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Costs of treatment and outcomes associated with second-line therapy and greater for relapsed ovarian cancer
Gynecologic Oncology 93 (2004) 223 – 228 www.elsevier.com/locate/ygyno
Costs of treatment and outcomes associated with second-line $ therapy and greater for relapsed ovarian cancer Monica Prasad, a Leah Ben-Porat, b Brad Hoppe, a Carol Aghajanian, a Paul Sabbatini, a Dennis S. Chi, c and Martee L. Hensley a,* a
Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021,USA b Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021,USA c Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021,USA Received 24 October 2003
Abstract Objective. Most women with epithelial ovarian cancer (EOC) will develop disease progression or recurrence with resistance to platinum therapy. We report overall costs and treatment outcomes associated with topotecan or gemcitabine administration in platinum- and paclitaxelresistant EOC patients. Methods. Patients who received topotecan (n = 51) or gemcitabine (n = 56) as second-line therapy or greater for platinum- and paclitaxelresistant EOC were retrospectively identified. Per patient costs for each regimen were determined and compared. Results. The mean total direct cost per cycle per patient of gemcitabine was $2732.28, with a median total direct cost per cycle of $1382.73. The mean total direct cost per cycle per patient of topotecan was $7832.07, with a median total direct cost per cycle of $4219.02. By comparison of the means, total direct cost per cycle per patient was significantly more expensive for topotecan ( P = 0.001). Fifty-six patients received a total of 415 cycles of gemcitabine, median 5 cycles per patient (range, 1 – 59). Thirteen (23.2%; 95% CI, 11.9 – 34.5%) of 56 patients displayed clinical benefit, with median PFS of 1.8 months and median overall survival (OS) of 8.2 months. Fifty-one patients received topotecan, for a total of 264 cycles, median 4 cycles per patient (range, 1 – 42). Twenty-eight (56%; 95% CI, 42.0 – 70.0%) of 50 patients achieved clinical benefit, with PFS and OS medians of 3.6 and 16.8 months, respectively. Conclusion. Gemcitabine and topotecan are active agents in heavily pretreated, platinum- and paclitaxel-resistant EOC patients. Topotecan was more costly to deliver. Although a larger percentage of patients received clinical benefit with topotecan use, this likely reflects physician selection for use of topotecan earlier in the course of disease. D 2004 Published by Elsevier Inc. Keywords: Second-line therapy; Ovarian cancer; Gemcitabine; Topotecan
Introduction It is estimated that 25,400 new cases of ovarian cancer will be diagnosed and 14,300 women will die of ovarian cancer this year [1]. While most patients achieve remission with optimal cytoreduction and adjuvant chemotherapy, the majority of these patients will eventually recur and die from
$ This work was supported by the National Institutes of Health (grant CA 52477). * Corresponding author. Developmental Chemotherapy Service, Department of Medicine, c/o Gynecology Service Academic Office, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room MRI-1027, New York, NY 10021. Fax: +1-212-717-3214. E-mail address: [email protected] (M.L. Hensley).
0090-8258/$ - see front matter D 2004 Published by Elsevier Inc. doi:10.1016/j.ygyno.2004.01.014
progression of disease, typically after developing resistance to multiple drugs including platinum and taxane compounds. The selection of chemotherapeutic agents for salvage treatment of patients with platinum-resistant, persistent, or recurrent epithelial ovarian cancer has largely been based on results from Phase II clinical trials in which the cytotoxic drugs have shown activity as second-line therapy. With the addition of paclitaxel to first-line therapy regimens [2], there has been a subsequent increase in resistance to paclitaxel and thus a need to discover drugs that are non-cross-resistant to both platinum and paclitaxel. Two cytotoxic drugs that have been shown in Phase II trials to produce a response in platinum-resistant ovarian cancer are the nucleoside analog gemcitabine [3,4] and the DNA
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topoisomerase I inhibitor topotecan [5 –8], which has also shown activity in a Phase III trial versus paclitaxel [9,10]. The aim of the present study was to determine the overall costs associated with a course of single-agent chemotherapy, either topotecan or gemcitabine, as second-line therapy or greater in a group of heavily pretreated patients with recurrent platinum- and paclitaxel-resistant EOC. We also report the response to chemotherapy within each cohort to identify whether responses to treatment in heavily pretreated patients approximate those that have been observed in less heavily treated patients in Phase II trials. Responses to the two chemotherapies were not compared, as the majority of patients who received topotecan did so as an earlier line of therapy, thus at an earlier time point in the course of their disease compared to the gemcitabine cohort.
