This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Markman, M. Articles by Bookman, M. A. Search for Related Content PubMed PubMed Citation Articles by Markman, M. Articles by Bookman, M. A.

Second-Line Treatment of Ovarian Cancer

^a The Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio, USA; ^b Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

Correspondence: Michael A. Bookman, M.D., Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111, USA. Telephone: 215-728-2987; Fax: 215-728-3877; e-mail: ma_bookman{at}fccc.edu

	Abstract

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Patients with epithelial ovarian cancer are often diagnosed with advanced-stage disease. Although clinical complete remissions are obtained in the majority of patients through a combination of cytoreductive surgery and chemotherapy, relapse is common. A number of agents with diverse biologic mechanisms have been identified with activity in the setting of recurrent disease. Strategies for management of patients with recurrent disease, including classification, treatment goals, and therapeutic options will be reviewed.

Key Words. Chemotherapy • Epithelial ovarian cancer • Platinum • Resistance

	Introduction

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Ovarian cancer is one of the most sensitive of all solid tumors to antineoplastic chemotherapy, and responses are expected in over 80% of women who receive standard platinum- and paclitaxel-based treatment [1]. Despite this fact, the majority of women with advanced ovarian cancer will ultimately relapse and develop drug-resistant disease [2, 3]. Thus, there is a common need in this cancer to consider the use of second-line chemotherapeutic options.

	Objectives of Second-Line Therapy

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
While the focus of this manuscript is systemic or regional chemotherapy, selected patients may benefit from secondary cytoreductive surgery or palliative radiation therapy. Due to the propensity for diffuse peritoneal spread, the extent of recurrent disease is often underestimated by conventional imaging modalities. This has led many oncologists to reserve surgery for symptomatic patients with localized bowel obstruction or other disease-related symptoms. However, some patients may develop a localized pelvic recurrence amenable to cytoreduction, which can be followed by chemotherapy or observation. In addition, it should be noted that radiation therapy can be useful for palliative management of pain or bleeding associated with bulky pelvic disease.

In any discussion of second-line ovarian cancer therapy clinicians and patients can benefit from a shared understanding of basic treatment goals. While clinically meaningful objective and subjective responses can occur in patients with resistant disease, and prolonged progression-free and overall survival may be observed in patients with platinum-sensitive disease, available data do not support the conclusion that therapy has a realistic potential to be curative in these settings.

In most patients, a progressive rise in serum CA-125 heralds the development of recurrent disease, raising questions about surveillance and the optimal timing of second-line chemotherapy. However, CA-125 is not truly tumor specific, and an elevated CA-125 could be secondary to increased production by chronically inflamed peritoneal mesothelium, rather than recurrent tumor. In this regard, some patients experience a modest postchemotherapy rise in CA-125 without associated symptoms or other evidence of progressive disease. In addition, depending on the extent of disease and balance between aggressive and indolent features, several months may elapse between the first elevation of CA-125 and the development of symptoms or clinical evidence of disease progression. These observations have contributed to a lively debate regarding surveillance and the optimal timing for intervention with second-line therapy.

The notion of aggressive monitoring of serum CA-125 with early initiation of second-line therapy is attractive to many patients and clinicians but has not been shown to be curative or superior to conventional monitoring with interventions based on clinical findings. In contrast to colorectal cancer where an asymptomatic rise in carcinoembryonic antigen (CEA) may signify an isolated hepatic metastasis or local recurrence that is amenable to surgical resection, recurrent ovarian cancer tends to spread by diffuse peritoneal implantation, which is not considered resectable for cure. In addition, false positive elevations of CA-125 are more common than CEA.

All cytotoxic chemotherapy is associated with the potential for host toxicity and a negative impact on quality of life, particularly for patients without pre-existing symptoms related to their disease. In addition, many of the symptoms associated with advanced peritoneal disease, such as intermittent bowel dysfunction, may persist even if the tumor responds to treatment. Thus, in the absence of data to support early intervention, it is reasonable to consider noncytotoxic alternatives for patients with an elevated CA-125 but without other clinical evidence of disease. However, this remains a controversial area that merits thoughtful discussion between the patient and medical team.

In summary, the general intent of treatment for patients with recurrent disease is palliative. As a result, the anticipated toxicity of proposed therapeutic regimens and their impact on the overall quality of life should be an important consideration in the selection of antineoplastic strategies in the second-line treatment setting.

	Definition of Treatment Populations

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
One of the difficulties with interpreting the reported activity of individual antineoplastic agents following second-line phase II studies has been characterization of the treated population. It is now well recognized that there is considerable heterogeneity among patients who receive second-line treatment and this can lead to wide variations in the anticipated objective response rates to second-line platinum-based therapy, ranging from less than 10% to greater than 40% [4]. More precise definition of the treated population makes it easier for results to be appropriately evaluated and applied in other settings, including the use of a particular regimen in routine clinical practice (Fig. 1).

View larger version (29K): [in this window] [in a new window]   Figure 1. Extent of disease after cytoreductivesurgery.

Resistant ovarian cancer is defined as disease that has responded to initial chemotherapy but demonstrates recurrence within a relatively short period of time following the completion of treatment. Again, GOG has decided that patients with documented recurrence within six months of completing initial therapy should be considered "platinum-resistant."

