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The Oncologist, Vol. 7, Suppl 5, 11-19, October 2002
© 2002 AlphaMed Press

Management of Treatment-Related Toxicity in Advanced Ovarian Cancer

Charles J. Dunton

Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA

Correspondence: Charles J. Dunton, M.D., Professor of Obstetrics and Gynecology, Albert Einstein Medical Center, Department of Obstetrics and Gynecology, 5501 Old York Road, Philadelphia, Pennsylvania 19141, USA. Telephone: 215-456-8386; Fax: 215-456-2386; e-mail: duntonc{at}einstein.edu


   LEARNING OBJECTIVES
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 Learning Objectives
Abstract
 Introduction
 Management of Treatment-Related...
 Summary
 References
 Selected Reading
 
After completing this course, the reader will be able to:

  1. Recognize the reversible and irreversible toxicities associated with the management of newly diagnosed ovarian cancer.
  2. Better manage recurrent ovarian cancer.
  3. Identify the range of chemotherapeutic options in managing recurrent ovarian cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
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 Learning Objectives
 Abstract
Introduction
 Management of Treatment-Related...
 Summary
 References
 Selected Reading
 
Recognition of recurrent ovarian cancer as a disease with significant secondary responses and remissions has led to an increase in the need for oncologists to plan for the long-term therapy of patients. However, many of the currently available front-line and salvage agents used in advanced ovarian cancer are associated with cumulative and/or irreversible toxicities that pose challenges in long-term planning. The irreversible effects associated with some of these therapies may render patients less tolerant to subsequent treatments and lead to a cycle of diminishing treatment options with each remission and disease relapse. Additionally, the potential for patients to experience cumulative toxicity must be carefully weighed against the goals of prolonging the disease-free interval and improving patient quality of life. A number of agents are available in the treatment armamentarium (platinum, paclitaxel, gemcitabine, etoposide, liposomal doxorubicin, and topotecan), many, but not all of which are associated with cumulative toxicity. For instance, cumulative neurotoxicity associated with cisplatin as first-line therapy may diminish the option for retreatment with platinum at first relapse. In contrast, the main toxicity associated with topotecan is noncumulative, manageable myelosuppression. In this review, the major toxicities associated with the predominant chemotherapy agents used in advanced ovarian cancer are discussed along with selected management approaches in the context of long-term treatment planning and sequencing.

Key Words. Doxorubicin • Drug toxicity • Neutropenia • Ovarian neoplasms • Topotecan • Etoposide


   INTRODUCTION
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 Learning Objectives
 Abstract
 Introduction
Management of Treatment-Related...
 Summary
 References
 Selected Reading
 
Because the early symptoms of ovarian cancer are easily overlooked, a diagnosis of ovarian cancer is infrequently made before the cancer has progressed to stage III or IV [1]. These advanced-stage cancers tend to recur (i.e., a series of remissions, each followed by disease recurrence), and disease palliation may require ongoing, long-term therapy.

The current standard of care for patients with advanced (stage III or IV) ovarian cancer is cytoreductive surgery followed by administration of systemic chemotherapy. First-line therapy consists of platinum (cisplatin or carboplatin) in combination with paclitaxel. Many oncologists prefer using carboplatin over cisplatin, based on the results of a recent phase III trial conducted by the Gynecologic Oncology Group (GOG-158) [2]. That trial showed that carboplatin/paclitaxel treatment offered efficacy comparable with that of cisplatin/paclitaxel, but did not exhibit the cumulative nephrotoxicity associated with cisplatin therapy. In addition, the International Collaborative Ovarian Neoplasm group studies suggested that the use of carboplatin as a single agent was an acceptable alternative first-line therapy for patients with advanced ovarian cancer [3, 4].

Irrespective of which platinum agent is used, the majority of patients with advanced ovarian cancer ultimately suffer a relapse and continue on with a series of treatments. The chronic natural history of recurrent ovarian cancer mandates that factors such as toxicity profiles, patient convenience, and cumulative effects be considered when planning treatment regimens for the ovarian cancer patient [5, 6]. Many of the agents used in front-line and second-line ovarian cancer therapies may cause permanent changes in the patient that alter tolerance profiles to future chemotherapeutic interventions, and irreversible adverse effects can negatively impact the quality of life of the patient. Although all chemotherapy agents have associated toxicity, acute and reversible side effects are better tolerated by the patient and impose fewer limitations on future treatment options, thereby providing the rationale for careful selection of treatment at each milestone in the natural progression of the disease. In this review, the serious toxicities associated with these agents (topotecan, gemcitabine, and liposomal doxorubicin) are discussed and management strategies provided.