until 30 days after the last dose was delivered, to capture potential charges associated with the effects of treatment, including toxicity and progression of disease. Direct medical charges were collected for the following categories: blood and blood processing, cardiopulmonary/electrocardiogram tests, drugs/intravenous delivery/clinical nursing care, laboratory tests, MRI/CT scan/ultrasound tests, other diagnostic radiology tests, operating room/recovery room, radiation therapy, hospitalization (room and board), and physician visits. Outpatient growth factor use was recorded for all patients and was included in the estimation of the total cost of treatment. Charges in each category were converted to approximate true costs using institutional, departmental or resource-use, category-specific ratios of charges to costs (RCCs). Conversion to true costs allows the data to be potentially compared across institutions.
Patients and methods
Objective clinical response and clinical benefit
Patients
Assessment of clinical response was based on CT scans and/or Rustin criteria. For Rustin criteria, objective clinical response was defined as a z50% decrease in the serum CA125 compared to pretreatment values maintained for two consecutive values measured 28 or more days apart, or a z75% decrease at one time point [12]. For CT scan response, a z25% decrease in sites of measurable disease by CT scan without any new sites of disease was considered to be an objective clinical response. For this purpose, bidimensional measurements from CT scan reports were used. This less-conventional method of calculating CT scan response was included in the study as it is the method most utilized in the ‘‘real-world’’ setting in which these patients were treated, and the method upon which treatment plans were based. Stable disease was defined as a <50% decrease in serum CA-125, with no increase in serum CA-125 values for two consecutive values 28 or more days apart. In addition, there could be no new lesions and no increase at sites of measurable disease on CT scan. The occurrence of either an objective clinical response or stable disease was defined as clinical benefit.
All patients who began treatment with topotecan or gemcitabine as second-line or greater therapy for persistent or recurrent platinum-resistant ovarian cancer at Memorial Sloan-Kettering Cancer Center from August 1, 1996 until July 31, 1999 were retrospectively identified from institutional databases and included in the current study. This study was reviewed and approved by the center’s Institutional Review Board. Initial adjuvant chemotherapy consisted of paclitaxel and platinum, with many patients receiving other salvage chemotherapy regimens for recurrence or progression before their treatment with either topotecan or gemcitabine. Topotecan was administered as a 5-day regimen every 21 days. Gemcitabine was administered once a week for 3 weeks, with one subsequent week of rest. Platinum resistance was defined as progression or recurrence of disease during or within 6 months of treatment with carboplatin or cisplatin [11]. The entire cohort of patients was considered to be resistant to both paclitaxel and platinum. Electronic medical records were reviewed to obtain patient demographics, including patient age, number of prior chemotherapy regimens for persistent/recurrent disease, duration of first clinical remission, time from last prior salvage treatment regimen, total dose of chemotherapy received, toxicity related to treatment (according to National Cancer Institute Common Toxicity Criteria, http://ctep.cancer.gov/ reporting/ctc.html), and clinical response. Direct costs All medical charges incurred during treatment were determined from patient billing records for both inpatient and outpatient care. The time period in which charges were examined started at 5 days before delivery of the first dose of topotecan or gemcitabine, to take into account physician visit and pretreatment laboratory test charges, and continued
Statistical methods A comparison of the means of the total direct costs per cycle per patient receiving gemcitabine or topotecan was calculated with the t test. Progression-free survival was calculated from the initial date of receiving topotecan or gemcitabine to the date of documented progression. Overall survival was calculated from the same initial date until the date of last follow-up or death. The Kaplan – Meier method was used to estimate progression-free survival and overall survival. Potential predictors of progression-free survival and overall survival were investigated using the Cox proportional hazards model. The covariates associated with clinical benefit were analyzed using multivariate logistic regression.
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Results
Table 2 Costs of chemotherapy
Patient characteristics
Chemotherapy
Mean patient cost per coursea
Cost per cycle per patienta,b
The median age for the 56 patients with platinum- and paclitaxel-resistant ovarian cancer who received gemcitabine was 59 years (range, 18 – 76 years). The median duration of first clinical remission was 5.3 months (range, 0.1 –50.0 months). Patients had received a median of three prior regimens (range, 0 – 8 regimens) for persistent/recurrent disease. This cohort received a total of 415 cycles of gemcitabine, with a median of five cycles per patient (range, 1 –59 cycles). The calculated median dose intensity was 497 mg/m2 per week (range, 129 –685 mg/m2 per week). The median age of the 51 patients who received topotecan was 56 years (range, 26– 75 years). The median duration of first clinical remission was 3 months (range, 0.4 –85.9 months). Patients had received a median of two prior chemotherapy regimens (range, 0– 7 regimens) for persistent/recurrent disease. The topotecan cohort underwent a total of 264 cycles, with a median of four cycles per patient (range, 1 – 42 cycles). A median dose intensity of 1.64 mg/m2 per week of topotecan was calculated (range, 1.0 –2.34 mg/m2 per week) (Table 1).
