High-grade serous and endometrioid carcinomas respond similarly to current systemic therapy and make up the vast majority of patients now included in trials of advanced ovarian carcinoma. For practical purposes, this review focuses on high-grade serous and endometrioid carcinomas.

The second of the key characteristics is stage. Determination of the extent of disease (stage) at the time of initial diagnosis is crucial to proper treatment planning.6 Management is based at least in part on the International Federation of Gynecology and Obstetrics (FIGO) stage; and patients are generally grouped as having either limited (stages I and IIA) disease or advanced (stages IIB to IV) disease. Because the primary route of spread is direct seeding throughout the peritoneal cavity and because grossly the disease remains predominately in the peritoneal cavity for much of its natural history, evaluation of the patient focuses on the abdomen and requires an exploratory laparotomy as the final step in staging and first step in treatment in the great majority of patients.

Additional key characteristics include age,7 volume of residual disease after surgical bulk reduction,8 and molecular biological features.9 A detailed evaluation of cooperative group data at the National Institute on Aging demonstrated that older patients have a much poorer prognosis stage for stage and appear to exhibit more biologically aggressive disease. Patients with bulkier disease, usually defined as nodules of tumor >2 cm in diameter, have a much poorer survival than those with small-volume residual disease. Other features associated with bulkier disease such as ascites and peritoneal carcinomatosis also adversely impact outcome. Patients who exhibit identifiable hereditary syndromes associated with BRCA1 and BRCA2 mutations develop the disease at a younger age and have a fairly better prognosis. These characteristics must be taken into account in determining management of these patients.

Finally, molecular biological features will eventually assume a dominant prognostic role. Current knowledge of these factors remains spotty at best. As a result, a treatment paradigm for now must rest on significant clinical factors such as those noted above.

On the basis of the key characteristics discussed above, patients are divided into those with advanced (stages IIB to IV) disease and those with limited (stages I and IIA) disease for purposes of clinical decision making (Table 1).

The international minimum standard of care for advanced ovarian carcinoma as determined by a consensus conference of the Gynecologic Cancer Intergroup, which is comprised of 24 cooperative groups worldwide running ovarian cancer trials, is an aggressive attempt at surgical bulk reduction followed by chemotherapy consisting of intravenous paclitaxel 175 mg/m² over 3 hours followed by intravenous carboplatin area under the curve (AUC) of 6 to 7.5 with the combination given every 3 weeks for 6 cycles.10 On the basis of at least 1 additional phase III trial supporting each, there are 4 modifications of this minimum approach that can be considered: intraperitoneal chemotherapy in patients with small-volume residual disease (3 phase III trials show a survival advantage for intraperitoneal chemotherapy albeit with substantial toxicity),11-13 weekly paclitaxel plus every-3-week carboplatin (progression-free and overall survival advantage in a large Japanese phase III trial),14 addition of bevacizumab to chemotherapy followed by bevacizumab maintenance (progression-free survival advantage in 3 trials involving almost 4000 patients),15-17 and maintenance paclitaxel in patients achieving a clinical complete response to initial chemotherapy (progression-free survival advantage in 1 phase III trial).18 The expectation is that more than half of all patients will achieve a clinical complete response, that median progression-free survival will range from 16 to 28 months, and that median overall survival will range from 30 months for those with bulky disease to >5 years for those with small-volume disease.11-13,19-21

For those patients fortunate enough to have their disease diagnosed while confined to the ovary (stage I) or to the pelvis (stage IIA), management is based on the probability of recurrence after complete surgical resection. Staging studies suggest that this population can be categorized as either low risk for recurrence or high risk for recurrence.22-24 Those patients who exhibit all of the low-risk characteristics experience a 10% recurrence rate after surgical resection and generally are followed without further treatment with an expected 90% survival rate. Those whose cancers feature 1 or more high-risk features have approximately a 40% probability of recurrence and, based on the largest randomized trial of this population, benefit from platinum-based adjuvant chemotherapy. The expectation with adjuvant chemotherapy is that survival will approximate 75% to 80% in the high-risk population. Current trials under development are looking for molecular markers that can identify more accurately patients at high risk for recurrence and provide targets for biological therapy.

Management approaches for newly diagnosed ovarian carcinoma identify 4 distinct patient populations. Understanding these 4 groups, their risk for recurrence or progression, and key characteristics critical to management at the time of recurrence or progression is essential to treatment planning for these patients.