Persistent ovarian cancer is the finding of residual disease in a patient who has completed, and apparently responded to, initial chemotherapy. For example, this would include a microscopic-positive second-look laparotomy in a patient who began chemotherapy with suboptimal or optimal residual disease after initial cytoreductive surgery. However, many patients begin chemotherapy in clinical complete remission after cytoreductive surgery, and persistence of small-volume disease may represent chemotherapy resistance rather than evidence of continued response, contributing to heterogeneity in this population.

Refractory ovarian cancer occurs in patients who have failed to achieve at least a partial response to therapy. This includes patients with either stable disease or actual disease progression during primary therapy, which occurs in approximately 20% of cases. As might be expected, this group has the lowest response rate to second-line therapy.

In many studies of second-line treatment, patients with resistant, persistent, and refractory disease are considered as one group, while individuals with platinum-sensitive recurrent disease are considered separately. Even within these more resistant populations there is still considerable heterogeneity with regard to overall drug sensitivity. Although the difference between drug-sensitive and drug-resistant disease was initially described in relationship to platinum-based therapy, these observations can be applied in a general sense to other chemotherapy regimens. However, the patterns of resistance and mechanisms of action for many drugs, such as paclitaxel, are distinct from platinum, and resistance to a combined regimen does not always imply complete resistance to both drugs in the regimen. Thus, a proportion of patients with "platinum-resistant" disease may respond to rechallenge with paclitaxel as a single agent, particularly with alternative schedules of drug administration, as discussed below.

	Approach in Recurrent (Potentially Platinum-Sensitive) Disease

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Extensive clinical experience has facilitated the development of rational treatment strategies in this setting. Patients who respond to initial platinum-based chemotherapy and who experience a "reasonable" treatment-free interval are considered to have disease that is potentially platinum-sensitive [6-9]. These patients are also likely to retain sensitivity to paclitaxel. In general, the longer the platinum-free interval, the greater the expectation of durable response to retreatment. Patients who remain disease-free for more than two years following primary therapy have the greatest likelihood of benefit and are usually retreated with a combination of platinum and paclitaxel [10, 11].

There is no absolute treatment-free interval that completely separates individuals with regard to potential sensitivity to platinum or paclitaxel after response to initial therapy [12, 13]. However, a six-month treatment-free interval, which is used to define resistant and recurrent ovarian cancer for the purpose of clinical trial design, is often employed to determine the "potentially platinum-sensitive" patient population [5].

Patients in this clinical setting are frequently considered candidates for retreatment with regimens similar to those previously received in the front-line setting, including cisplatin, carboplatin, or paclitaxel as single agents or in combination [11]. However, there is currently no evidence from prospective randomized trials that combination chemotherapy achieves superior outcomes with regard to survival or quality of life compared to the use of sequential single agents. In addition, early retreatment with platinum places the patient at risk for cumulative hematologic (carboplatin) and nonhematologic (cisplatin) toxicity that can limit further therapy and diminish the overall quality of life. In selected patients, the use of a nonplatinum regimen, as discussed below, may extend the platinum-free interval with less risk of cumulative toxicity. Initially, such patients should consider participation in phase II clinical trials to evaluate new treatment strategies, as they are better able to tolerate multiple cycles of therapy and more likely to respond to a given treatment regimen compared to patients with more extensive prior therapy.

	Approach in Persistent Disease

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Patients with evidence of persistent disease (e.g., elevation of CA-125, microscopic-positive residual disease at reassessment laparotomy, abnormalities on computerized tomography imaging, or findings on physical examination) after initial chemotherapy can be divided into at least two groups with different expectations and treatment options. Those patients with gross residual disease after initial surgery (suboptimal cytoreduction) who then exhibit a major response to treatment are considered to have potentially chemoresponsive persistent disease, and efforts have focused on consolidation to maximize the progression-free interval. Those patients with small volume residual disease after initial surgery (optimal cytoreduction) who continue to have small volume or microscopic disease after systemic chemotherapy are more likely to be chemoresistant, and efforts have focused on the development of non-cross-resistant regimens.

Several treatment approaches can be considered for the chemoresponsive population. First, patients may continue to receive the drugs to which their disease has responded. This might include giving several additional courses of a platinum-paclitaxel combination, or single-agent paclitaxel. The optimal number of chemotherapy cycles to be administered in this setting is unknown, and it remains to be established if continued treatment in a responding patient will impact favorably on long-term clinical outcomes. In this regard, randomized trials are in progress to evaluate the potential benefit of continued therapy with paclitaxel in responding patients. Alternatively, patients may be treated with one of a number of agents demonstrated to have activity in the second-line setting (see below).

For patients who have achieved a major response to treatment with persistence of small volume residual disease (i.e., microscopic peritoneal disease and/or tumor nodules <0.5 cm in maximum diameter), it is not unreasonable to consider a dose-intensive approach to maximize response and the progression-free interval. Strategies that have been employed in this setting include intraperitoneal therapy [14], and high-dose intravenous chemotherapy with marrow or peripheral progenitor cell support [15-17]. Efforts to evaluate high-dose consolidation in a prospective randomized trial were organized by the GOG and the National Cancer Institute but were terminated prematurely due to poor accrual.