   MANAGEMENT OF TREATMENT-RELATED TOXICITY IN OVARIAN CANCER
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 Learning Objectives
 Abstract
 Introduction
 Management of Treatment-Related...
Summary
 References
 Selected Reading
 
The first criterion that must be assessed when considering second-line therapy for recurrent ovarian cancer is whether the regimen will extend the patient’s overall survival and maintain the patient’s quality of life. Although the prognosis for patients with relapsed ovarian cancer is poor, chemotherapy is often used to palliate symptoms and maintain quality of life [7]. When selecting a therapeutic regimen, the acute and cumulative long-term toxicity profiles of the treatment options must be taken into consideration. Because ovarian cancer management is an ongoing process, the cumulative and irreversible adverse effects of these agents must be weighed against their potential benefits. The side-effect profiles of approved second-line and salvage chemotherapeutic agents for ovarian cancer treatment are further discussed below, with an emphasis on cumulative toxicity data and potential permanent adverse effects.

Platinum Agents
Cisplatin (Platinol®; Bristol-Myers Squibb; Princeton, NJ) is a first-line cytotoxic agent that is often used in second-line therapy to treat platinum-sensitive ovarian cancer. However, cisplatin is associated with several cumulative toxicities, including dose-dependent renal tubule toxicity and neurotoxicity [8]. Extensive renal damage can occur before there are detectable changes in serum creatinine levels, making it difficult to assess the ongoing toxicity of the regimen without regular monitoring of renal function [9]. Additionally, renal impairment can lead to a reduction in the clearance of some cytotoxic agents, potentially exacerbating severe toxicities accompanying the use of these agents. Vigorous hydration or diuresis is necessary during cisplatin administration to minimize the risk and severity of acute nephrotoxicity.

Neurotoxicity, including paresthesias and permanent high-tone hearing loss, also occurs in up to 23% and 45% of patients receiving cisplatin therapy, respectively [10]. In addition, the risk of an allergic hypersensitivity response increases with continued use. Prophylactic treatment with steroids and antihistamines and a slow infusion rate may minimize this risk, although fatal anaphylaxis has still been reported despite these precautions [11]. As a consequence, patients should be closely monitored during all courses of cisplatin therapy [12].

Gastrointestinal adverse events are also common with cisplatin therapy and may be acute or delayed in onset. The resulting nausea and vomiting are the major complaints among cisplatin-treated patients [13]. Use of 5-hydroxytryptamine 3 inhibitors (e.g., granisetron, ondansetron, and tropisetron) can reduce the incidence and severity of these effects [14]. Leukopenia and anemia occur in approximately half of cisplatin-treated patients with advanced ovarian cancer [15]. Treatment with recombinant human erythropoietin (epoetin alfa, Procrit®; Ortho Biotech Products, LP; Raritan, NJ) at the onset of anemia can reduce the need for red blood cell transfusions during cisplatin therapy [16].

The cumulative and irreversible toxicities associated with cisplatin may reduce the potential options for future treatment on relapse. Given the antitumor activity of cisplatin in ovarian cancer, many new platinum-based formulations have been derived to minimize the severe toxicity profiles associated with cisplatin treatment. These compounds include carboplatin (which is currently approved for use in ovarian cancer), oxaliplatin, nedaplatin, satraplatin, and the investigational drugs BBR3464 and ZD0473 [17].

Carboplatin (Paraplatin®; Bristol-Myers Squibb) is an alternative platinum therapy that exhibits considerably lower nephrotoxicity than cisplatin. However, renal function must be monitored when determining dosage regimens to avoid acute toxicity, because renal clearance is the primary means by which carboplatin is cleared from the body. Carboplatin causes dose-limiting and cumulative myelosuppression, characterized by thrombocytopenia, granulocytopenia, and anemia. Thrombocytopenia following carboplatin therapy is frequent and severe [18, 19]. Treatment with growth factors (G-CSF [Neupogen®; Amgen Inc.; Thousand Oaks, CA] in conjunction with epoetin alfa) can mitigate leukopenia and anemia, but abrogation of thrombocytopenia without transfusions remains a challenge [20, 21].