The 4 distinct patient populations with newly diagnosed disease include: large-volume residual advanced disease, small-volume residual advanced disease, high-risk limited disease, and low-risk limited disease. Among patients with advanced disease who have been treated appropriately as outlined earlier in this discussion, those with large-volume residual advanced disease (1 or more residual neoplastic masses >2 cm in diameter) have a probability of recurrence at 10 years that exceeds 80%. Those with small-volume residual advanced disease (no residual masses >2 cm in diameter) fare much better with a probability of recurrence by 10 years that exceeds 60%. Among patients with limited disease managed as outlined earlier, those at high risk for recurrence have a probability of recurrence by 10 years of 20% to 25%; whereas those at low risk for recurrence exhibit a probability of recurrence of approximately 10% by 10 years. If the relative frequencies of each of these 4 situations (advanced disease 3 to 4 times as common as limited disease) are taken into account and the appropriate calculations are done, the disease will recur in 60% to 65% of patients with newly diagnosed disease and will require further therapy.25

At the time of recurrence or progression of disease, the physician should consider several patient characteristics that will impact management choices: the goals of management, the extent and nature of the recurrence or progression, the patient's prior therapy including her type and duration of response to the most recent treatment, and the toxicity associated with the prior therapy whether persistent at the time of recurrence or progression or not.

Treatment of newly diagnosed ovarian carcinoma is associated with long-term survival and possible cure even in a small percentage of those patients with large-volume residual advanced disease. The primary goal of initial treatment is therefore cure. For patients with recurrent or progressive disease, however, few, if any, patients will achieve cure.26 The patient and the physician must understand that the goals of management have changed because the disease is now a chronic disease that will require ongoing treatment for much of the remainder of the patient's life. In contrast, proper management can achieve a number of worthy goals: prolongation of survival, prolongation of progression-free survival, objective regression of disease (response), which is almost always associated with diminished symptoms associated with the disease, and improved quality of life.

Proper management of disease progression or recurrence requires an objective assessment of the extent and nature of the progression or recurrence. The purpose of this assessment is to determine whether secondary surgical bulk reduction has a role to play. Retrospective data suggest that, if the disease can be surgically bulk-reduced to no gross residual, the patient will experience prolonged survival and improved response to chemotherapy.27,28 Each patient should therefore be assessed by a gynecologic oncologist at the time of recurrence for the feasibility of removal of all gross disease. Characteristics associated with successful secondary bulk reduction to no gross residual include: an excellent response to prior chemotherapy, isolated recurrence or progression in a small number of areas confined to the peritoneal cavity, good performance status (preferably a fully ambulatory patient with or without symptoms equating to a GOG performance status of 0 or 1), and the absence of ascites or peritoneal carcinomatosis.

The first consideration regarding additional systemic therapy focuses on how the patient responded to the most recent prior therapy and how long that response lasted.29-31 Patients should be classified into 2 groups on the basis of these considerations (Table 2): chemosensitive if the patient achieved a clinical complete response to the last prior regimen and if that response lasted for a reasonable period of time (usually designated as 6 mo) before evidence of recurrence manifested; and chemoresistant if the patient's disease progressed or at best was stable while on the prior therapy or if the response was only partial or lasted less than a reasonable period of time (usually <6 mo). For the purpose of these definitions, evidence of recurrence or progression included only objectively evaluable evidence of disease other than serum markers such as CA-125.

Three initial reports supported these definitions, and subsequent studies have further confirmed the practical utility of them 29,30 to the point that they form the basis for the current paradigm for treatment of recurrent or persistent epithelial ovarian cancer. There are, however, several aspects of these definitions that need to be clearly understood. Firstly, the commonly used cutoff of a 6-month duration of response to define chemosensitive and chemoresistant disease is an arbitrary point on a continuum. The general principle is that the longer the duration of the treatment-free interval, the greater the likelihood of response to subsequent treatment with a regimen that is the same as or similar to the last prior therapy (eg, platinum-based regimen). Secondly, the definitions apply most commonly to sensitivity to platinum-containing regimens because virtually all patients receive such a regimen as initial therapy. Thirdly, in the setting of platinum sensitivity, retreatment with a platinum-based regimen yields a better outcome than does any alternative, non-platinum-based treatment. Finally, there is no clear clinical evidence that the "platinum-free interval" can be artificially prolonged to restore platinum sensitivity by inserting a nonplatinum regimen before subsequent retreatment with a platinum-based regimen in those whose initial platinum-free interval was <6 months.

One of the major goals of treatment in the setting of recurrence/progression is improved quality of life. Cumulative toxicity from therapy has a major adverse impact on quality of life; hence, the physician must take into account any major toxicities from prior therapy, particularly those toxicities that have persisted after cessation of prior therapy. For patients with ovarian carcinoma, virtually all will be treated with paclitaxel/carboplatin initially; and the cumulative toxicity associated with this treatment is neurotoxicity.31,32 More than 75% of patients will experience some degree of neurotoxicity. Approximately 35% will experience grade 2 or greater neurosensory toxicity and 6.4% grade 2 or greater neuromotor toxicity. More importantly, for purposes of managing patients with recurrent disease, 20% of patients will experience ongoing neuropathy >2 years after completion of initial therapy. Because a major consideration in patients with recurrent or progressive ovarian carcinoma is retreatment with a platinum-based regimen, whether the patient has residual neurotoxicity will impact the choice of systemic therapy.

