Management of Ovarian Cancer

In a 1981 review article published in the Annals of Internal Medicine discussing "current strategies" in the management of ovarian cancer, the authors noted the controversies regarding the role of a single agent vs combination chemotherapy, and single-agent chemotherapy vs radiation therapy in stage III disease, as well as the lack of a clearly established role for the "new" cytotoxic drug cisplatin(Drug information on cisplatin).[1] This paper further noted that the "age-adjusted death rate from ovarian cancer has remained unchanged over the past 20 years despite attempts at earlier diagnosis and more aggressive treatment." In commenting on the data regarding the risk of secondary alkylating agent-associated acute leukemia, the authors stated,[2,3] "clearly, the benefits of adjuvant chemotherapy and prolonged chemotherapy in ovarian cancer patients need closer scrutiny." Finally, although the article described the "significant" toxicities of chemotherapy (including cisplatin)—which "may include troublesome nausea and vomiting, renal impairment, ototoxicity, and peripheral sensorimotor neuropathy, and unusual side effects such as anaphylactic reactions and clinical tetany from hypomagnesemia"—there was no discussion regarding the impact of these effects on either overall short-term or long-term quality of life.

It is important to understand the state of affairs regarding the treatment of ovarian cancer in the early 1980s to truly appreciate the enormous changes in disease management since that time, and evidence for substantial improvement in both the duration of survival and quality of life for patients with the disease. This paper will briefly discuss the increasingly favorable impact of evolving treatment paradigms in improving these critical parameters, and note future directions for clinical research in this complex disease process.

Primary Treatment of Ovarian Cancer

Central Role of Platinum Agents

Multiple randomized trials and several meta-analyses have clearly established the role of platinum agents (cisplatin and carboplatin(Drug information on carboplatin)) in the primary chemotherapeutic management of ovarian cancer.[4-7] The most recent phase III study, which directly compared single-agent cisplatin to single-agent paclitaxel(Drug information on paclitaxel) as front-line treatment of advanced ovarian cancer, demonstrated that cisplatin produced a substantially higher objective response rate, compared to what many consider to be the "second-most-active drug" in the malignancy.[8]

Based on this extensive experience revealing the critical role of platinum agents in ovarian cancer,[4-7] it is difficult to see a justification for future front-line chemotherapy trials in this malignancy to attempt to find substitutes for this class of cytotoxic drugs. Rather, research efforts should be focused on discovering agents that can add to the activity of platinum agents. (Of course, if a well conceived and conducted prospective phase III randomized trial demonstrates that a pretherapy "in vitro diagnostic test" can reliably determine that the ovarian cancer in a particular patient is highly resistant to platinum drugs, it would be appropriate to consider treatment with alternative strategies.[9])

Studies have now convincingly shown that carboplatin is equivalent to cisplatin when combined with either cyclophosphamide(Drug information on cyclophosphamide)[10,11] or paclitaxel[12] in the primary treatment of advanced ovarian cancer, with the carboplatin-based regimen generally being preferred by most oncologists (and patients) due to its more favorable toxicity profile (eg, less emesis, neuropathy, nephrotoxicity). However, it remains uncertain whether this same statement can be made for the equivalence of cisplatin and carboplatin when delivered by the intraperitoneal route as primary treatment of small-volume residual advanced ovarian cancer.

Based on the results of a series of excellent phase III clinical trials, it is appropriate to conclude there are three intravenous platinum-based primary chemotherapy regimens acceptable for use outside the setting of a clinical trial (Table 1).[12-15] As previously noted, the carboplatin-based programs are more likely to be employed in routine practice, not because of superior efficacy, but due to less toxicity and ease of administration (eg, when given with cisplatin, a 24-hour paclitaxel infusion is required to reduce the risk of severe neurotoxicity).[16]

Clinical Research Efforts in Advanced Disease

For more than a decade investigators have explored methods to improve the primary treatment of advanced ovarian cancer. The substitution of paclitaxel for an alternative second agent (eg, cyclophosphamide), when combined with cisplatin, has been shown to substantially (and statistically significantly) improve both progression-free and overall survival in the malignancy.[13,16]

When combined with carboplatin, docetaxel(Drug information on docetaxel) has been demonstrated to be equivalent to paclitaxel in the treatment of advanced ovarian cancer (Table 1), but the two taxanes have different toxicity profiles.[14] The docetaxel-containing regimen is associated with a greater risk of potentially clinically relevant neutropenia compared to paclitaxel, while the paclitaxel program is more likely to produce a sensory peripheral neuropathy. The decision regarding which taxane to employ as a component of primary chemotherapy in ovarian cancer should be based on the experience of the oncologist with the agents, unique clinical characteristics (eg, preexisting neuropathy from diabetes, elderly patient with a concern for bone marrow suppression), and patient choice.

