Salvage therapy for recurrent epithelial ovarian cancer

Hematol Oncol Clin N Am 17 (2003) 977 988 Salvage therapy for recurrent epithelial ovarian cancer Vicki V. Baker, MD Karmanos Cancer Institute, Wayne State University, 3990 John R. Hudson Building, Suite 4924, Detroit, MI 48201, USA Epithelial ovarian cancer is diagnosed in approximately 23,300 women annually and results in 13,900 cancer-related deaths annually [1]. Similar data were reported in 1991, when the disease was diagnosed in 20,700 women and resulted in 12,020 cancer-related deaths [2]. Ovarian cancer is notable for many reasons, including its remarkable sensitivity to first-line combination chemotherapy. Clinical response rates exceed 75% in patients with advanced stage disease (III and IV) after combination therapy with paclitaxel (Taxol) and carboplatin. These patients typically exhibit progression-free intervals ranging from 18 to 22 months [3,4]. Most women show an excellent response to initial treatment with chemotherapy, but most also develop recurrent disease and require additional therapy. Although therapy for recurrent ovarian cancer is rarely curative, women now live much longer with their disease. This situation has led to a shift in the perception of ovarian cancer from a quickly fatal disease to one that is more chronic in nature, requiring repeated rounds of chemotherapy. A review of the data compiled by the SEER program indicates that the prevalence of ovarian cancer approximates almost 200,000 cases per year. Most of these women are receiving or have received chemotherapy for recurrent disease. Although the incidence of ovarian cancer is small, the prevalence is much larger. This observation underscores the magnitude of the clinical problem facing the oncologist who is involved in the care of women diagnosed with ovarian cancer. Commonly used drugs to treat recurrent disease Although there is little debate that recurrent ovarian cancer characterized by the appearance of ascites, a demonstrable mass on physical examination or E-mail address: vbaker@med.wayne.edu 0889-8588/03/$ see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/s0889-8588(03)00057-1

978 V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 imaging studies, or obstructive gastrointestinal symptoms warrants intervention, there is considerable controversy concerning the management of the asymptomatic patient with a modestly elevated serum CA 125. Elevated CA 125 values may precede the appearance of clinical symptoms or documented disease by many months [5]. Patients who exhibit an increase in CA 125 to levels that are two times normal after initial chemotherapy have a 98% chance of developing recurrent disease within 12 months [6]. Although counterintuitive, there are no published data that earlier intervention offers an improved outcome in the salvage setting. This is in contradistinction to the situation involving the early detection of initial disease, which is associated with improved survival. The hazards of overly aggressive treatment include depletion of the bone marrow, the induction of tumor resistance, adverse effects on quality of life, and the occurrence of treatment-related complications, some of which can be life-threatening. Failure to initiate treatment for recurrent disease in a timely fashion might compromise disease-free survival, however. Two randomized, prospective trials currently are under way in Europe to address this important issue. At this time, there are few proscriptions when recommending chemotherapy in the setting of recurrent disease apart from avoiding cross-resistant agents and the exacerbation of existing toxicities and comorbidities. The absence of detailed recommendations concerning the selection and sequence of drugs for recurrent ovarian cancer reflects several factors. Ovarian cancer is a heterogeneous disease. The biology and clinical course of this disease is a function of patient age, performance status, histology, extent of initial surgery, prior chemotherapy, stage of disease, volume of disease within each stage, cellular differentiation, and individual molecular genetic profiles. To date, there is a relative paucity of prospective comparative trials concerning recurrent ovarian cancer, although there is a plethora of published phase II studies and anecdotal series of treatment results. When chemotherapy is considered an appropriate option, many drugs may be considered (Table 1). All of these drugs are characterized by modest response rates of limited duration when used in the setting of recurrent disease. Although individual phase II studies may report strikingly high response rates, it is important to recognize the nonrandomized nature of these trials and their inherent selection bias. These shortcomings often limit the applicability of these observations to the general population of women with recurrent ovarian cancer. Molecular profiling and in vitro tests, although theoretically appealing, exhibit variable sensitivities and specificities. The following information is a synopsis of the more commonly prescribed drugs for the treatment of recurrent ovarian cancer. Topotecan is approved by the United States Food and Drug Administration (FDA) for the treatment of recurrent ovarian cancer. In patients who have received prior platinum/paclitaxel therapy, a 13.7% response rate has been observed in patients with a disease-free interval less than 6 months compared with a 19% response rate in patients with a disease-free interval greater than 6 months. In addition, 23% to 48% of patients achieve disease stabilization [7]. Topotecan typically is administered daily for 5 consecutive days at a dose of 1.5 mg/m 2 and is repeated