To sum up, patients who present with recurrent or progressive disease will require assessment of a number of factors before the physician can make an informed decision about further management. Firstly, the patient and physician should clearly understand that the ovarian cancer has become a chronic disease that will require ongoing treatment but will benefit from a rational plan for that management. Secondly, the extent and nature of the recurrent disease should be carefully evaluated to determine whether the areas of recurrence can be completely resected grossly and thus whether secondary surgical bulk reduction is indicated. Thirdly, the patient's disease should be classified as either chemosensitive or chemoresistant on the basis of the type and duration of response to prior therapy. This should become the primary basis for the choice of systemic therapy. Finally, the patient should be assessed for residual toxicity from prior therapy that might dictate a change in choice of systemic therapy.

The choice of systemic therapy for patients with chemosensitive disease after any surgery that might be indicated should focus on platinum-based regimens. The specific choice of a platinum-based regimen should be guided by the results of 3 recently completed randomized phase III trials that assessed the efficacy of combination chemotherapy versus single-agent platinum treatment (Table 3).

The first randomized phase III trial to assess the efficacy of combination chemotherapy in chemosensitive recurrent or progressive disease was ICON 4, a collaborative effort of several cooperative groups in Europe.33 Patients with ovarian carcinoma that had recurred >6 months after achievement of a clinical complete response and completion of initial platinum-based therapy were randomized to receive either a platinum-based regimen without a taxane or a taxane-platinum-based regimen. Although specific drugs, doses, and schedules were not specified in the study, the majority (71%) of patients assigned to the nontaxane regimen received single-agent carboplatin; whereas the majority (81%) of patients assigned to the taxane-platinum regimen received paclitaxel/carboplatin. The primary endpoint of the trial was overall survival. Three features of the 801 patients randomized on study are noteworthy: 75% of the patients had a treatment-free interval before recurrence of >12 months, a fact that makes this population a very favorable population; only 43% of the patients had been exposed to a taxane as a part of their initial therapy, a percentage substantially less than would be expected in a similar population in the United States where the vast majority of patients receive paclitaxel/carboplatin as initial therapy; and, as best as can be determined, very few of the study patients received further therapy after progression.

Published results showed that patients assigned to the taxane-platinum regimen experienced a higher response rate (66% vs. 54%, P=0.06, based on the 247 of the 801 patients who had measurable disease), a superior progression-free survival [50% progression free at 1 year with the combination compared with 40% progression free at 1 year with the single agent, P=0.001, hazard ratio (HR)=0.76], and a superior overall survival (57% alive at 2 years with the combination vs. 50% alive with the single agent, P=0.023, HR=0.82). Toxicity differences with the combination included greater grade 2 or higher neurotoxicity (20% vs. 1%), less myelosuppression (29% vs. 46%), and more alopecia (86% vs. 25%). Overall toxicity was therefore not substantially greater than that seen with the nontaxane regimen.

The study concluded that the doublet of paclitaxel plus carboplatin was the preferred treatment for patients with recurrent chemosensitive ovarian carcinoma.

The German AGO group initially participated in ICON 4 but became dissatisfied with the amount of neurotoxicity associated with the taxane-platinum regimen. After a pilot study demonstrated the feasibility of gemcitabine/carboplatin with apparently substantially less neurotoxicity, they initiated a randomized phase III trial to compare carboplatin alone at an AUC of 5 every 3 weeks for 6 cycles versus gemcitabine 1000 mg/m² days 1 and 8 and carboplatin AUC of 4 day 1 repeated every 3 weeks for 6 cycles.34 The primary endpoint of the trial was progression-free survival. The same 3 features described above for ICON 4 are noteworthy of the patient population in AGO OVAR 2.5: 60% of the patients experienced a treatment-free interval before recurrence of >12 months, which makes this population essentially identical to what one would expect to see in the United States and substantially less favorable than the ICON 4 population; 70% of the patients had been exposed to a taxane as a part of their initial therapy, a percentage more closely resembling what would be expected in a similar population in the United States; and 80% of the patients received considerable additional treatment after progression on study as would be expected in a US population.

Published results showed that patients assigned to gemcitabine/carboplatin experienced a higher response rate (47% vs. 31%, P=0.0016), a superior progression-free survival (median 8.6 vs. 5.8 mo, P=0.0031, HR=0.72), but no difference in overall survival (median 18 vs. 17.3 mo, P=0.7349, HR=0.96). Toxicity differences with the combination included substantially more myelosuppression and more alopecia (14% vs. 2%). The overall tolerability of the combination was judged to be excellent.

The study concluded that the doublet of gemcitabine plus carboplatin was the preferred treatment for patients with recurrent chemosensitive ovarian carcinoma. The extensive additional treatment received by patients after progression rendered the survival endpoint difficult to interpret at best, and the Food and Drug Administration (FDA) agreed by approving the combination for use in patients with platinum-sensitive recurrent ovarian carcinoma.