Gemcitabine
$13,937.28 ($1824.30 – $82,339.63)
Topotecan
$28,098.10 ($5383.97 – $157,170.17)
Mean $2732.28 Median $1382.73 ($530.30 – $26,954.73) Mean $7832.07 Median $4219.02 ($2325.12 – $54,494.76)
Costs of treatment After conversion of direct medical charges to true costs, the costs per cycle and costs per course of chemotherapy were calculated to compare costs associated with singleagent salvage treatment of gemcitabine or topotecan. All 56 patients who received gemcitabine were evaluable for cost analysis. The mean total direct cost per cycle per patient of gemcitabine was $2732.28, with a median total direct cost per cycle of $1382.73. Forty-six of 51 patients who received topotecan were evaluable for cost analysis. Of these patients, the mean total direct cost per cycle per patient of topotecan was $7832.07, with a median total direct cost per cycle of $4219.02. A comparison of the means of the total
Table 1 Treatment cohorts Patient characteristics
Gemcitabinea,b (n = 56)
Topotecana,c (n = 51)
Patient age, years 59 (18 – 76) 56 (26 – 75) Number cycles per patient 5 (1 – 59) 4 (1 – 42) Duration of first remission, 5.3 (0.1 – 50.0) 3.0 (0.4 – 85.9) months Number of prior regimens for 3 (0 – 8) 2 (0 – 7) persistent/recurrent disease Time from last prior treatment for 1.47 (0.1 – 21.3) 1.07 (0.2 – 28.3) recurrent/persistent disease, months Dose intensity, mg/m2 per week 497 (129 – 685) 1.64 (1.0 – 2.3)
a b
All values in parentheses represent range of costs. P = 0.001 for the comparison of mean cost per cycle per patient.
direct costs per cycle per patient found topotecan to be significantly more expensive than gemcitabine ( P = 0.001). The average per patient cost for a course of drug was calculated utilizing the definition of a course as the time period from the time of start of drug plus 5 days prior, until the time of cessation of drug due to progression of disease or unacceptable toxicity plus 30 days after cessation to capture all treatment-related costs. The average per patient cost for recurrent/persistent ovarian cancer was $13,937.28 for a course of gemcitabine and $28,098.10 for a course of topotecan (Table 2). When the individual cost components were examined, it was found that the highest percentage of total cost was attributable to chemotherapy drug cost/drug delivery in both cohorts of patients, accounting for 46% of the total costs in each group. In the gemcitabine cohort, the next major cost component was hospitalization, comprising 22%, while inpatient and outpatient physician charges accounted for 15% of total costs. The percentage attributable to physician costs was higher in the topotecan group, and amounted to 21% of the total cost, while hospitalization costs were less, at 16%. Response and survival Among the 56 patients who received gemcitabine, 13 (23.2%; 95% confidence interval [CI], 11.9 –34.5%) displayed clinical benefit while undergoing treatment. This included 10 (17.8%) patients who had an objective clinical response and three patients who achieved stable disease. The median time to progression was 1.8 months (Fig. 1), with a median overall survival of 8.2 months (Table 3). Of the 51 patients who received topotecan, follow-up data on response could be obtained for 50 patients. Twenty-eight (56%, 95% CI, 42.0 – 70.0%) patients showed clinical benefit, and 24 (48%) had an objective clinical response. Four patients had stable disease, and the median time to progression for the entire topotecan cohort was 3.6 months (Fig. 2), with a median overall survival of 16.8 months. Predictors of response
a
All values represent median (range). Total number of cycles of gemcitabine = 415. c Total number of cycles of topotecan = 264. b
Potential predictors of response were evaluated for possible associations with the outcomes of clinical benefit,
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Fig. 1. Progression-free survival—gemcitabine.