Although cumulative myelosuppression is the main toxicity associated with carboplatin, there is also a significant risk of neurotoxicity and hypersensitivity reactions. A recent study at the Cleveland Clinic Cancer Center [22] reported that hypersensitivity to carboplatin developed in 12% of carboplatin-treated patients. Because of the possibility of fatal cross-hypersensitivity, the use of cisplatin in patients who have developed hypersensitivity to carboplatin is not recommended [23]. Although carboplatin and cisplatin are the current standards of care for first-line therapy of ovarian cancer, their long-term toxicities present challenges in the treatment of patients with relapsed ovarian cancer.

Paclitaxel
Paclitaxel (Taxol®; Bristol-Myers Squibb) is a nonplatinum-based cytotoxic agent approved for the first-line treatment of advanced ovarian cancer. Paclitaxel exhibits high antitumor activity when used in combination with carboplatin [24]. However, the use of paclitaxel may be limited by cumulative peripheral neurotoxicity, and a rapid-onset sensory neuropathy can occur, especially with high-dose regimens [25]. The peripheral neuropathy is due to axonopathy, and motor and autonomic nerves appear to be unaffected by paclitaxel [26]. The resultant painful myalgias and arthralgias can severely impact the patient’s quality of life [27]. The acute dose-limiting toxicity of paclitaxel is granulocytopenia; however, other common acute adverse events include alopecia, nausea, vomiting, diarrhea, mucositis, and hypersensitivity [28].

To decrease the incidence and severity of hypersensitivity reactions, patients should receive pretreatment with steroids. Concomitant steroid therapy allows paclitaxel to be administered over a 3-hour infusion period, which is less myelosuppressive than the 24-hour infusion protocol used previously [29]. A limited phase I evaluation of escalating-dose paclitaxel administered weekly as a 1-hour infusion demonstrated a lack of cumulative myelosuppression, mucositis, or grade III neuropathy with this regimen, though the efficacy of this regimen remains to be determined [30]. These results underscore the relationship between toxicity and method of administration, as well as the importance of considering the mode of delivery when assessing any potential cumulative effects of the patient’s previous treatment regimen(s).

Oral Etoposide
Etoposide (VePesid®; Bristol-Myers Squibb) is a semisynthetic derivative of the plant lignin podophyllotoxin. This agent generates breaks in cellular DNA, either through interactions with DNA topoisomerase II or through the formation of reactive free radicals. The results from a phase II trial by the GOG demonstrated that prolonged administration of etoposide was active as second-line therapy for advanced ovarian cancers, with the following response rates, grouped according to disease history: platinum-sensitive (34%), platinum-resistant (27%), and platinum-resistant and paclitaxel-treated (32%) [31]. Unfortunately, higher cumulative doses and longer therapy durations of etoposide are known to contribute to the development of secondary myelodysplasia and acute leukemias [32]. Additionally, severe hematologic toxicities are common during long-term etoposide therapy. Grade 3/4 neutropenia and leukopenia occur in 45% and 41% of etoposide-treated patients, respectively. Deaths from neutropenic sepsis have been reported. Thrombocytopenia and anemia also occur, albeit at a lower incidence compared with neutropenia and leukopenia [31]. Myelosuppression from etoposide is generally reversible, and no cumulative bone marrow toxicity has been reported. Alopecia, nausea, and vomiting represent other common adverse events. Although etoposide is available in an easily administered oral formulation, care should be taken, as anaphylaxis, mucositis, and acute hypo- and hypertensive responses have been reported [33, 34].