A third trial of a new carboplatin-based doublet, the CALYPSO trial, compared the doublet of PLD 30 mg/m² plus carboplatin AUC of 5 every 4 weeks to paclitaxel 175 mg/m² over 3 hours plus carboplatin AUC of 5 every 3 weeks. This study is based on a large 105-patient phase II trial that produced a response rate of 63%, a clinical complete response rate of 38%, a median progression-free survival of 9 months, and overall survival of 31.1 months.35 The CALYPSO trial included 976 patients with platinum-sensitive recurrent disease and showed superiority for the PLD/carboplatin regimen (median progression-free survival of 11.3 vs. 9.4 mo, HR=0.82, P=0.005) in a study powered for progression-free survival as the primary endpoint.36 Survival data are as yet insufficiently mature to permit meaningful analysis. In addition, the PLD/carboplatin exhibited a favorable therapeutic index (less early discontinuation, less neuropathy, fewer hypersensitivity reactions, and less alopecia as opposed to more hand-foot syndrome, more nausea, and more mucositis).

An appropriate conclusion would be that these data support the use of the doublet of PLD plus carboplatin to treat patients with platinum-sensitive recurrent ovarian carcinoma.

Evidence clearly supports the superiority of 3 carboplatin-based doublets over single-agent carboplatin in the treatment of patients with chemosensitive recurrent ovarian carcinoma. Choice of specific regimen should focus on the 3 platinum-based doublets vetted in phase III trials: paclitaxel/carboplatin, gemcitabine/carboplatin, and PLD/carboplatin. Questions remain, however, regarding duration of treatment and repetitive treatment. Although these issues have not been well studied, common sense suggests the following principles. Firstly, treatment should be continued until 1 of 3 things occurs: progression of disease on treatment mandating a change of therapy, unacceptable toxicity also mandating a change of treatment, or the achievement of a clinical complete response, which would permit cessation of therapy until disease recurrence or progression. Secondly, if a patient achieves a clinical complete remission on therapy and experiences a reasonable (>6 mo) treatment-free interval before recurrence, retreatment with a carboplatin-based doublet again should produce the best results. Repetitive treatment should continue until the patient becomes chemoresistant by definition, and only then should alternative nonplatinum regimens be considered. Thirdly, hypersensitivity reactions to carboplatin should prompt desensitization according to 1 of several methods reported in the literature followed by continuation of the carboplatin unless the reaction was life threatening. In the latter case, a nonplatinum regimen should be instituted. At a later point, after exhaustion of reasonable nonplatinum alternatives, an attempt at desensitization and further platinum-based therapy can be considered in the context of close monitoring in an intensive care environment.

Patients whose disease either progresses through prior therapy, is at best stable disease, or responds with a complete response that lasts <6 months are by definition chemoresistant (at least to platinum-based regimens). In these patients, clinical benefit can be achieved by the use of nonplatinum agents with demonstrated activity in chemoresistant ovarian carcinoma (Table 3). There are a plethora of these agents currently with more on the way (Table 4). The following discussion first identifies the active agents and then presents a coherent approach to choosing specific regimens.

Active agents other than the platinum compounds in the management of ovarian carcinoma fall into 2 categories: cytotoxic or chemotherapeutic agents and targeted or biological agents. The cytotoxic agents will be considered first.

Cytotoxic agents: Active cytotoxic agents to consider seriously for use in the treatment of chemoresistant disease include PLD, topotecan, gemcitabine, oral etoposide, paclitaxel, docetaxel, and pemetrexed. Other active agents, with little evidence to support, used in the chemoresistant setting include vinorelbine, ifosfamide, 5-FU/leucovorin, altretamine, melphalan, and cyclophosphamide. The first 3 have been evaluated in recently completed phase III trials and will be presented in terms of those trials. The remaining agents will be presented in light of their activity in cooperative group studies where possible.

PLD versus topotecan: Two FDA-approved active agents, PLD and topotecan, have been directly compared in a randomized phase III trial.37 PLD consists of doxorubicin in an aqueous solution surrounded by a liposomal capsule and then by polyethylene glycol. This formulation increases the circulation half life from 2 to 3 hours to 55 hours and concentrates the drug in the tumor and in damaged capillary beds such as those of the palms and soles. The toxicity profile of the drug is also markedly changed with significantly less myelosuppression, alopecia, and cardiac toxicity. Topotecan is a topoisomerase I inhibitor with a dose-limiting toxicity of myelosuppression. This study randomized 474 patients with recurrent or persistent ovarian carcinoma to either PLD 50 mg/m² intravenously every 4 weeks (109 chemosensitive and 130 chemoresistant patients) or topotecan 1.5 mg/m² intravenously days 1 to 5 every 3 weeks (111 chemosensitive and 124 chemoresistant patients). In each case, the dose and schedule of the agent was the FDA-approved dose and schedule because this trial was a registration trial for PLD.