Again, it must be emphasized that data do not currently exist from randomized controlled trials to demonstrate that any therapeutic approach, including a variety of dose-intensity strategies, has curative potential in the second-line treatment of advanced ovarian cancer. As a result, the potential significant toxicities of these regimens must be kept in mind when considering possible strategies in this clinical setting.

	Approach in Resistant/Refractory Disease

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Patients with platinum-resistant ovarian cancer that did not respond to initial therapy, or with disease that recurred after a short (<six-month) treatment-free interval, pose a particular challenge. Similarly, patients with recurrent disease after retreatment with platinum-based therapy are often drug resistant, and may also be more difficult to treat due to cumulative hematologic and nonhematologic toxicity, as well as declining performance status due to persistent disease. However, there are a number of antineoplastic treatment options which may be considered based on recent clinical trials.

Platinum remains the single most important drug employed in the therapy of advanced ovarian cancer, and selected patients with platinum-sensitive disease may benefit from retreatment with either cisplatin or carboplatin. However, the majority of patients with recurrent ovarian cancer eventually develop platinum-resistant disease, in which case the potential risks of cumulative toxicity outweigh any potential benefits. In some cases, prolongation of the platinum-free interval can improve the likelihood of response to retreatment with platinum due to partial reversal of acquired drug resistance. This phenomenon has been documented in a small number of patients with cisplatin-refractory disease who have responded to retreatment with carboplatin after extension of the platinum-free interval using nonplatinum-based chemotherapy [18]. As discussed below, a number of agents have recently been described with moderate activity against platinum-resistant disease, and these agents may contribute to extension of the platinum-free interval, opening an opportunity for eventual rechallenge with platinum.

With one important exception, trials of second-line therapy in ovarian cancer have been phase II noncomparative studies with objective response rates in patients with measurable disease that have ranged from 10% to 35%. While the duration of these responses has generally been short (<8 months), some patients may continue to respond or maintain stable disease for a more extended interval. In this palliative setting, the development of stable disease is also considered to be a positive, but limited, outcome that is achieved in an additional 35% to 50% of patients. In the absence of dose-limiting toxicity or clinical evidence of progressive disease, it is reasonable to continue therapy in such patients, depending on their overall quality of life and performance status.

Few phase II trials of second-line chemotherapy of ovarian cancer have included formal quality-of-life evaluations, or have even attempted to relate objective tumor shrinkage to symptomatic improvement. Therefore, it is difficult to know how these responses have translated into actual clinical benefit for the responding patients. However, it is not unreasonable to speculate that objective responses observed in symptomatic patients often translate into an improvement in the symptoms of disease.

In view of the number and diversity of active agents presently available for second-line treatment of ovarian cancer, clinicians and patients often consider treatment beyond the second-line setting, assuming adequate organ function and overall performance status. Unfortunately, there are limited data to predict activity of these agents against tumors that are refractory to multiple chemotherapy regimens. In these circumstances it is reasonable to choose an agent with a different mechanism of action and limited potential for serious toxicity. Response should be evaluated after two or three cycles. Once again, the attainment of stable disease with acceptable levels of toxicity is a valid clinical endpoint.

	Overview of Specific Agents for Systemic Therapy

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Topotecan
After platinum and paclitaxel, topotecan is the agent that has undergone the most extensive testing to define a role as second-line therapy for recurrent ovarian cancer [19, 20], and has been approved by the U.S. Food and Drug Administration (FDA) for that indication. A randomized phase III trial compared the activity of topotecan and paclitaxel in individuals who previously received platinum-based front-line therapy. Patients were not permitted to have previously received paclitaxel. The study demonstrated externally verified response rates of 20.5% (23/122) for topotecan and 14% (15/114) for paclitaxel with similar progression-free and overall survival for the two agents [19].

As paclitaxel is currently employed in the initial therapy of ovarian cancer, a nonrandomized phase II study was performed to evaluate the activity of topotecan following platinum and paclitaxel. Objective responses were observed in 13.7% (19/139) of patients after failing prior platinum and paclitaxel, with a slightly higher response rate of 19% (5/26) among those patients with potentially platinum-sensitive recurrent disease [21].

The standard five-day topotecan regimen (1.5 mg/m²/day) results in considerable bone marrow suppression in previously treated ovarian cancer patients, with 80% grade 4 neutropenia and 25% grade 4 thrombocytopenia [19-21]. Nonhematologic toxicities are generally mild and not dose-limiting. Hematologic toxicity usually occurs during the first cycle and can be managed with dose reduction and/or introduction of hematopoietic growth factors without evidence of cumulative toxicity. The five-day schedule can be inconvenient for patients and their families, however, the relative lack of acute toxicity makes topotecan a good candidate for home-based therapy in selected patients. In addition, an oral formulation is under investigation with preliminary evidence of good bioavailability and similar antitumor efficacy. Shorter schedules (three daily treatments or a 24-h continuous infusion) are also under investigation, but may have less activity than the five-day schedule.