V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 979 Table 1 Chemotherapy options for patients with recurrent epithelial ovarian cancer Drug Dosage Platinum Carboplatinum 5 7.5 AUC q 3 wk Cisplatin 50 75 mg/m 2 IVq3wk Taxanes Paclitaxel 40 75 mg/m 2 /wk IV Docetaxel 60 75 mg/m 2 IV q 21 days Topotecan 1.0 1.5 mg/m 2 IV daily 5 every 21 days Etoposide 50 mg/m 2 po daily 14 or 21 days, repeated every 28 days 50 100 mg/day po daily 21 days, repeated every 28 days Doxorubicin 50 mg/m 2 q 3 weeks not to exceed a cumulative dose of 550 mg/m 2 Liposomal doxorubicin 40 50 mg/m 2 IV q 28 days Gemcitabine 800 1250 mg/m 2 IV on days 1, 8, and 15 every 4 wk Vinorelbine (Navelbine) 25 30 mg/m 2 IV q week Ifosfamide 1.8 mg/m 2 /day 3 days, 4 wk Hexamethylmelamine 260 mg/m 2 po daily 14 days, repeated every 28 days every 21 days. The dose should be reduced in the presence of impaired renal function. The primary adverse effect of treatment is noncumulative hematologic toxicity [8]. Fatigue also may be a significant side effect. Topotecan does not cause or exacerbate peripheral neuropathy, which is an advantage in patients who have received prior paclitaxel/platinum based therapy, in whom the incidence of neuropathy may be 25% to 35% [9,10]. More recently, investigations have focused on alternative dosing schedules. Morris and Munkarah [11] reported preliminary data indicating that weekly topotecan is associated with comparable efficacy but reduced toxicity compared with the 5-day treatment regimen. Paclitaxel may be administered in doses ranging from 135 to 175 mg/m 2 by a 3-hour infusion every 3 weeks to treat recurrent ovarian cancer. Zanotti et al [12] reported a 44% objective response rate with a median progression-free interval of 8.6 months. An additional 41% of patients achieved disease stabilization that lasted a median of 7.4 months. Neuropathy was infrequent and mild. As expected, the responses were better in platinum-sensitive compared with platinum-resistant patients, but these differences did not achieve statistical significance. Paclitaxel also may be administered weekly as a 1-hour infusion of 60 to 80 mg/m 2 [13]. Weekly paclitaxel is exceptionally well tolerated and is comparable to paclitaxel administered every 3 weeks in terms of response rate, time to

980 V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 progression, and overall survival [14]. Weekly paclitaxel therapy is effective in some patients who have progressed on prior platinum/paclitaxel administered every 3 weeks [15]. Docetaxel is structurally related to paclitaxel but has a different spectrum of toxicities. Administered at a dose of 100 mg/m 2 intravenously every 3 weeks, a 30% response rate of 6 months duration has been reported [16]. Doxorubicin is associated with response rates ranging from 10% to 30% [17]. At cumulative doses exceeding 550 mg/m 2, at least 7.5% of patients develop clinical cardiomyopathy [18]. Among patients who develop dose-limiting cardiotoxicity, approximately 50% die within 2 years [19]. The risk of cardiac toxicity is reduced significantly when doxorubicin is encapsulated in liposomes. Liposomal doxorubicin (Myocet) and pegylated liposomal doxorubicin (Doxil, Caelyx) are associated with response rates similar to doxorubicin, but the risk of adverse cardiac effects is reduced significantly [20,21]. Liposomal encapsulated doxorubicin exhibits a smaller volume of distribution and a prolonged circulation time. Theoretically the encapsulated drug extravasates through the abnormal tumor vasculature, resulting in its preferential sequestration and prolonged retention within the tumor. Palmar-plantar erythrodysesthesia (PPE), also called hand-foot syndrome, is an adverse event that may limit the total number of cycles of liposomal doxorubicin that can be administered. This syndrome occurs in 30% of patients treated with liposomal doxorubicin doses of 50 mg/m 2 per cycle. It is characterized by painful erythema of the hands and feet. Grade 3 and 4 PPE occur in 23% of patients [22]. Prophylactic measures to minimize this side effect that do not compromise therapeutic efficacy include oral pyridoxine (100 mg/d) and the use of a 40 mg/m 2 dose of doxorubicin every 4 weeks as opposed to the 50 mg/m 2 dose that was approved by the FDA [23,24]. In the presence of PPE, blood flow reduction, systemic steroids, and topical dimethyl sulfoxide (99%) may ameliorate the symptoms of pain and burning. Although most often considered in the context of liposomal doxorubicin therapy, PPE also may occur after treatment with cytarabine, docetaxel, and fluorouracil [25]. Gemcitabine is a pyrimidine analogue of deoxycytidine that has been approved by the FDA for use in pancreatic and non small cell lung cancer. In ovarian cancer, response rates of 13% to 20% have been reported [26,27]. It seems to be active in platinum-sensitive and platinum-resistant disease [28]. In recurrent ovarian cancer, gemcitabine is administered as single-agent therapy once a week for 3 consecutive weeks followed by no therapy during the fourth week. Doses ranging from 800 to 1100 mg/m 2 are administered as a 30-minute infusion. Treatment with gemcitabine is well tolerated with manageable toxicities that may include myelosuppression and fatigue. Ifosfamide is an alkylating agent that is associated with response rates of 10% to 20% [29]. Doses of 1.2 to 1.5 g/m 2 /day mixed with mesna, 1.2 to 1.5 g/day in 2 to 3 L of normal saline are infused over 24 hours for 5 days. The cycle is repeated every 4 weeks. Mesna is administered as a rescue agent to prevent hemorrhagic cystitis. In addition to neutropenia and hemorrhagic cystitis, drug-induced