The study showed no significant difference between PLD and topotecan, respectively, in response rate in either the chemosensitive (28% vs. 29%) or chemoresistant (12% vs. 7%) subsets. Patients receiving PLD demonstrated a small but significant survival advantage (median 62.7 vs. 59.7 wk, P=0.05). A subset analysis revealed that the advantage was primarily in chemosensitive patients (112 vs. 77 wk, P=0.002, HR=0.63) with no difference observed in the chemoresistant subset. Toxicities were very different for the 2 agents as would be expected. PLD produced more hand-foot syndrome (23% grades 3 and 4) and stomatitis (8% grades 3 and 4). Topotecan produced more myelosuppression (77% grades 3 and 4 neutropenia and 34% grades 3 and 4 thrombocytopenia).

The best interpretation of the trial is that both agents are active in ovarian cancer and that the 2 agents have roughly equal efficacy in the key subset of chemoresistant disease.

PLD versus gemcitabine: A second trial compared PLD 40 mg/m² intravenously every 4 weeks (the most common starting dose in practice) to gemcitabine (1000 mg/m² intravenously weekly 3 weeks out of every 4).38 A total of 153 patients (56% chemoresistant and 44% chemosensitive with a treatment-free interval of 7 to 12 mo) were randomized. As regards toxicity, gemcitabine produced primarily myelosuppression, and PLD produced primarily hand-foot syndrome as significant effects. Response rate favored gemcitabine but was not significantly different (28% vs. 16%, P=0.07). Progression-free survival was not significantly different (median 20 vs. 16 wk, P=0.4), nor was survival (median 50 vs. 55 wk, P=0.17). Quality of life analyses favored PLD.

The best interpretation of this trial is the same as the previously discussed PLD versus topotecan. The 2 agents are both clearly active with roughly equal efficacies. Toxicities are different as expected. The quality of life advantage for PLD probably makes it the preferred agent to be used first in the chemoresistant setting, although all 3 of these agents will probably be used in most patients.

Other active agents in chemoresistant disease: Other agents have been demonstrated in phase II cooperative group trials of the GOG to have significant activity in chemoresistant disease with 1 or 2 prior regimens. These include oral etoposide, weekly paclitaxel, docetaxel, and pemetrexed.

Oral etoposide was studied in 41 patients with chemoresistant disease at a dose of 50 mg/m² orally daily for 21 days repeated every 28 days.39 Three complete and 4 partial responses were observed for an overall response rate of 27%. The principle observed toxicity was neutropenia.

Weekly paclitaxel in a dose of 80 mg/m² intravenously weekly produced an overall 21% response rate (2 complete and 8 partial responses) in 48 patients with chemoresistant disease.40 The most commonly observed adverse effects included grades 2 and 3 neuropathy (25%) and grade 3 fatigue (8%).

Docetaxel in a dose of 100 mg/m² intravenously every 3 weeks yielded a response rate of 22% (3 complete and 10 partial responses) in a series of 58 patients with chemoresistant disease.41 The most commonly observed adverse effect was grade 4 neutropenia in 75% of the patients.

Pemetrexed in a dose of 900 mg/m² intravenously every 3 weeks with appropriate vitamin supplementation produced a response rate of 21% (1 complete and 9 partial responses) in a series of 48 patients with chemoresistant disease.42 The most commonly observed adverse effect in this trial was myelosuppression.

In addition, cytotoxic agents with reported activity in other platinum-resistant studies include vinorelbine,42 ifosfamide,43 and 5-fluorouracil/leucovorin.44 Two additional investigational agents with reported activity are also of note: NKTR-102 45 and EC-145.46 The former is irinotecan attached to a polymer to alter favorably the pharmacokinetics of the agent. The latter attaches a vinca alkaloid to a folate to target cells rich in folate receptors. Both agents have been reported to have substantial activity against platinum-resistant disease.

Targeted agents: The GOG has conducted a series of 12 phase II trials of targeted agents in patients with recurrent or progressive ovarian carcinoma to date. Two of these agents have shown significant activity and will be highlighted: bevacizumab 47,48 and tamoxifen.49 Two additional agents have shown at best modest activity: sorafenib 50 and temsirolimus.51 Eight agents showed insufficient activity to warrant further study by the GOG: trastuzumab,52 human interleukin 12,53 gefitinib,54 imatinib,55 lapatinib,56 vorinostat,57 enzastaurin,58 and mifepristone.59

Bevacizumab: Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor. The initial clinical trial of this agent in ovarian carcinoma focused on patients with recurrent/persistent ovarian carcinoma with 1 or 2 prior regimens.47 Bevacizumab at a dose of 15 mg/kg intravenously every 3 weeks was given to 62 patients. The primary endpoint was the percentage of patients without progression at 6 months. Study results showed an objective response rate of 21% (2 complete and 11 partial responses) and 40% of patients were progression-free at 6 months. Serious or life-threatening (grades 3 and 4) adverse effects included 4 gastrointestinal problems (6%), 2 cases of venous thromboembolism (3%), 4 cases of hypertension (6%), and 3 cases of severe pain (5%).