Liposomal Doxorubicin
Doxorubicin (Rubex®; Bristol-Myers Squibb) is a DNA-intercalating agent purified from Streptomyces peucetius var. caesius. Doxorubicin therapy is associated with irreversible and cumulative cardiotoxicity, which may manifest itself as life-threatening arrhythmias during the acute phase of treatment and leads to a greater risk of congestive heart failure. Doxil® encapsulates doxorubicin hydrochloride into polyethylene glycol-coated Stealth® liposomes (Johnson and Johnson; New Brunswick, NJ) and has much lower associated cardiotoxicity [35]. However, such modification increases the risk of other side effects, such as mucositis [36]. Although hematologic toxicity is common and may be dose limiting, the myelosuppression, particularly leukocytopenia, anemia, and thrombocytopenia, is usually transient. The cumulative cardiotoxicity of the liposomal formulation has not been established and, therefore, extended use of liposomal doxorubicin or use of liposomal doxorubicin in patients with impaired myocardial function is contraindicated [37].

Liposomal doxorubicin also exhibits other common adverse events that, although not life threatening, have severe quality-of-life implications (Table 1Go) [3, 28, 31, 38–41].Mild to moderate alopecia is reported in approximately 16% of patients. Additionally, acute nausea and vomiting, which are sometimes severe, and stomatitis and esophagitis can occur [42]. Ulceration and necrosis of the colon may occur, and severe secondary complications can result if ulcers in the mouth and colon become sites for infection. The severity of such infections may be exacerbated by the myelosuppressive effects of doxorubicin alone or in combination with other chemotherapeutic agents [43].


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  		Table 1. Summary of grade 3 or 4 toxic events and cumulative toxicities of chemotherapeutic agents for advanced ovarian cancer
 
Another notable adverse event associated with liposomal doxorubicin is palmar-plantar erythrodysesthesia (PPE), a cutaneous reaction in the palms of the hands and the soles of the feet, which can result in severe pain and cracking of the skin, followed by bleeding episodes. Approximately 50% of all patients receiving liposomal doxorubicin experience PPE. Grade 3/4 PPE occurs in 23% of liposomal doxorubicin-treated patients and must be managed by dose reduction, delay, or discontinuation of therapy, as there is no established pharmacologic intervention for this condition [38]. Although PPE is not a serious complication from a clinical perspective, the pain associated with this reaction should be addressed. Palliative therapies for PPE include the use of salves and behavior modification to prevent cracking of the skin. However, these treatments fail to control the progression of PPE, which may have a strong emotional impact on the patient. For this reason, despite the efficacy of liposomal doxorubicin, only 64% of patients exhibit maintenance or benefit in their pain scores following treatment [3].

Unlike the platinum-based therapies, doxorubicin is cleared from the body primarily via the hepatobiliary route. Patients with impaired hepatic function must be treated with a modified dose schedule to decrease the risk of acute toxicity. Significant decreases in doxorubicin clearance rates also occur in obese patients. Further, tolerance is lower in heavily pretreated women, and no uniform toxicity management has been established for liposomal doxorubicin treatment [42].

Gemcitabine
Gemcitabine (Gemzar®; Eli Lilly; Indianapolis, IN) is a synthetic nucleoside analogue that interferes with DNA replication. Currently, gemcitabine is prescribed in combination with platinum in second-line ovarian cancer therapy. However, in a recent limited phase II study, single-agent gemcitabine was found to offer promising results in second-line treatment of patients with advanced ovarian cancer [44]. Myelosuppression is the primary dose-limiting toxicity of gemcitabine, especially when administered in conjunction with cisplatin or carboplatin therapy because of overlapping toxicity. Frequent monitoring of hematologic parameters and dose modifications is needed to manage the anemia, leukopenia, and thrombocytopenia associated with gemcitabine therapy [39]. Thrombocytopenia is usually most pronounced at higher doses [45].

Other common adverse events associated with gemcitabine include flu-like symptoms (including fever, rigors, and malaise) and lethargy (38% incidence) [46]. Less common is dyspnea, which may occur in conjunction with bronchospasms, in approximately 13% of patients [47, 48].Gemcitabine-induced dyspnea must be distinguished from the symptoms of drug-induced pneumonitis and noncardiogenic pulmonary edema (NCPE), which are rare but potentially life-threatening adverse events. To avoid potentially fatal pulmonary toxicity, NCPE must be diagnosed and treated promptly with intensive supportive therapy [40]. Although the effects of NCPE are usually reversible with immediate intervention, gemcitabine therapy should be halted at the first signs of NCPE [49].