As topotecan can inhibit DNA repair, there has been an ongoing effort to develop combinations with cisplatin or carboplatin, which act through DNA damage. For example, GOG is conducting a front-line phase I trial in combination with cisplatin and paclitaxel [22] after completing a second-line trial in combination with paclitaxel [23]. Although active, each of these regimens has been complicated by frequent and severe hematologic toxicity, even with reduced dosages of all components. The use of sequential doublets with carboplatin and topotecan followed by carboplatin and paclitaxel may reduce the degree of bone marrow toxicity and facilitate incorporation of topotecan. At this point, single-agent therapy remains the most appropriate option for patients with recurrent disease.

Liposomal Doxorubicin
Doxorubicin in known to be an active agent in ovarian cancer, and has been evaluated in front-line therapy with cisplatin and cyclophosphamide, achieving a small impact on long-term survival that was detectable in a meta-analysis of randomized trials prior to the advent of paclitaxel [24]. Stealth liposomal doxorubicin (Doxil) is a formulation of doxorubicin encapsulated in polyethylene-glycol (PEG)-coated liposomes associated with a dramatic alteration in pharmacokinetics characterized by a prolonged circulation time and a small volume of distribution [25]. Liposomes can eventually extravascate through abnormally permeable vessels, which are frequently associated with tumors, and can theoretically deliver high local levels of doxorubicin.

Doxil is associated with dose-limiting hand-foot syndrome characterized by painful erythema, peeling, and occasional blistering, which can generally be managed by prolongation of the treatment interval to four weeks and/or dose reduction. The risk of cardiomyopathy with Doxil is reduced compared to free doxorubicin. Histologic examination of cardiac biopsies from patients who received cumulative doses of Doxil from 440 to 840 mg/m², without prior anthracycline exposure, revealed significantly less cardiac toxicity than in matched doxorubicin controls [26].

Phase I studies in solid tumors confirmed preclinical pharmacokinetics and provided preliminary evidence of activity in ovarian cancer, with a maximum tolerated dose established at 50 mg/m² every three weeks [27]. In a phase II study at this dose, Doxil was evaluated as a single agent in ovarian cancer patients who failed previous paclitaxel- and platinum-based therapies. In this heavily pretreated population, 9 of 35 (25.7%) patients responded to Doxil with a median progression-free interval of 5.7 months [28]. In view of this activity, GOG has initiated a front-line phase I study of Doxil in combination with carboplatin and paclitaxel, as well as a series of nonplatinum doublets with Doxil in patients with recurrent disease.

Oral Etoposide
The "standard" three-day intravenous etoposide regimen, as originally developed in lung cancer, has limited activity in ovarian cancer. However, several studies have reported that a prolonged 21-day low-dose oral etoposide regimen (50 mg/m²/day) results in a 25% objective response rate in the second-line setting in patients with ovarian cancer [29, 30]. As might be expected, in individuals with more extensive prior therapy the objective response rate appears somewhat lower [31].

The major toxicity of oral etoposide is bone marrow suppression, which can be significant in this setting, and patients should be monitored with weekly blood counts. Gastrointestinal effects, including nausea and mucositis, can also occur. Etoposide carries a risk of secondary myelodysplasia and acute leukemia that is related to the cumulative dose and duration of therapy. However, this is of limited significance in patients receiving palliative therapy for recurrent disease. Oral etoposide has a clear advantage of convenient home administration, requiring clinic evaluation prior to each four-week cycle.

In view of the activity demonstrated as second-line therapy, GOG has completed a front-line phase I study of oral etoposide with carboplatin and paclitaxel [32]. However, the potential risks associated with secondary myelodysplasia or acute leukemia are greater in this population with more prolonged survival, and extended observation of treated patients will be required prior to further evaluation in randomized trials of front-line therapy. For patients with recurrent disease managed outside of a clinical trial, single-agent therapy remains the most appropriate option.

Altretamine
Altretamine (hexamethylmelamine) has been examined for a number of years in the treatment of ovarian cancer in both second- and first-line settings. Several recent studies have demonstrated the drug has modest activity (approximately 10% response rate) in patients who were well-defined as having platinum refractory or resistant ovarian cancer [33, 34].

While altretamine offers the convenience of an oral formulation, there is a high incidence of nausea and vomiting. For an oral agent that must be taken for 14 days each month, this can pose a formidable challenge to both patients and their families. An intensive antiemetic regimen can reduce the incidence of gastrointestinal toxicity, but this increases the overall complexity of the therapeutic program.

Gemcitabine
Gemcitabine, recently approved by the FDA for treatment of pancreatic cancer, has been demonstrated to be an active second-line agent in ovarian cancer. Several phase II trials have revealed a 15% to 20% response rate in this clinical setting [35, 36], although minimal activity was apparent when evaluated as front-line therapy in poor prognosis patients with advanced disease [37]. Gemcitabine is generally administered on a weekly schedule for three consecutive weeks followed by a one-week treatment break using a dose of 800 to 1,100 mg/m²/week as a 30-min infusion. Gemcitabine has been reasonably well tolerated, with the major side effects being neutropenia, thrombocytopenia, fatigue, myalgias, skin rash, and fever. The weekly treatment schedule can be inconvenient for patients and families, but home administration is feasible.