time to progression, and overall survival. Patient age, number of prior salvage chemotherapy regimens, time from last prior treatment for recurrent/persistent disease, and duration of first clinical remission were all tested for possible association with clinical outcomes. There were no significant associations between any of these variables and clinical benefit, time to progression, or overall survival for either gemcitabine or topotecan. In the gemcitabine group, however, increasing time from last prior treatment for recurrent/persistent disease approached significance in association with an increased time to progression and greater overall survival, with P = 0.05 and 0.06, respectively. Toxicity and growth factor use Overall, grade 3 or 4 toxicity was observed in 31/56 (55.4%) patients receiving gemcitabine and 27/51 (52.9%) patients receiving topotecan. Severe anemia (23/51, 45.1%) and myelosuppression (16/51, 31.4%) were most commonly seen with topotecan, with 47.1% (24/51) of patients receiving erythropoietin and 84.3% (43/51) receiving G-CSF. Neutropenia was the most common grade 3 or 4 toxicity observed in the gemcitabine group (17/56, 30.4%). However, few of these patients received growth factor, with
Table 3 Treatment outcomes of gemcitabine or topotecan as second-line therapy or greater for platinum-resistant ovarian cancer Chemotherapy
Outcome
Value (95% CI)
Gemcitabine
Clinical benefit
Topotecan
Median survival (months) Median time to progression (months) Clinical benefit
13/56 = 23.2% (11.9% – 34.5%) 8.2 (range, 5.9 – 12.1) 1.8 (range, 1.5 – 2.6)
Median survival (months) Median time to progression (months)
28/50 = 56% (42.0% – 70.0%) 16.8 (range, 13.9 – 24.9) 3.6 (range, 3.0 – 5.5)
Fig. 2. Progression-free survival—topotecan.
16.1% (9/56) and 33.9% (19/56) of patients receiving GCSF and erythropoietin, respectively.
Discussion There is currently no standard therapy for patients with persistent or recurrent, platinum-resistant epithelial ovarian cancer. Few phase II clinical trials have focused specifically on assessing chemotherapy efficacy among patients with both platinum- and paclitaxel-resistant disease who have previously received multiple other salvage chemotherapy regimens. Clinicians are thus faced with the difficult task of extrapolating from phase II studies conducted in less resistant and nearly always less heavily pretreated patients to make decisions regarding further salvage treatment for this ovarian cancer population. The data presented here suggest that topotecan and gemcitabine are both active as single agents and associated with moderate rates of objective clinical response and clinical benefit in heavily pretreated platinum- and paclitaxel-resistant patients. We sought to examine costs of salvage treatment as well as treatment outcomes outside the clinical trial setting in the current study, thus approximating many clinicians’ practices. In a previous study by our institution, a cost analysis of liposomal doxorubicin was performed and its efficacy was examined in a similar group of heavily pretreated patients [13]. The reported costs associated with liposomal doxorubicin administration were a mean total direct cost per cycle per patient of $5763 and a mean per patient cost per course of $16,173. It thus appears that gemcitabine was least expensive, with an average cost of $13,937 per course delivered, while topotecan had an average cost per patient of $28,098 per course and was most expensive among the three chemotherapeutic agents to administer in the salvage setting to patients with platinum- and paclitaxel-resistant ovarian cancer. The major cost driver was the drug acquisition/delivery cost, which accounted for 46% of the total
M. Prasad et al. / Gynecologic Oncology 93 (2004) 223 – 228
costs in each cohort. This is consistent with previous data on liposomal doxorubicin costs in which the major cost drivers were chemotherapy drug costs (43%) and hospitalizations (29%) [13]. Outpatient and inpatient physician visit costs comprised 21% of the topotecan costs, compared to 15% with gemcitabine and 11% with liposomal doxorubicin. In addition, hospitalization cost was a major contributor, comprising 22% and 16% of total costs of treatment in the gemcitabine and topotecan cohorts, respectively. The increase in the percentage of physician costs in the topotecan group is possibly due to the high level of grade 3 and 4 anemia and myelosuppression associated with its administration in the 5-day schedule, thus requiring close monitoring and frequent physician visits. In the current study, the 5-day regimen of topotecan was utilized every 21 days. There are reports that support the use of topotecan as a 3-day regimen [14] or at a reduced dosage [15], resulting in a more convenient treatment schedule with lower toxicity. These factors could potentially decrease the costs associated with topotecan while maintaining drug efficacy in the salvage setting. If efficacy were maintained with lower doses, the need for growth factor support could also be reduced and may thus contribute to a reduction of the total cost of delivering topotecan. Weekly dosing of topotecan is emerging as a possible alternative to the 5-day and 3-day regimens; however, an optimal dosing schedule has not yet been identified and efficacy has not been firmly established in phase II trials [16,17]. Furthermore, it is unclear if the weekly dosing of topotecan will be beneficial for patients with platinum- and paclitaxel-resistant disease. If the weekly dosing is found to be effective in this patient population, potential cost benefits should be studied, since the