These results suggest that bevacizumab has major activity against ovarian carcinoma. A second phase II trial in 44 patients showed similar results with 1 major difference.48 In this trial, patients were more heavily pretreated, with half having received 3 prior regimens. The response rate (16%) and percentage of patients progression-free at 6 months were similar to those in the GOG trial (27%); but the incidence of grades 3 and 4 toxicity, particularly gastrointestinal toxicity, was substantially higher.

These 2 studies taken together suggest that bevacizumab has major activity against recurrent or persistent ovarian carcinoma. Significant adverse effects appear to increase with the number of prior therapies and suggest that this agent would be better used early in the course of ovarian carcinoma. This led the GOG to open 2 major phase III trials evaluating bevacizumab in combination with paclitaxel/carboplatin in newly diagnosed patients (GOG 218)15 and in those with a chemosensitive first relapse (GOG 213). In addition, a second front-line trial, ICON 7,16 and a platinum-sensitive recurrent disease trial (OCEANS)17 evaluated bevacizumab in combination with chemotherapy. As noted in the brief overview of front-line therapy, all 3 completed and reported trials showed a significant improvement in progression-free survival with the addition of bevacizumab to chemotherapy followed by bevacizumab maintenance. As a result, bevacizumab has been approved in Europe for ovarian carcinoma; but the FDA in the United States is yet to consider the data because of their reluctance to accept progression-free survival as a regulatory endpoint.

These data support the view that bevacizumab has a definite role in the management of ovarian carcinoma. The delineation of that role is not yet clear. It seems clear that bevacizumab has a role in combination with chemotherapy to improve progression-free survival in newly diagnosed and platinum-sensitive recurrent disease. It is also clear that bevacizumab is active in patients with platinum-resistant disease. What impact front-line use has on the activity in recurrent disease is not yet clear but is under investigation.

Tamoxifen: The GOG has conducted a large study of tamoxifen in recurrent or persistent ovarian carcinoma. Nineteen responses were observed among 105 patients (18%). A subsequent reanalysis of these data separated chemoresistant from chemosensitive patients and found 10 responses among 77 chemoresistant patients.49 These data suggest that tamoxifen has clear activity in recurrent or persistent disease.

Other active targeted agents in chemoresistant disease: Other targeted agents with reported activity in platinum-resistant disease include olaparib,60 cediranib,61 and cabozantinib.62 Olaparib in particular is a poly(ADP-ribose) polymerase inhibitor and is of interest in BRCA-mutated patients who have defects in the usual mechanisms of DNA repair. The biggest question at present is whether certain non-BRCA patients with other DNA repair defects also respond. This is the subject of ongoing investigation.

In addition to those agents noted above, an extensive array of agents with different targets are currently under study.5 The continued expansion of the number of targeted agents will reflect the continued development of knowledge regarding the molecular biology of ovarian carcinoma.

The evidence that has been cited shows clearly that there are a number of active agents in chemoresistant disease: PLD, topotecan, gemcitabine, oral etoposide, weekly paclitaxel, docetaxel, and pemetrexed among cytotoxic drugs and bevacizumab and tamoxifen among targeted agents. Effective use of this therapeutic armamentarium in patients with chemoresistant disease is governed by 4 basic principles at the current time.

The first principle is that chemoresistant patients should be treated with single agents because there are no data to show an advantage for the administration of combinations of these agents. Three considerations are at play in the selection of the order in which to use the agents: efficacy, toxicity, and patient convenience (schedule). As has been shown from the data cited above, the efficacy of the 9 principle agents is similar. The 2 randomized trials that have been completed to date support the concept that there are no major differences in efficacy in the resistant population. Toxicity is different, however, and forms a major part of the rationale for drug selection along with patient convenience.

The second principle is that, once therapy is started with a particular agent, the drug should be continued until 1 of 3 situations presents itself: progression of disease, unacceptable toxicity, or clinical complete response. The first 2 mandate change for obvious reasons. The third provides an opportunity for a drug holiday for the patient until progression occurs yet again.

The third principle states that a single agent should be used until the agent no longer works or causes unacceptable toxicity. The patient should then receive the next drug in line until it no longer works or causes unacceptable toxicity. This process continues until the supply of active agents has been exhausted or until the patient's wishes or overall condition mandate cessation of further specific treatment. Most patients will receive 3 or more lines of therapy for chemoresistant disease.

The final principle simply postulates that, should a patient achieve a complete response with a particular drug and then experience a treatment-free interval of >6 months, retreatment with that agent at the time of relapse is reasonable. This issue has never been directly studied in a clinical trial except for the platinum compounds as noted previously, but it is reasonable to assume that it would apply to agents other than the platinum compounds.