Again, because of the ability of gemcitabine to inhibit DNA repair, combinations with cisplatin and carboplatin are under development [38-40]. In patients with platinum-resistant disease after multiple prior therapies, a combination of gemcitabine and cisplatin has demonstrated impressive activity in a pilot study [41]. Preliminary data using front-line combinations with platinum, paclitaxel, and gemcitabine have also been presented [42], and GOG is conducting a front-line phase I trial of gemcitabine in combination with carboplatin and paclitaxel to define a feasible regimen for phase III evaluation. Other nonplatinum combinations are also under development, and may show promise as second-line therapy. However, at the present time, single-agent therapy, or possibly a conservative combination with cisplatin, due to the risk of cumulative nonhematologic toxicity, are the most appropriate options for patients with recurrent disease.

Ifosfamide
Several clinical trials have demonstrated ifosfamide to be an active agent in ovarian cancer patients after initial platinum-based therapy (10%-20% objective response rate) [43-45]. As an older agent, most of the experience with ifosfamide has been in patients previously treated with a combination of platinum and cyclophosphamide, prior to the incorporation of paclitaxel. It has been suggested that the current second-line activity of ifosfamide might be enhanced as a consequence of a reduction in the use of cyclophosphamide during initial therapy of ovarian cancer. However, a recently reported trial of single-agent ifosfamide in patients refractory to both platinum and paclitaxel has revealed an objective response rate of only 15%, similar to that achieved in patients previously treated with cyclophosphamide [46].

Ifosfamide has a number of important toxicities to be considered in the ovarian cancer population, including neutropenia, renal dysfunction, injury to the urothelium (hemorrhagic cystitis), and reversible central nervous system dysfunction. Risk for these toxicities is increased in elderly patients with renal dysfunction and low serum albumin, which are common findings in recurrent ovarian cancer. The drug also has the disadvantage of being administered over multiple days, or requiring a 24-h intravenous infusion.

Vinorelbine
Vinorelbine has been explored in the treatment of ovarian cancer when administered by one of several schedules, including 25 to 30 mg/m²/week [47, 48], and 20 mg/m²/day for three days repeated on an every-three-week schedule [49]. Objective responses have been observed in approximately 15% to 30% of the patients defined in the trials as having platinum resistant or refractory disease.

The major toxicities of vinorelbine are neutropenia and anemia. In addition, the drug can result in a worsening of a pre-existing peripheral neuropathy from the initial platinum/ paclitaxel treatment program.

Paclitaxel
Paclitaxel has been established as an important initial component of ovarian cancer chemotherapy [2], and should be considered in the management of patients with recurrence. Of interest, the spectrum of toxicity varies widely depending on the schedule of drug administration, which raises a possibility that alternative schedules may increase the likelihood of response in patients with recurrent disease. In addition, the mechanisms of acquired drug resistance are different between paclitaxel and platinum, and not all patients with platinum-resistant disease are resistant to paclitaxel, even if paclitaxel was included in their front-line treatment program.

As a component of initial platinum-based chemotherapy, paclitaxel is currently administered as either a 3-h (175 mg/m²) or 24-h (135 mg/m²) intravenous infusion. Phase III randomized trials in patients with recurrent disease have evaluated dose intensity (135 versus 175 and 175 versus 250 mg/m²) and infusion duration (3 versus 24 h) without a clear advantage to either higher doses or prolonged infusion [50, 51], and a well-tolerated dose of 175 mg/m² as a 3-h infusion has been commonly employed for the management of recurrent disease.

A prolonged 96-h infusion at a total dose of 120 to 160 mg/m² was reported to have good activity in breast cancer, but was evaluated in recurrent ovarian cancer following multiple prior therapies with unimpressive results [52]. In contrast, experience at one center has revealed that ovarian cancer patients who are classified as having "paclitaxel-resistant" disease may respond to the same drug when delivered at a lower dose (60 to 80 mg/m²) using a 1-h infusion on a weekly schedule [53]. This particular schedule is associated with minimal noncumulative hematologic and nonhematologic toxicity, including a reduction in alopecia. Peripheral neurotoxicity is not uncommon, particularly with higher cumulative doses in patients with pre-existing neuropathy, but this can usually be managed with treatment breaks and/or dose reduction. While these data need to be confirmed in a larger patient population, they suggest a reasonable therapeutic option for individuals with resistant or refractory disease. Overall, the weekly schedule appears less toxic and more convenient than the prolonged 96-h infusion. However, the optimal schedule for administration of paclitaxel has yet to be defined. A phase III randomized trial of cisplatin in combination with 96-h paclitaxel is in progress within GOG. If this trial shows an advantage for the 96-h infusion, this issue will certainly be re-examined. Of interest, studies are also being initiated with alternative formulations of paclitaxel in liposomes or polymer-based microspheres to maintain continuous serum or peritoneal levels after intermittent dosing.

Docetaxel
Docetaxel has been examined in several clinical trials for management of platinum-resistant ovarian cancer, with an objective response rate of approximately 20% to 35% being documented in this clinical setting [54-56]. This level of activity is comparable to that of paclitaxel observed in a similar patient population.

The dose of single-agent docetaxel in these studies has been 100 mg/m², delivered on an every-three-week schedule. It is not known if a lower dose regimen (e.g., 60 or 80 mg/m²) might result in a similar response rate with reduced toxicity. The drug is generally well tolerated in this setting, with the major toxicity being neutropenia and a capillary leak syndrome with fluid accumulation that is related to the cumulative dose and number of cycles.