costs of higher doses of drug utilized in the weekly setting may offset the cost benefits derived from decreased delivery times and potentially fewer hospitalizations due to less toxicity. Gemcitabine has been shown to have response rates of 11– 22% when administered as a second-line agent [3,4,18]. Our data concur with the previously reported rates, showing that 17.8% of patients displayed an objective clinical response by CT scan or CA-125 level reduction. The cohort that received topotecan had an unexpectedly high objective clinical response rate of 48%, supporting the idea that topotecan is non-cross-resistant to paclitaxel, as all patients were resistant to both platinum and paclitaxel [10]. Our observed response rate for topotecan was considerably higher than the rates of 12.4% to 17.8% [5– 8] that have been reported from phase II trials. This may be due to several factors including the relatively low number of prior salvage regimens, a selection bias in choosing which patients received topotecan, the use of CA-125 reduction as a measurement of response [12], as well as a nonstandard method of response measurement by CT scan as opposed to the more standard WHO criteria used in phase II trials. In addition, a large percentage of patients received G-CSF support during topotecan treatment, and this may have
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allowed for maintenance of greater dose intensity, perhaps leading to an improved chance of response. We specifically report the response, including indices such as dose intensity, and survival outcomes associated with each drug to show that these drugs can be administered in doses approximating those of phase II trials and that they remain active even in heavily pretreated patients with platinum and paclitaxel resistance. The overall survival rates for patients who received topotecan, gemcitabine, or liposomal doxorubicin in the salvage setting suggest that all three agents display efficacy in this patient population. The median overall survival for patients receiving liposomal doxorubicin was previously reported to be 9.6 months, with a median time to progression of 2.2 months [13], similar to what is seen with gemcitabine and seemingly worse in terms of overall survival compared to topotecan. We did not compare response or survival data between different chemotherapies in this study because of the variability in our patient population as shown in Table 4. When the number of prior therapies in each chemotherapy group was examined, it was found that 80% (45/56) of the patients who received gemcitabine were undergoing fourth-line therapy or greater, and only 2% (1/56 patients) received gemcitabine as second-line therapy. Similarly, liposomal doxorubicin was given to 8% (5/62) of patients as second-line therapy and to 64% (40/62) of patients as fourth-line therapy or greater. Topotecan, on the other hand, was given to 22% (11/51) of patients as second-line therapy and 51% (26/51) as fourthline therapy or greater. It is likely that the high response rates observed with topotecan are actually a reflection of the earlier time point in the disease process in which the drug was administered rather than an intrinsic effect of the drug itself. Further support of this is the fact that median time to progression for each of the three drug regimens is similar, suggesting similar efficacy as salvage agents. Over 50% of the patients in both the topotecan and gemcitabine cohorts experienced grade 3 or 4 toxicity. The most common toxicities were hematologic and were reversible with dose and schedule adjustments. An increase in the use of growth factors in the future for ovarian cancer patients undergoing salvage therapy may aid in decreasing the severity of hematologic toxicity but is likely to impact overall survival. The limitations of this study are related to its retrospective design and to the examination of salvage therapy in the nonclinical-trial setting. Although the definitions of clinical response and benefit are accepted in most clinical practices, Table 4 Number of prior chemotherapy regimens for persistent/recurrent disease Line of therapy
Gemcitabine (n = 56)
Topotecan (n = 51)
Liposomal doxorubicin (n = 62) [13]
2nd 3rd 4th 5th or greater
1 (2%) 10 (18%) 11 (20%) 34 (60%)
11 14 12 14
5 17 15 25
(22%) (27%) (24%) (27%)
(8%) (27%) (24%) (40%)
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they are not typically used in formal, prospective phase II trials. In addition, there were no strict criteria employed for dosage adjustments or for growth factor use. The cost analysis shows that these drugs are expensive and that topotecan is significantly more expensive than gemcitabine in the salvage setting. It may be that these differences in costs are less pronounced than was seen upon retrospective examination, and this question could be further explored by the inclusion of formal cost data in prospective trials. A true cost-effectiveness analysis of the drugs would require a prospective, randomized comparison of these agents in the salvage setting. Because any potential survival advantage is likely to be small, assessment of quality of life for patients receiving salvage therapy would be equally important. The nonclinical-trial setting of this study most closely resembles the majority of clinicians’ practices. Our data suggest that in this ‘‘real-world’’ setting, single-agent administration of topotecan or gemcitabine, although expensive, results in clinical benefit with acceptable toxicity for heavily pretreated patients with relapsed platinum- and paclitaxel-resistant epithelial ovarian cancer.