V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 981 encephalopathy, the risk of which is increased in the presence of renal insufficiency or hypoalbuminemia, may be observed in 10% to 15% of patients. This side effect can be prevented by the administration of intravenous methylene blue [30]. Vinorelbine (Navelbine) is associated with response rates of 15% to 30% with durations of response that are generally less than 8 months. Stable disease may be observed in an additional 35% to 50% of patients. This drug can be given weekly as a 25 to 30 mg/m 2 dose or as a dose of 20 mg/m 2 /day for 3 days every 3 weeks [31,32]. Apart from the predictable side effects of neutropenia and anemia, this drug may worsen a preexisting neuropathy. Nausea and constipation also are commonly observed adverse effects. Additional therapy with cisplatin or carboplatin is most beneficial in patients with a platinum-free interval greater than 6 months. The longer the platinum-free interval, the greater is the likelihood of response to retreatment with cisplatin or carboplatin. An emerging problem with repeat platinum therapy is the unpredictable occurrence of hypersensitivity reactions, some of which may be life-threatening. Patients receiving fewer than six courses of carboplatin exhibit a 1% incidence of hypersensitivity reactions, whereas this increases to 27% in patients who have received more than seven courses of this drug [33]. A skin testing protocol to identify patients at increased risk of hypersensitivity reactions to carboplatin has been described [34]. A 0.02-mL intradermal injection of an undiluted aliquot of the planned carboplatin infusate is administered 1 hour before each planned infusion. A positive test is defined as a wheal measuring greater than 5 mm with surrounding flare. A desensitization protocol for patients with a history of hypersensitivity reactions or patients identified as being at increased risk has been published [34]. Dexamethasone is administered at a dosage of 20 mg daily for 4 days before chemotherapy. Carboplatin is infused using a dose escalation protocol in which 1/1000 of the full dose is given over 30 minutes, followed by 1/100 of the full dose administered over 15 minutes, followed by the remaining dose over 30 minutes. This altered schedule of administration does not prevent the occurrence of hypersensitivity reactions. Death secondary to an anaphylactic reaction to carboplatin has been reported after the administration of carboplatin using the desensitization protocol [35]. Cross-allergies also may occur between carboplatin and cisplatin. Treatment of carboplatin-allergic patients with cisplatin has been associated anecdotally with severe hypersensitivity reactions, including death in one case [36]. As an alkylating agent, platinum-based therapy is associated with a doserelated risk of leukemia [37]. With regard to ovarian cancer, this has been an uncommon problem in the past because most exposed patients died of disease progression. A more recent study of the mechanism of leukemogenesis identified only 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer [38]. Platinum-induced leukemia may emerge as a more