Docetaxel has the advantage of being administered as a 1-h infusion on an every-three- to four-week schedule, improving patient convenience of the treatment program.

Preliminary data suggest that some patients with paclitaxel resistance may respond to subsequent therapy with docetaxel [57], and additional clinical trials are in progress to examine this interesting and potentially important issue.

Tamoxifen
Tamoxifen is one of several compounds that modulate activity of the estrogen receptor in a tissue-specific manner. Tamoxifen may exhibit selective agonist or antagonist effects depending on competition with circulating estrogens and receptor biology. Ovarian tumors often express estrogen, progesterone, and androgen receptors, but receptor expression has not been reliably correlated with the potential for hormonal response. Several clinical trials have documented that tamoxifen is an active antineoplastic agent in platinum-resistant ovarian cancer, with an objective response rate of approximately 15% [58-61]. As the published experience with tamoxifen occurred prior to the introduction of paclitaxel, the level of activity in both platinum- and paclitaxel-resistant disease is unknown.

The major advantage of tamoxifen in this clinical setting is the highly favorable toxicity profile for the agent, certainly compared to cytotoxic chemotherapy. As a result, tamoxifen may be considered the "treatment of choice" in several specific circumstances in the second-line setting for patients with ovarian cancer.

First, as CA-125 is commonly utilized to monitor ovarian cancer patients following the completion of initial chemotherapy, a significant percentage of individuals are documented to have disease recurrence prior to the onset of symptoms or any other objective evidence of the presence of disease [62]. In the absence of any data to demonstrate that the initiation of cytotoxic chemotherapy in this specific setting improves time to symptomatic-disease progression or ultimate survival, the use of tamoxifen has great appeal. In addition to being relatively nontoxic and impacting minimally on the individual's otherwise good quality of life, administration of the hormone will allow the physician (and patient) to evaluate the tempo of disease. If symptoms or other objective evidence of the cancer should develop, whether weeks or months later, cytotoxic drug therapy can be reinitiated.

Second, in the patient who has failed several (or many) second-line treatment approaches, or where the patient's performance status does not permit cytotoxic drug delivery, tamoxifen can serve as a valid therapeutic strategy that should not negatively influence quality of life.

Herceptin
Herceptin is a recombinant humanized monoclonal antibody that targets her2/neu, one component of a transmembrane growth factor receptor family that is similar to the receptor for epidermal growth factor. Binding of herceptin to the receptor is associated with activation and intracellular signal transduction through protein phosphorylation. Receptor-mediated signaling can result in growth interruption and has also been reported to enhance the activity of chemotherapy in preclinical models. Clinical trials in patients with breast cancer that overexpress her2/neu demonstrated a confirmed response rate of approximately 12% [63], and randomized trials have suggested a survival and response advantage when combined with chemotherapy [64].

Preclinical data suggest that the biologic activity of herceptin correlates with the degree of antigen expression, and that patients with tumors that have high-level overexpression of her2/neu would be most likely to benefit. Historical data indicated that approximately 25% of ovarian cancers might exhibit overexpression. However, in the process of screening over 500 patients for a phase II GOG trial of herceptin in recurrent ovarian cancer, preliminary data indicate that the frequency of overexpression might be less than 12%, which would greatly limit any potential application of herceptin in this setting (M. Bookman, unpublished observation, GOG160).

As a humanized protein, toxicities associated with herceptin are generally mild and not dose-limiting. However, there have been a small number of reports of cardiomyopathy in breast cancer patients that received herceptin in conjunction with doxorubicin, and this is under further investigation.

At this point, there are no firm data to establish a role for herceptin in the management of recurrent ovarian cancer, and patients with her2/neu overexpression are encouraged to participate in clinical trials. Of note, there is no evidence that herceptin would provide any benefit for the majority of patients with tumors that have low or undetectable expression of her2/neu, either alone or in combination with chemotherapy.

	Conclusion

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 
Second-line treatment of ovarian cancer continues to evolve as new agents with diverse mechanisms of action are introduced into the oncologist's armamentarium. Patients with recurrent disease also provide an important clinical setting for the development of new and novel treatment strategies that may ultimately be incorporated into the initial management of ovarian cancer. As noted throughout, patients should be encouraged to participate in clinical trials when available. Outside of a clinical trial, there are a number of standard regimens that can be safely administered with good tolerance in the majority of patients. Selected patients with localized disease may also be suitable candidates for secondary cytoreductive surgery or palliative radiation therapy. In view of the chronic nature of recurrent ovarian cancer, the achievement of stable disease with maintenance of performance status is an acceptable goal for many patients.