With regard to the order in which the single agents should be used, the every-4-week schedule and favorable toxicity profile of PLD recommends it as the first agent to be used in the chemoresistant setting. After PLD, almost any order that meets the preferences of the patient and the physician is acceptable. As an example, 1 such reasonable order would be as follows: PLD, then topotecan, then gemcitabine, then oral etoposide, then the taxanes.

Discussions to this point have focused entirely on the use of the results of clinical trials to guide the choice of therapy. Because ovarian carcinoma provides a single-cell suspension in many patients in the form of malignant ascites and because samples thus obtained are easier to grow in culture, patients with ovarian carcinoma have provided a logical target for the use of in vitro assays of drug resistance and/or sensitivity to determine the choice of specific therapy. There are multiple methods that have been tested in patients with ovarian carcinoma, and many of these are commercially available to patients currently.

The question that remains is whether these in vitro tests provide a reliable or superior approach to selection of therapy among the many options available now to the patient and physician. No definitive trial results are available to answer this crucial question. How then should a prudent physician answer the question as to whether, particularly in the chemoresistant setting, to use these assays for selection of therapy?

This issue has been evaluated by the American Society of Clinical Oncology,63 and this statement provides perhaps the best answer to that question:

Based on the evidence from studies that compared outcomes for patients treated with empiric chemotherapy, the use of chemoresistance/sensitivity assays (CRSA) is not recommended outside of the clinical trial setting.

In short, the selection of specific agents for use in patients with recurrent/persistent ovarian carcinoma should be based on the results of clinical trials rather than unproven assays even in the chemoresistant patient.

Evidence supports the current paradigm for the management of patients with recurrent or persistent ovarian carcinoma.

Choices of specific regimens should be based on the results of clinical trials and, particularly in the setting of chemoresistance, should focus on efficacy, toxicity, and patient convenience.

This paradigm will eventually be replaced by an approach on the basis of the specific molecular biology of the particular patient's cancer (personalized medicine), but our level of knowledge is not sufficient to use such an approach at present. In lieu of such knowledge, the current paradigm has served well to improve outcome in patients with recurrent or persistent ovarian carcinoma.

1. Cancer Facts and Figures 2012, American Cancer Society, 2012 [Context Link]

2. Kurman RJ, Shih LM. The origin and pathogenesis of epithelial ovarian cancer-a proposed unifying theory. Am J Surg Path. 2010;34:433-443 [Context Link]

3. Gilks CB, Ionescu DN, Kalloger SE, et al. Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Human Path. 2008;39:1239-1251 [Context Link]

4. Bookman M, Brady M, McGuire W, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27:1419-1425 [Context Link]

5. Mackay HJ, Brady MF, Oza AM, et al. Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer. Int J Gynecol Cancer. 2010;20:945-952 [Context Link]

6. . Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet. 2009;105:3-4 [Context Link]

7. Thigpen T, Brady M, Omura GA, et al. Age as a prognostic factor in ovarian carcinoma. Cancer. 1993;71:606-614 [Context Link]

8. Hoskins WJ, Bundy BN, Thigpen JT, et al. The influence of cytoreductive surgery on recurrence-free interval and survival in small volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecologic Oncology. 1992;47:159-166 [Context Link]

9. Tagawa T, Morgan R, Yun Y, et al. Ovarian cancer: opportunity for targeted therapy. J Oncol. 2012 . [Epub ahead of print] [Context Link]

10. Thigpen T, DuBois A, McAlpine J, et al. First line therapy in ovarian cancer trials. Int J Gynecol Cancer. 2011;21:756-762 [Context Link]

11. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955 [Context Link]

12. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-1007 [Context Link]

13. Armstrong D, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43 [Context Link]

14. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374:1331-1338 [Context Link]

15. Burger R, Brady M, Bookman M, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473-2483 [Context Link]

16. Kristensen G. Results of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer. Proc ASCO. 2011;29:333s (abstr LBA5006) [Context Link]

17. Aghajanian C. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. Proc ASCO. 2011;29:333s (abstr LBA5007) [Context Link]

18. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21:2460-2465 [Context Link]

19. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:3194-3200 [Context Link]

20. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1-6 [Context Link]

21. Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2000;18:106-115 [Context Link]

22. Young RC, Walton LA, Ellenberg SS, et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med. 1990;322:1021-1027 [Context Link]

23. Sevelda P, Vavra N, Schemper M, et al. Prognostic factors for survival in stage I epithelial ovarian carcinoma. Cancer. 1990;65:2349-2352 [Context Link]

24. Vergote IB, Kaern J, Abeler VM, et al. Analysis of prognostic factors in stage I epithelial ovarian carcinoma: importance of degree of differentiation and deoxyribonucleic acid ploidy in predicting relapse. Am J Obstet Gynecol. 1993;169:40-52 [Context Link]

25. Thigpen JTAbeloff M, Armitage J, Lichter A, et al. Cancers of the ovary and fallopian tubes. Clinical Oncology. 20043rd ed NY Churchill-Livingstone [Context Link]