Other common side effects of gemcitabine that affect the quality of life of patients with relapsed ovarian cancer include grade 3 vomiting (38%), clinically manageable fever (32%), and peripheral edema (40%) [47]. The development of rashes is occasional. Cases of anal pruritus have been reported, and patients are often too embarrassed to mention their discomfort until it becomes severe [50]. Gemcitabine-induced alopecia is rarely worse than grade 2, and no cumulative hepatic or direct renal toxicities have been reported for gemcitabine [51]. However, the development of thrombotic microangiopathy may result after extended use of gemcitabine [41], and potentially life-threatening hemolytic uremia can occur secondary to this effect [52, 53].

Topotecan
Topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA) is a water-soluble derivative of camptothecin, a natural topoisomerase I inhibitor derived from Camptotheca acuminata [54]. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of the single-strand breaks that are created in the DNA by topoisomerase I to relieve torsional strain during gene expression and DNA replication. Irreparable double-stranded breaks in the DNA occur during replication, triggering programmed cell death. The efficacy of topotecan in advanced ovarian cancer patients is comparable with that of both paclitaxel and liposomal doxorubicin [38, 55, 56]. However, unlike doxorubicin and paclitaxel, the majority of topotecan’s serious adverse events are short-lived, reversible, and noncumulative. Therefore, the toxicity profile of topotecan presents fewer challenges for the oncologist in the development of ongoing cancer management strategies.

An emerging challenge in ovarian cancer management is the effect of prior treatment regimens on the patient’s response to subsequent courses of chemotherapy. For example, topotecan is not associated with significant nephrotoxicity, but the impaired renal function that often results from front-line chemotherapy can adversely affect the pharmacokinetics of drug delivery. As shown in Figure 1Go, the renal clearance of topotecan correlates with creatinine clearance, and creatinine clearance rates are a good indication of topotecan dose tolerance [57]. Armstrong et al. [58] have proposed modified dosing guidelines to limit topotecan-induced toxicity in patients with impaired renal function (Table 2Go) [59]. Although the liver also contributes to the clearance of topotecan, no dose modifications are necessary in patients with impaired hepatic function [60].



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  		Figure 1. Topotecan clearance versus creatinine clearance rates. O’Reilly et al. [57] have investigated the effects of renal function on clearance of topotecan. Topotecan clearance (in liters/hour) shows a correlation with the measured creatinine clearance rate (in ml/minute) of the patient.

 

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  		Table 2. Topotecan dosing recommendations for patients with renal impairment and prior myelosuppressive therapy*
 
The depletion of bone marrow is an ongoing challenge during prolonged cancer therapy. The dose-limiting effect for topotecan is short-term, noncumulative neutropenia, and dose-dependent thrombocytopenia and anemia are common. The reported incidence rates for these acute effects are summarized in Table 1Go [3, 28, 31, 38–41]. A number studies have shown that multiple factors may affect the severity of myelosuppression in response to topotecan therapy. Dosage schedules should be adjusted based on the patient’s treatment history, as bone marrow transplantation, radiation therapy, or prior therapy with agents that have cumulative myelotoxicity (e.g., carboplatin) predispose the patient to more severe episodes of myelosuppression. Dose reductions have not been shown to decrease response rates [61]. In the event of febrile or persistent neutropenia or infection, neutrophil recovery can be facilitated with the support of G-CSF. Thrombocytopenia can be managed with platelet transfusion. Epoetin alfa has been used prophylactically during topotecan therapy, and red blood cell transfusions can also be administered as clinically warranted [58]. Whereas other chemotherapeutic agents display cumulative hematological toxicities, Goldwasser et al. [62] have shown that topotecan displays decreased thrombocytopenic effects with each dosing cycle, even in patients who have been heavily pretreated with other chemotherapeutic agents. These findings suggest that platelets and hematopoietic progenitor cells might downregulate the cellular targets for this agent during extended therapy

Alopecia is the only cumulative toxicity reported during long-term topotecan therapy [63]. Other nonhematologic side effects occur with relatively low frequency. In a large, phase III trial, low-grade (<2) stomatitis and PPE were reported in 15% and 1% of topotecan-treated patients, respectively [38]. Following that study, 81% of topotecan-treated patients reported maintenance or improvements in their pain scores, and 74% reported increased emotional function [37].