982 V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 common problem in the future because patients now survive for a much longer time. Etoposide is a topoisomerase II inhibitor that exhibits modest activity against recurrent ovarian cancer. Better response rates have been reported after the oral administration of this agent when compared with intravenous therapy. A 21-day regimen of 50 mg/m 2 /day repeated every 28 days has been associated with an objective response rate of 25% [39]. Patients with platinum-refractory disease exhibited a 27% response rate, and platinum-sensitive patients exhibited a 34% response rate. Common toxicities include myelosuppression, alopecia, and mucositis. An increase in the dose-related risk of leukemia has been noted when cumulative doses exceed 2000 mg/m 2. Hexamethylmelamine is another oral agent that is used occasionally to treat recurrent ovarian cancer. In a phase II study conducted by the Gynecologic Oncology Group, a 10% response rate was observed after treatment with 260 mg/m 2 /day of hexamethylmelamine for 14 days in a 29-day course [40]. Manetta et al [41] reported that in a small subset of women with recurrent ovarian cancer, therapy with this drug may result in extended, disease-free survival. The most common side effect of hexamethylmelamine therapy is nausea. For this reason, it is not frequently chosen for patients with gastrointestinal symptoms. This medication also may cause peripheral neuropathy and is not the first drug of choice for patients with recurrent ovarian cancer who have diabetes or a preexisting chemotherapy-induced neuropathy. Concepts that guide the selection of chemotherapy for recurrent ovarian cancer Although many questions are unanswered concerning the specifics of salvage therapy, some general concepts are useful when considering treatment options, as follows: Treatment is palliative, not curative. The interval to first relapse predicts the response to salvage therapy. Combination therapy is not superior to single-agent therapy. Comorbidities and prior toxicities may limit treatment options. Disease stabilization may be beneficial. Cross-resistance among related compounds is variable. With each recurrence, the likelihood of response and its duration decrease. What is said may be different from what is heard. There is a point at which additional treatment is futile. First and foremost, the treatment of recurrent ovarian cancer is palliative in most situations. Although objective responses may be observed and prolonged progression-free intervals may be achieved, cure is not generally a realistic goal.

V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 983 The probability of response to salvage therapy is related to the disease-free interval. The Gynecologic Oncology Group arbitrarily divided epithelial ovarian cancer into platinum-sensitive and platinum-resistant disease based on the absence or presence of disease within 6 months from the completion of firstline chemotherapy [42]. In practice, the response to platinum retreatment occurs over a continuum, and there is no time interval that consistently predicts sensitivity or resistance to this drug. In general, platinum-sensitive patients respond more favorably than platinum-resistant patients to salvage therapy with any agent [43 45]. In addition, the longer the disease-free interval, the better the response. Response rates of 26% have been reported when the disease recurs within 12 months after initial therapy and may be 77% when the treatment-free interval is greater than 24 months [46]. The duration of the response to salvage therapy also is greater in patients with a longer disease-free interval [47]. Patients who progress during first-line therapy with paclitaxel/platinum based treatment are unlikely to respond to other chemotherapy agents and should be offered an opportunity to participate in an investigational study. There are few studies that report the results of third-line and fourth-line therapy. It is a common clinical observation, however, that the likelihood of a response and the duration of the response decrease with each successive recurrence. Villa et al [48] published their experience with 47 patients who received third-line salvage therapy. Among this group of patients, 27% exhibited a complete response, and 21% exhibited a partial response. The median duration of the response was 6 months for the group. As expected, patients with a complete response had a longer progression-free interval (median 16 months) compared with patients who did not have a complete response (median 9 months). Having noted the poor long-term prognosis of recurrent disease and its increasing resistance to treatment, it seems that disease stabilization may be of benefit to patients with recurrent ovarian cancer. Cesano et al [49] reported that the categories of stable disease and partial response were associated with a survival benefit compared with progressive disease. Of particular note, there was no difference in survival among patients who exhibited a partial response compared with patients who exhibited stable disease. This was a retrospective study, however, and these observations should be verified in prospective studies. It is a fundamental principle of chemotherapy that the use of several drugs with different mechanisms of action and nonoverlapping toxicities is of greater therapeutic benefit than the use of single-agent therapy. There is a surprising paucity of data, however, concerning this subject with regard to the treatment of recurrent ovarian cancer. Bolis et al [50] compared carboplatin versus carboplatin and epidoxorubicin as second-line therapy for patients with platinum-sensitive ovarian cancer. There were no significant differences in response or progression, although the toxicities were greater in the group treated with combination therapy. These observations suggest that there is little benefit in using combination therapy as opposed to single-agent therapy for women with recurrent cancer. In an editorial accompanying this article, it was noted, however, that the progression-free interval and overall survival at 3 years increased from 12%