	References

Top Abstract Introduction Objectives of Second-Line... Definition of Treatment... Approach in Recurrent... Approach in Persistent Disease Approach in Resistant/Refractory... Overview of Specific Agents... Conclusion References

 

1. Cannistra SA. Cancer of the ovary. N Engl J Med 1993;329:1550-1559.[Free Full Text]
2. 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.[Abstract/Free Full Text]
3. Bookman MA, McGuire WP III, Kilpatrick D et al. Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. J Clin Oncol 1996;14:1895-1902.[Abstract/Free Full Text]
4. Markman M, Hoskins W. Responses to "salvage" chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 1992;10:513-514.[Free Full Text]
5. Thigpen JT, Blessing JA, Ball H et al. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 1994;12:1748-1753.[Abstract/Free Full Text]
6. 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.[Abstract]
7. Gershenson DM, Kavanagh JJ, Copeland LJ et al. Re-treatment of patients with recurrent epithelial ovarian cancer with cisplatin-based chemotherapy. Obstet Gynecol 1989;73:798-802.[Abstract/Free Full Text]
8. Hoskins PJ, O'Reilly SE, Swenerton KD. The ‘failure free interval' defines the likelihood of resistance to carboplatin in patients with advanced epithelial ovarian cancer previously treated with cisplatin: relevance to therapy and new drug testing. Int J Gynecol Cancer 1991;1:205-208.
9. Gore ME, Fryatt I, Wiltshaw E et al. Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 1990;36:207-211.[CrossRef][Medline]
10. McGuire WP, Ozols RF. Chemotherapy of advanced ovarian cancer. Semin Oncol 1998;25:340-348.[Medline]
11. Rose PG, Fusco N, Fluellen L et al. Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma. J Clin Oncol 1998;16:1494-1497.[Abstract/Free Full Text]
12. Markman M. "Recurrence within 6 months of platinum-therapy": an adequate definition of "platinum-refractory" ovarian cancer? Gynecol Oncol 1998;69:91-92.[CrossRef][Medline]
13. Markman M, Kennedy A, Webster K et al. Evidence that a "treatment-free interval of < 6 months" does not equate with clinically defined platinum resistance in ovarian cancer or primary peritoneal carcinoma. J Cancer Res Clin Oncol 1998;124:326-328.[CrossRef][Medline]
14. Markman M. Intraperitoneal therapy of ovarian cancer. Semin Oncol 1998;25:356-360.[Medline]
15. Stiff PJ, Bayer R, Kerger C et al. High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol 1997;15:1309-1317.[Abstract/Free Full Text]
16. Legros M, Dauplat J, Fleury J et al. High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: long-term results. J Clin Oncol 1997;15:1302-1308.[Abstract/Free Full Text]
17. Morgan MA, Stadtmauer EA, Luger SM et al. Cycles of dose-intensive chemotherapy with peripheral stem cell support in persistent or recurrent platinum-sensitive ovarian cancer. Gynecol Oncol 1997;67:272-276.[CrossRef][Medline]
18. Kavanagh H, Tresukosol D, Edwards C et al. Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer. J Clin Oncol 1995;13:1584-1588.[Abstract/Free Full Text]
19. Ten Bokkel Huinink W, Gore M, Carmichael J et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183-2193.[Abstract/Free Full Text]
20. Cremers GJ, Bolis G, Gore M et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 1996;14:3056-3061.[Abstract]
21. Bookman MA, Malmström H, Bolis G et al. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy containing cisplatin or carboplatin and paclitaxel. J Clin Oncol 1998;16:3345-3352.[Abstract]
22. Armstrong DK, O'Reilly S, Bookman M et al. A phase I study of topotecan (T), cisplatin (C), and paclitaxel (P) in newly diagnosed epithelial ovarian cancer, a Gynecologic Oncology Group (GOG 9602) study. Proc Annu Meet Am Soc Clin Oncol 1998:17:A1351.
23. O'Reilly S, Fleming GF, Baker SD et al. Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group Study. J Clin Oncol 1997;15:177-186.[Abstract/Free Full Text]
24. Ovarian Cancer Meta-Analysis Project: cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin, and cisplatin chemotherapy of ovarian carcinoma: a meta-analysis. J Clin Oncol 1991;9:1668-1674.[Abstract]
25. Gabizon A, Catane R, Uziely R et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 1994;54:987-992.[Abstract/Free Full Text]
26. Berri G, Billingham M, Alderman E et al. The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's Sarcoma patients with pegylated liposomal doxorubicin. Ann Oncol 1998;9:711-716.[Abstract/Free Full Text]
27. Uziely B, Jeffers S, Isacson R et al. Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995;13:1777-1785.[Abstract/Free Full Text]
28. Muggia FM, Hainsworth JD, Jeffers S et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997;15:987-993.[Abstract/Free Full Text]
29. 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.[Abstract]
30. Hoskins PJ, Swenerton KD. Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 1994;12:60-63.[Abstract]
31. Markman M, Hakes T, Reichman B et al. Phase 2 trial of chronic low dose oral etoposide as salvage therapy of platinum-refractory ovarian cancer. J Cancer Res Clin Oncol 1992;119:55-57.[CrossRef][Medline]
32. Rose PG, Rodriguez M, Waggoner S et al. A phase I study of paclitaxel, carboplatin, and increasing doses of prolonged oral etoposide in ovarian, peritoneal, and tubal carcinoma: a Gynecologic Oncology Group study. Proc Annu Meeting Soc Gynecol Oncol 1999;18:A109.