References [1] Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53(1):5 – 26. [2] McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, 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):1 – 6. [3] Lund B, Hansen OP, Neijt JP, Theilade K, Hansen M. Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients. Anticancer Drugs 1995;6(Suppl. 6):61 – 2. [4] Friedlander M, Millward MJ, Bell D, Bugat R, Harnett P, Moreno JA, et al. A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 1998;9(12): 1343 – 5. [5] Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, 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(12):3056 – 61.
[6] Swisher EM, Mutch DG, Rader JS, Elbendary A, Herzog TJ. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997;66(3):480 – 6. [7] Kudelka AP, Tresukosol D, Edwards CL, Freedman RS, Levenback C, Chantarawiroj P, et al. Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996;14(5):1552 – 7. [8] Bookman MA, Malmstrom H, Bolis G, Gordon A, Lissoni A, Krebs JB, et al. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 1998;16(10):3345 – 52. [9] ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15(6):2183 – 93. [10] Gore M, ten Bokkel Huinink W, Carmichael J, Gordon A, Davidson N, Coleman R, et al. Clinical evidence for topotecan – paclitaxel non-cross-resistance in ovarian cancer. J Clin Oncol 2001; 19(7):1893 – 900. [11] Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9(3):389 – 93. [12] Rustin GJ, Nelstrop AE, McClean P, Brady MF, McGuire WP, Hoskins WJ, et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 1996;14(5): 1545 – 51. [13] Hensley ML, Hoppe B, Leon L, Sabbatini P, Aghajanian C, Chi D, et al. The costs and efficacy of liposomal doxorubicin in platinumrefractory ovarian cancer in heavily pretreated patients. Gynecol Oncol 2001;82(3):464 – 9. [14] Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer. Gynecol Oncol 2000;79(1):116 – 9. [15] Gronlund B, Hansen HH, Hogdall C, Engelholm SA. Efficacy of lowdose topotecan in second-line treatment for patients with epithelial ovarian carcinoma. Cancer 2002;95(8):1656 – 62. [16] Morris RT. Weekly topotecan in the management of ovarian cancer. Gynecol Oncol 2003;90(3 Pt 2):S34 – 8. [17] Hoskins P, Eisenhauer E, Beare S, Roy M, Drouin P, Stuart G, et al. Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 1998;16(6): 2233 – 7. [18] Silver DF, Piver MS. Gemcitabine salvage chemotherapy for patients with gynecologic malignancies of the ovary, fallopian tube, and peritoneum. Am J Clin Oncol 1999;22(5):450 – 2.
Costs of treatment and outcomes associated with second-line $ therapy and greater for relapsed ovarian cancer Monica Prasad, a Leah Ben-Porat, b Brad Hoppe, a Carol Aghajanian, a Paul Sabbatini, a Dennis S. Chi, c and Martee L. Hensley a,* a
Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021,USA b Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021,USA c Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021,USA Received 24 October 2003
Abstract Objective. Most women with epithelial ovarian cancer (EOC) will develop disease progression or recurrence with resistance to platinum therapy. We report overall costs and treatment outcomes associated with topotecan or gemcitabine administration in platinum- and paclitaxelresistant EOC patients. Methods. Patients who received topotecan (n = 51) or gemcitabine (n = 56) as second-line therapy or greater for platinum- and paclitaxelresistant EOC were retrospectively identified. Per patient costs for each regimen were determined and compared. Results. The mean total direct cost per cycle per patient of gemcitabine was $2732.28, with a median total direct cost per cycle of $1382.73. The mean total direct cost per cycle per patient of topotecan was $7832.07, with a median total direct cost per cycle of $4219.02. By comparison of the means, total direct cost per cycle per patient was significantly more expensive for topotecan ( P = 0.001). Fifty-six patients received a total of 415 cycles of gemcitabine, median 5 cycles per patient (range, 1 – 59). Thirteen (23.2%; 95% CI, 11.9 – 34.5%) of 56 patients displayed clinical benefit, with median PFS of 1.8 months and median overall survival (OS) of 8.2 months. Fifty-one patients received topotecan, for a total of 264 cycles, median 4 cycles per patient (range, 1 – 42). Twenty-eight (56%; 95% CI, 42.0 – 70.0%) of 50 patients achieved clinical benefit, with PFS and OS medians of 3.6 and 16.8 months, respectively. Conclusion. Gemcitabine and topotecan are active agents in heavily pretreated, platinum- and paclitaxel-resistant EOC patients. Topotecan was more costly to deliver. Although a larger percentage of patients received clinical benefit with topotecan use, this likely reflects physician selection for use of topotecan earlier in the course of disease. D 2004 Published by Elsevier Inc. Keywords: Second-line therapy; Ovarian cancer; Gemcitabine; Topotecan
Introduction It is estimated that 25,400 new cases of ovarian cancer will be diagnosed and 14,300 women will die of ovarian cancer this year [1]. While most patients achieve remission with optimal cytoreduction and adjuvant chemotherapy, the majority of these patients will eventually recur and die from
$ This work was supported by the National Institutes of Health (grant CA 52477). * Corresponding author. Developmental Chemotherapy Service, Department of Medicine, c/o Gynecology Service Academic Office, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room MRI-1027, New York, NY 10021. Fax: +1-212-717-3214. E-mail address: [email protected] (M.L. Hensley).