26. Ozols R. Intraperitoneal therapy in ovarian cancer: time's up. J Clin Oncol. 1991;9:197-199 [Context Link]

27. Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol. 2009;112:256-274 [Context Link]

28. Harter P, Hahmann M, Lueck HJ, et al. Surgery for recurrent ovarian cancer: role of peritoneal carcinomatosis: exploratory analysis of the DESKTOP I trial about risk factors, surgical implications, and prognostic value of peritoneal carcinomatosis. Ann Surg Oncol. 2009;16:1324-1330 [Context Link]

29. Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9:389-393 [Context Link]

30. Blackledge G, Lawton F, Redman C, et al. Response of patients in phase II studies of chemotherapy in ovarian cancer: implications for patient treatment and the design of phase II trials. Br J Cancer. 1989;59:650-653 [Context Link]

31. du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003;95:1320-1330 [Context Link]

32. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699-4707 [Context Link]

33. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099-2106 [Context Link]

34. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699-4707 [Context Link]

35. Ferrero J, Weber B, Geay J, et al. Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse. Ann Oncol. 2007;18:263-268 [Context Link]

36. Pujade-Lauraine E, Wagner U, Aavail-Lundqvist E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol. 2010;28:3323-3329 [Context Link]

37. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312-3322 [Context Link]

38. Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008;26:890-896 [Context Link]

39. Rose PG, Blessing JA, Mayer AR, et al. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1998;16:405-410 [Context Link]

40. Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel (80 mg/m²) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436-440 [Context Link]

41. Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003;88:130-135 [Context Link]

42. Bajetta E, Di Leo A, Biganzoli L, et al. Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1996;14:2546-2551 [Context Link]

43. Markman M, Hakes T, Reichman B, et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1992;10:243-248 [Context Link]

44. Look KY, Muss HB, Blessing JA, et al. A phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study. Am J Clin Oncol. 1995;18:19-22 [Context Link]

45. Vergote I, Micha J, Pippitt C Jr, et al. Phase II study of NKTR-102 in women with platinum resistant/refractory ovarian cancer. Proc ASCO. 2010;28:393s (abstr 5013) [Context Link]

46. Naumann RW, Symanowski J, Ghamande S, et al. PRECEDENT: a randomized phase II trial comparing EC-145 and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in subjects with platinum-resistant ovarian cancer. Proc ASCO. 2010;28:952s (abstr LBA5012b) [Context Link]

47. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:5165-5171 [Context Link]

48. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25:5180-5186 [Context Link]

49. Markman M, Iseminger KA, Hatch KD, et al. Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group ancillary report. Gynecol Oncol. 1996;62:4-6 [Context Link]

50. Matei D, Sill W, Lankes H, et al. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a Gynecologic Oncology Group trial. J Clin Oncol. 2011;29:69-75 [Context Link]

51. Kohn E. A phase II study of intermittent sorafenib with bevacizumab in bevacizumab-naive epithelial ovarian cancer patients. Proc ASCO. 2011;29:336s (abstr 5019) [Context Link]

52. Bookman M, Darcy K, Clarke-Pearson D, et al. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2003;21:283-290 [Context Link]

53. Hurteau JA, Blessing JA, DeCesare SL, et al. Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study. Gynecol Oncol. 2001;82:7-10 [Context Link]

54. Schilder RJ, Sill MW, Chen X, et al. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin Cancer Res. 2005;11:5539-5548 [Context Link]

55. Schilder RJ, Sill MW, Lee RB. Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2008;26:3418-3425 [Context Link]

56. Garcia AA, Sill MW, Lankes HA, et al. A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2011 . [Epub ahead of print] doi:10.1016/j.ygyno.2011.10.022 [Context Link]

57. Modesitt SC, Sill M, Hoffman JS, et al. A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;109:182-186 [Context Link]

58. Usha L, Sill MW, Darcy KM, et al. A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol Oncol. 2011;121:455-461 [Context Link]

59. Rocereto TF, Brady WE, Shahin MS, et al. A phase II evaluation of mifepristone in the treatment of recurrent or persistent epithelial ovarian, fallopian or primary peritoneal cancer: a gynecologic oncology group study. Gynecol Oncol. 2010;116:332-334 [Context Link]

60. Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2011 30:372-379 [Context Link]

61. Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol. 2009;27:5601-5606 [Context Link]

62. Buckanovitch R. Activity of cabozantinib in advanced ovarian cancer patients: results from a phase II randomized discontinuation trial. Proc ASCO. 2011;29:334s (abstr 5008) [Context Link]

63. Schrag D, Garewal HS, Burstein HJ, et al. American Society of Clinical Oncology technology assessment: chemotherapy sensitivity and resistance assays. J Clin Oncol. 2004;22:3631-3638 [Context Link]

Key words: chemosensitive recurrent disease; chemoresistant recurrent disease