Because the hematologic toxicities of topotecan are predictable and manageable, and because the nonhematologic side effects do not increase patients’ pain indices, long-term therapy with topotecan is possible. A recent analysis by Möbus et al. [63] of 33 patients receiving a total of 343 courses of topotecan therapy (average of 10.4 courses per patient, with a range of 7 to 33 courses) reported predictable, manageable noncumulative hematologic toxicity and a low incidence of nonhematologic side effects. In agreement with the findings of Goldwasser et al., fewer patients required blood cell transfusions or growth factor support to manage the hematologic toxicity of topotecan during later courses of therapy. Although no absolute remission data could be generated from that study, all of the patients achieved a complete or partial remission or stable disease during the course of topotecan treatment [64]. That study supports the safe and long-term use of topotecan as palliative therapy for the advanced ovarian cancer patient.


   SUMMARY
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 Learning Objectives
 Abstract
 Introduction
 Management of Treatment-Related...
 Summary
References
 Selected Reading
 
Unfortunately, despite continued gains in survival and other clinical end points in advanced ovarian cancer, the goal of offering long-term remission with existing therapies is all too infrequently realized. However, palliative chemotherapy can provide an extension of life span and an improvement in patient quality of life. Because most patients undergo a series of remissions and recurrences, the additive or cumulative toxicity of cancer therapy must be factored into the treatment plan. Particular emphasis should be placed on cumulative and irreversible toxicities versus reversible and noncumulative side effects, as irreversible toxicity can preclude or limit further treatment options and severely impact the patient’s outlook and quality of life.

Although therapeutic regimens that couple platinum-based therapy with other cytotoxic agents are the current standard of care for advanced ovarian cancer patients, the cumulative toxicities of cisplatin and carboplatin can present barriers to the long-term use of these agents. Further, the severe myelogenic toxicity and greater incidences of secondary myelodysplasia and leukemia associated with prolonged and cumulative etoposide treatment must also be considered. Cumulative doxorubicin and paclitaxel exposure must also be monitored to minimize the risk of patient morbidity due to cardiotoxicity and neuropathy, respectively. Gemcitabine shares many overlapping toxicities with other agents, and care must be taken during combination regimens to avoid synergy of these effects.

As with many cytotoxic agents, topotecan is associated with predictable acute and dose-limiting myelosuppression. However, topotecan-associated myelosuppression is reversible and noncumulative and does not generally compromise future treatment options [6]. Furthermore, topotecan-induced myelosuppression can be managed by supportive therapy with growth factors. In contrast, the toxicity of previous therapies can impact the pharmacokinetics and resulting tolerance profiles of topotecan in the second-line and salvage settings. Dose modifications are usually sufficient to minimize the severity of myelosuppression and other side effects.

Because many of the available agents in first-line and recurrent ovarian cancer treatment exhibit nonoverlapping mechanisms of action, a number of novel combinations with potential for synergy are under active investigation. For instance, the combination of topotecan and gemcitabine has complementary actions on DNA metabolism, and neither agent is associated with cumulative toxicity. In a limited phase I trial, the combination was well tolerated and active in patients with advanced refractory solid tumors [65]. In addition, a phase III GOG trial (GOG-0182) is currently under way to compare the relative efficacies of topotecan, gemcitabine, and liposomal doxorubicin as single agents or in combination therapies [32]. The results of these studies will hopefully provide further treatment options and toxicity management approaches for use in the long-term treatment planning of patients with advanced ovarian cancer.


   ACKNOWLEDGMENT
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 Learning Objectives
 Abstract
 Introduction
 Management of Treatment-Related...
 Summary
 References
 Selected Reading
 
Supported by an unrestricted educational grant from GlaxoSmithKline, Philadelphia, Pennsylvania. Charles J. Dunton receives research support from and is a member of the Speakers’ Bureau for GlaxoSmithKline.


   SELECTED READING
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 Learning Objectives
 Abstract
 Introduction
 Management of Treatment-Related...
 Summary
 References
 Selected Reading
 


   REFERENCES
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 Management of Treatment-Related...
 Summary
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Selected Reading
 
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Received June 17, 2002; accepted for publication July 19, 2002.




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