0090-8258/$ - see front matter D 2004 Published by Elsevier Inc. doi:10.1016/j.ygyno.2004.01.014
progression of disease, typically after developing resistance to multiple drugs including platinum and taxane compounds. The selection of chemotherapeutic agents for salvage treatment of patients with platinum-resistant, persistent, or recurrent epithelial ovarian cancer has largely been based on results from Phase II clinical trials in which the cytotoxic drugs have shown activity as second-line therapy. With the addition of paclitaxel to first-line therapy regimens [2], there has been a subsequent increase in resistance to paclitaxel and thus a need to discover drugs that are non-cross-resistant to both platinum and paclitaxel. Two cytotoxic drugs that have been shown in Phase II trials to produce a response in platinum-resistant ovarian cancer are the nucleoside analog gemcitabine [3,4] and the DNA
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topoisomerase I inhibitor topotecan [5 –8], which has also shown activity in a Phase III trial versus paclitaxel [9,10]. The aim of the present study was to determine the overall costs associated with a course of single-agent chemotherapy, either topotecan or gemcitabine, as second-line therapy or greater in a group of heavily pretreated patients with recurrent platinum- and paclitaxel-resistant EOC. We also report the response to chemotherapy within each cohort to identify whether responses to treatment in heavily pretreated patients approximate those that have been observed in less heavily treated patients in Phase II trials. Responses to the two chemotherapies were not compared, as the majority of patients who received topotecan did so as an earlier line of therapy, thus at an earlier time point in the course of their disease compared to the gemcitabine cohort.
until 30 days after the last dose was delivered, to capture potential charges associated with the effects of treatment, including toxicity and progression of disease. Direct medical charges were collected for the following categories: blood and blood processing, cardiopulmonary/electrocardiogram tests, drugs/intravenous delivery/clinical nursing care, laboratory tests, MRI/CT scan/ultrasound tests, other diagnostic radiology tests, operating room/recovery room, radiation therapy, hospitalization (room and board), and physician visits. Outpatient growth factor use was recorded for all patients and was included in the estimation of the total cost of treatment. Charges in each category were converted to approximate true costs using institutional, departmental or resource-use, category-specific ratios of charges to costs (RCCs). Conversion to true costs allows the data to be potentially compared across institutions.
Patients and methods
Objective clinical response and clinical benefit
Patients
Assessment of clinical response was based on CT scans and/or Rustin criteria. For Rustin criteria, objective clinical response was defined as a z50% decrease in the serum CA125 compared to pretreatment values maintained for two consecutive values measured 28 or more days apart, or a z75% decrease at one time point [12]. For CT scan response, a z25% decrease in sites of measurable disease by CT scan without any new sites of disease was considered to be an objective clinical response. For this purpose, bidimensional measurements from CT scan reports were used. This less-conventional method of calculating CT scan response was included in the study as it is the method most utilized in the ‘‘real-world’’ setting in which these patients were treated, and the method upon which treatment plans were based. Stable disease was defined as a <50% decrease in serum CA-125, with no increase in serum CA-125 values for two consecutive values 28 or more days apart. In addition, there could be no new lesions and no increase at sites of measurable disease on CT scan. The occurrence of either an objective clinical response or stable disease was defined as clinical benefit.