984 V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 and 29% in the single-agent arm to 25% and 42%. Although these differences did not achieve statistical significance, the point was raised that a larger study may have detected a significant difference. Additional studies are required to resolve this question. Another principle of chemotherapy is that resistance to one agent generally is accompanied by resistance to structurally related agents. Although it has been shown repeatedly that cisplatin and carboplatin are cross-resistant and that progression during treatment with one agent precludes treatment with the other, cross-resistance among related compounds does not always occur. Tumors that exhibit resistance to paclitaxel may respond to treatment with the structurally similar compound docetaxel [51]. Similar observations have been made with regard to ifosfamide and cyclophosphamide (Cytoxan). The management of recurrent ovarian cancer is an ongoing process. The cumulative and occasionally irreversible adverse effects must be borne in mind when making treatment recommendations. After first-line therapy with paclitaxel and platinum, some patients exhibit a peripheral neuropathy. This side effect may preclude later therapy with hexamethylmelamine, platinum, and paclitaxel. Cumulative myelosuppression with its attendant episodes of prolonged neutropenia and thrombocytopenia also limits future treatment options. The anorexia and wasting of advanced cancer exacerbate these comorbidities and toxicities. Ultimately the patient is in a situation in which the treatment and its adverse effects outweigh any realistic hope of palliative benefit. Counseling patients with recurrent ovarian cancer is a difficult clinical challenge for many reasons. Occasionally, what is said is not what is heard. There may be significant differences between the perceptions of health care providers and patients regarding the benefits and potential adverse effects of investigational therapy. Patients offered participation in phase I studies tend to be optimistic about the potential of the treatment, whereas physicians are considerably less optimistic. In one study of patients considered candidates for phase I studies, 33% expected a cure, 22% expected a beneficial response to treatment, and 25% expected control of the cancer. These same patients also valued quality of life as much as quantity of life; 67% of the respondents said each had equal value, 26% rated quality as more important, and 3% rated quality as the only important consideration [52]. Patients have high expectations of salvage therapy. In a study reported by Doyle et al [53], 42% of women with recurrent ovarian cancer receiving secondline and third-line salvage therapy thought that chemotherapy would have a moderate-to-high chance of curing their disease. Although this is not the case, patients receiving salvage therapy reported an improvement in quality of life, specifically in emotional function, despite toxicities [53]. An improvement in overall quality of life in response to salvage therapy also has been reported by Lakusta et al [54]. In contrast to the responses by physicians and the general public who do not have cancer, most patients offered chemotherapy with only a 1% chance of cure accept it, and 40% of patients would accept chemotherapy if it could prolong

V.V. Baker / Hematol Oncol Clin N Am 17 (2003) 977 988 985 their lives by only 3 months [55]. As a practical matter, only a few patients with a cancer diagnosis refuse chemotherapy [56]. Donovan et al [57] studied patient preferences for treatment versus best supportive care in the setting of recurrent disease. Women with recurrent cancer overwhelmingly opted for quantity of time over quality of time. There is a point in the course of the disease when additional chemotherapy, or any life-sustaining intervention, is inappropriate. This issue has been discussed eloquently in an editorial by Partridge [58]. In the context of an incurable disease, additional therapy for recurrent ovarian cancer should palliate symptoms and maximize quality of life. When the known toxicities of treatment exceed any hope of benefit, best supportive care becomes the most appropriate option. This is often an exceedingly difficult situation, but the physician must not abdicate his or her responsibilities. As the risk-to-benefit ratio begins to shift toward supportive care, some patients no longer are able to participate in the decision-making process. This situation underscores the importance of candid discussions concerning endof-life decisions earlier rather than later in the course of recurrent disease. Summary There are no comparative prospective trials to support dogmatic statements concerning the sequence and duration of therapy in the salvage setting. Although the literature offers many examples of chemotherapy studies conducted in the salvage setting, these studies typically involve relatively small numbers of younger patients whose disease shows good performance. The extrapolation of these observations to the practice setting, compounded by the clinical and molecular heterogeneity of epithelial ovarian cancer, further exacerbates the difficulties encountered in individual treatment recommendations. References [1] Jemal A, et al. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23 47. [2] Boring CC, et al. Cancer statistics, 1991. CA Cancer J Clin 1991;41:19 36. [3] 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. [4] Nejit JP, Engelholm SA, Tuxen MK, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000;18:3084 92. [5] Markman M. Follow-up of the asymptomatic patient with ovarian cancer. Gynecol Oncol 1994;55:S134 7. [6] Rustin GJS, Nelstrop AE, Tuxen MK, et al. Defining progression of ovarian carcinoma during follow-up according to CA125: a North Thames Ovary Group Study. Ann Oncol 1996;7:361 4. [7] Bookman MA, Malmstrom 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 52. [8] Mobus V, Pfaff PN, Volm T, et al. Long time therapy with topotecan in patients with recurrence of ovarian carcinoma. Anticancer Res 2001;21:3551 6.

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