Unfortunately, other attempted modifications of the "established" ovarian cancer treatment program, examined in prospective phase III randomized trials, have not been shown to favorably affect outcome in the disease. These changes include (1) "doubling" platinum dose intensity (eg, cisplatin, from 50 to 100 mg/m2; carboplatin, from AUC 4 to AUC 8; or AUC 6 to AUC 12)[17-19]; (2) extending the paclitaxel infusion schedule from 24 to 96 hours; and (3) adding a third drug to a platinum/taxane program (eg, topotecan(Drug information on topotecan) [Hycamtin], epirubicin(Drug information on epirubicin) [Ellence]). Of note, the preliminary results of a large (4,000-patient) international phase III ovarian cancer primary chemotherapy trial directly comparing several three-drug combination regimens to a carboplatin/paclitaxel program should be available within the next year.

Duration of Primary Chemotherapy in Advanced Disease

Several research groups have explored the concept of extending the duration of primary cisplatin-based chemotherapy regimen, from a standard 5 or 6 treatment cycles, to as many as 10 to 12 courses.[20-22] Unfortunately, prospective phase III trials have failed to reveal any additional benefits from this approach, but toxicity was clearly increased.

Despite this outcome with extended platinum-based primary chemotherapy in advanced ovarian cancer, interest was generated for examining a consolidation, or maintenance, strategy using paclitaxel, a cycle-specific agent that had previously been shown to exhibit a relatively acceptable toxicity profile when delivered for prolonged time periods (> 1-2 years) in the second-line treatment of the malignancy.[23-26] In a somewhat controversial phase III trial, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) randomized women with advanced ovarian cancer who had achieved a clinically defined complete response to primary platinum/paclitaxel chemotherapy to receive either 3 or 12 additional cycles of single-agent paclitaxel (175 mg/m2) delivered on an every-28-day schedule.[27]

The study was discontinued by its Data Safety and Monitoring Committee when approximately one-half of the intended patient population had been entered, because of a highly statistically significant difference in progression-free survival in favor of the 12-cycle arm (28 vs 21 months; P = .002).[27] Although the monitoring committee has the absolute prerogative to independently assess the ethical justification for continuing any randomized study, the decision to close the trial has been criticized, as it essentially eliminated any possibility that the trial would reveal an overall survival benefit associated with this novel strategy, if one truly exists.

For the present, it is reasonable to conclude that women with advanced ovarian cancer who achieve a clinically defined complete response to primary platinum/taxane-based chemotherapy (eg, normal physical exam and computed tomography scan of the abdomen and pelvis, normal serum CA-125 antigen level) should be informed of the results of this trial and be given the option of receiving this therapy, in the absence of clear treatment-related contraindications (eg, prior chemotherapy-induced neuropathy). In this discussion, the possible benefits (ie, extended time to disease relapse, improvement in overall survival) will need to be balanced against the potential harms (eg, development of treatment-related peripheral neuropathy).

Cisplatin-Based Intraperitoneal Chemotherapy of Small-Volume Residual Advanced Disease

For more than 50 years, researchers have been interested in the intraperitoneal delivery of cytotoxic agents in the management of ovarian cancer, largely based on the anatomic location of the malignancy and its propensity for malignant ascites formation.[28] In the late 1970s, a solid pharmacokinetic rationale for this strategy was presented by Dedrick and his colleagues at the National Cancer Institute (NCI), which led a number of research groups to systematically explore the approach.[29]

These efforts culminated in three multicenter NCI cooperative group-based randomized phase III trials (Table 2),[30-32] which have unequivocally demonstrated the superiority of intraperitoneal cisplatin compared to intravenous cisplatin, when employed as primary chemotherapy of small-volume residual advanced ovarian cancer (variously defined as the largest residual tumor nodule being < 1-2 cm in maximal diameter following initial cytoreductive surgery).