33. Markman M, Blessing JA, Moore D et al. Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial. Gynecol Oncol 1998;69:226-229.[CrossRef][Medline]
34. Vergote I, Himmelmann A, Frankendal B et al. Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer. Gynecol Oncol 1992;47:282-286.[CrossRef][Medline]
35. Lund B, Hansen OP, Theilade K et al. Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. Cancer Inst 1994;86:1530-1533.[Abstract/Free Full Text]
36. Shapiro JD, Millward MJ, Rischin D et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996;63:89-93.[CrossRef][Medline]
37. Underhill C, Parnis FX, Highley M et al. A phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer (EOC). Proc Annu Meet Am Soc Clin Oncol 1996;15:A795.
38. Peters GJ, Bergman AM, Ruiz van Haperen VW et al. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995;22(suppl 11):72-79.
39. Pedersen AG. Phase I studies of gemcitabine combined with carboplatin or paclitaxel. Semin Oncol 1997;24(suppl 7):64-68.
40. Bauknecht T, Grieshaber C, Breitbach G-P et al. Gemcitabine (GEM) in combination with cisplatin (CP) in previously untreated patients 60 years with FIGO stage IIIC or IV epithelial ovarian cancer: a phase II study: preliminary results. Proc Annu Meet Am Soc Clin Oncol 1998;17:A1376.
41. Kunkel LM, Evans SS, Dottino PR et al. Cisplatin (CDDP) & gemcitabine (DFDC) in relapsed ovarian cancer. Proc Annu Meet Am Soc Clin Oncol 1998;17:A1379.
42. Geertsen P, Hansen M, Strøyer I et al. Combination chemotherapy with platinum, paclitaxel, and gemcitabine in patients with relapsed ovarian carcinoma. Proc Annu Meet Am Soc Clin Oncol 1999;18:A1395.
43. Sutton GP, Blessing JA, Homesley HD et al. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1989;7:1672-1676.[Abstract]
44. Sorensen P, Pfeiffer P, Bertelsen K. A phase 2 trial of ifosfamide/mesna as salvage therapy in patients with ovarian cancer refractory to or relapsing after prior platinum-containing chemotherapy. Gynecol Oncol 1995;56:75-78.[CrossRef][Medline]
45. 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 1991;10:243-248.[Abstract]
46. Markman M, Kennedy A, Sutton G et al. Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent. Gynecol Oncol 1998;70:272-274.[CrossRef][Medline]
47. 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.[Abstract]
48. George MJ, Heron JF, Kerbrat P et al. Navelbine^® in advanced ovarian epithelial cancer: a study of the French Oncology Centers. Semin Oncol 1989;16(suppl 4):30-32.
49. Gershenson DM, Burke TW, Morris M et al. A phase I study of a daily x3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer. Gynecol Oncol 1998;70:404-409.[CrossRef][Medline]
50. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994;12:2654-2666.[Abstract/Free Full Text]
51. Omura GA, Brady MF, Delmore JE et al. A randomized trial of paclitaxel (T) at 2 dose levels and filgrastim (G; G-CSF) at 2 doses in platinum (P) pretreated epithelial ovarian cancer (OVCA): a Gynecologic Oncology Group, SWOG, NCCTG and ECOG Study. Proc Annu Meet Am Soc Clin Oncol 1996;15:A755.
52. Markman M, Rose PG, Jones E et al. Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens. J Clin Oncol 1998;16:1849-1851.[Abstract]
53. Fennelly D, Aghajanian C, Shapiro F et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187-192.[Abstract/Free Full Text]
54. Francis P, Schneider J, Hann L et al. Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer. J Clin Oncol 1994;12:2301-2308.[Abstract/Free Full Text]
55. Kaye SB, Piccart M, Aapro M et al. Docetaxel in advanced ovarian cancer: preliminary results from three phase II trials. Eur J Cancer 1995;31A(suppl 4):S14-S17.
56. Piccart MJ, Gore M, ten Bokkel Huinink W et al. Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 1995;87:676-681.[Abstract/Free Full Text]
57. Kavanagh JJ, Winn R, Steger M et al. Docetaxel for patients with ovarian cancer refractory to paclitaxel, an update. Proc Annu Meet Am Soc Clin Oncol 1999;18:A1423.
58. Hatch KD, Beecham JB, Blessing JA et al. Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients. Cancer 1991;68:269-271.[CrossRef][Medline]
59. 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.[CrossRef][Medline]
60. Ahlgren JD, Ellison NM, Gottlieb RJ et al. Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program. J Clin Oncol 1993;11:1957-1968.[Abstract/Free Full Text]
61. Williams CJ. Tamoxifen in relapsed ovarian cancer: a systematic review. Int J Gynecol Cancer 1998;8:89-94.
62. Markman M. Follow-up of the asymptomatic patient with ovarian cancer. Gynecol Oncol 1994;55:S134-S137.[CrossRef][Medline]
63. Baselga J, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996;14:737-744.[Abstract/Free Full Text]
64. Norton L, Slamon D, Leyland-Jones B et al. Overall survival (OS) advantage to simultaneous chemotherapy (CRx) plus the humanized anti-HER2 monoclonal antibody herceptin (H) in HER2-overexpressing (HER2+) metastatic breast cancer (MBC). Proc Annu Meet Am Soc Clin Oncol 1999;18:A483.

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Markman, M. Articles by Bookman, M. A. Search for Related Content PubMed PubMed Citation Articles by Markman, M. Articles by Bookman, M. A.