The randomized trials have revealed that cisplatin-based intraperitoneal chemotherapy programs are associated with somewhat greater acute toxic effects compared to an "all-intravenous" regimen, but the studies also showed no increase in treatment-related mortality. Further, a finding of great importance emerged from the most recently reported phase III trial, which compared a regimen of intravenous cisplatin/paclitaxel to a program of intraperitoneal cisplatin plus both intravenous and intraperitoneal paclitaxel: While there was a greater decline in formally assessed quality of life during treatment with the regional strategy, when examined at 12 months' follow-up, there was no difference between the two study arms.[32] Thus, it is reasonable to conclude that all women with small-volume residual advanced ovarian cancer who do not have contraindications to intraperitoneal drug delivery (eg, extensive abdominal adhesions, infectious peritonitis) should be considered for management by this approach.

Several options for primary intraperitoneal chemotherapy may be considered, including the exact regimen utilized in the most recent GOG trial.[32] However, it is also rational to argue that the tolerability of regional treatment could be enhanced without compromising the major survival advantage of this approach, by reducing the dose of cisplatin from 100 mg/m2, as employed in each of the three randomized trials, to a dose of 75-80 mg/m2.[29-33]

Future research efforts in this area will hopefully build upon current experience and explore other agents for regional delivery. Ongoing studies designed to improve the technology of drug delivery (eg, by optimizing catheter insertion or developing strategies to prevent adhesion formation) have the realistic potential to further enhance the efficacy of this novel management approach.

'High-Risk' Early-Stage Disease

It has been known for more than a decade that the administration of cytotoxic chemotherapy could delay the time to disease progression in women with "high-risk" early-stage (eg, stage IC or II) ovarian cancer, but data were not available to document whether such "adjuvant" treatment would favorably impact overall survival.

This controversy has now been resolved to the satisfaction of most ovarian cancer clinical investigators with the publication of results from a combined analysis of two large randomized phase III trials (N = 1,000), which directly compared adjuvant platinum-based chemotherapy to an observation strategy until disease relapse in women with high-risk early-stage cancer.[34,35] The studies revealed an improvement in both 5-year disease-free survival (76% vs 65%; P = .001) and, most importantly, 5-year overall survival (82% vs 74%; P = .008), associated with the early (adjuvant) treatment approach.[34,35]

The optimal number of platinum-based chemotherapy cycles to be delivered in this setting remains somewhat unsettled.[36] Nevertheless, a strong argument can be made (both on theoretical grounds and considering limited existing data) that the same number of courses routinely employed in advanced disease should be utilized in this patient population, in the absence of excessive toxicity experienced by an individual patient (eg, early development of platinum-induced peripheral neuropathy).

'Second-Line' Therapy

Despite the substantial improvement in the outcome of patients with ovarian cancer, demonstrated both in individual randomized trials and in population-based studies,[37] the majority of women who present with advanced disease ultimately die as a result of complications of progressive cancer. Before discussing the treatment of individuals whose malignancy has "failed to respond completely" to primary chemotherapy, or those in whom this state has been attained but the "cancer has recurred," it is relevant to note an evolving conceptual change in the general management of this population—that of viewing ovarian cancer as a chronic disease process.[38] In this somewhat complex, and unquestionably controversial analysis, it is argued that an increasingly large percentage of patients with persistent/recurrent ovarian cancer can be anticipated to live for extended periods of time (often measured in years), despite the fact that the cancer can only be "controlled" and never eliminated.

Considered in this light, it becomes critically important to focus not only on the short-term side effects of treatment, but also on the longer-term toxicities. These effects may not only substantially interfere with a patient's quality of life, but may also impair her ability to subsequently receive drugs that might further delay the development of symptomatic disease progression. This is far from a trivial matter, as there are an increasing number of antineoplastic agents with documented activity in well-defined "platinum-resistant" ovarian cancer, and it is not uncommon for a patient to receive five or more regimens during the course of her illness.

Thus, for example, if aggressive dosing of a particular treatment program has a reasonably high probability of producing persistent peripheral neuropathy—such that it may be impossible to administer other neurotoxic agents in subsequently delivered regimens—it is difficult (if not impossible) to understand the justification for such an approach, in the absence of evidence-based data (prospective phase III randomized trials) revealing the superiority of an aggressive strategy, compared to more modest dosing programs.