All patients who began treatment with topotecan or gemcitabine as second-line or greater therapy for persistent or recurrent platinum-resistant ovarian cancer at Memorial Sloan-Kettering Cancer Center from August 1, 1996 until July 31, 1999 were retrospectively identified from institutional databases and included in the current study. This study was reviewed and approved by the center’s Institutional Review Board. Initial adjuvant chemotherapy consisted of paclitaxel and platinum, with many patients receiving other salvage chemotherapy regimens for recurrence or progression before their treatment with either topotecan or gemcitabine. Topotecan was administered as a 5-day regimen every 21 days. Gemcitabine was administered once a week for 3 weeks, with one subsequent week of rest. Platinum resistance was defined as progression or recurrence of disease during or within 6 months of treatment with carboplatin or cisplatin [11]. The entire cohort of patients was considered to be resistant to both paclitaxel and platinum. Electronic medical records were reviewed to obtain patient demographics, including patient age, number of prior chemotherapy regimens for persistent/recurrent disease, duration of first clinical remission, time from last prior salvage treatment regimen, total dose of chemotherapy received, toxicity related to treatment (according to National Cancer Institute Common Toxicity Criteria, http://ctep.cancer.gov/ reporting/ctc.html), and clinical response. Direct costs All medical charges incurred during treatment were determined from patient billing records for both inpatient and outpatient care. The time period in which charges were examined started at 5 days before delivery of the first dose of topotecan or gemcitabine, to take into account physician visit and pretreatment laboratory test charges, and continued
Statistical methods A comparison of the means of the total direct costs per cycle per patient receiving gemcitabine or topotecan was calculated with the t test. Progression-free survival was calculated from the initial date of receiving topotecan or gemcitabine to the date of documented progression. Overall survival was calculated from the same initial date until the date of last follow-up or death. The Kaplan – Meier method was used to estimate progression-free survival and overall survival. Potential predictors of progression-free survival and overall survival were investigated using the Cox proportional hazards model. The covariates associated with clinical benefit were analyzed using multivariate logistic regression.
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Results
Table 2 Costs of chemotherapy
Patient characteristics
Chemotherapy
Mean patient cost per coursea
Cost per cycle per patienta,b
The median age for the 56 patients with platinum- and paclitaxel-resistant ovarian cancer who received gemcitabine was 59 years (range, 18 – 76 years). The median duration of first clinical remission was 5.3 months (range, 0.1 –50.0 months). Patients had received a median of three prior regimens (range, 0 – 8 regimens) for persistent/recurrent disease. This cohort received a total of 415 cycles of gemcitabine, with a median of five cycles per patient (range, 1 –59 cycles). The calculated median dose intensity was 497 mg/m2 per week (range, 129 –685 mg/m2 per week). The median age of the 51 patients who received topotecan was 56 years (range, 26– 75 years). The median duration of first clinical remission was 3 months (range, 0.4 –85.9 months). Patients had received a median of two prior chemotherapy regimens (range, 0– 7 regimens) for persistent/recurrent disease. The topotecan cohort underwent a total of 264 cycles, with a median of four cycles per patient (range, 1 – 42 cycles). A median dose intensity of 1.64 mg/m2 per week of topotecan was calculated (range, 1.0 –2.34 mg/m2 per week) (Table 1).
Gemcitabine
$13,937.28 ($1824.30 – $82,339.63)
Topotecan
$28,098.10 ($5383.97 – $157,170.17)
Mean $2732.28 Median $1382.73 ($530.30 – $26,954.73) Mean $7832.07 Median $4219.02 ($2325.12 – $54,494.76)
Costs of treatment After conversion of direct medical charges to true costs, the costs per cycle and costs per course of chemotherapy were calculated to compare costs associated with singleagent salvage treatment of gemcitabine or topotecan. All 56 patients who received gemcitabine were evaluable for cost analysis. The mean total direct cost per cycle per patient of gemcitabine was $2732.28, with a median total direct cost per cycle of $1382.73. Forty-six of 51 patients who received topotecan were evaluable for cost analysis. Of these patients, the mean total direct cost per cycle per patient of topotecan was $7832.07, with a median total direct cost per cycle of $4219.02. A comparison of the means of the total
Table 1 Treatment cohorts Patient characteristics
Gemcitabinea,b (n = 56)
Topotecana,c (n = 51)
Patient age, years 59 (18 – 76) 56 (26 – 75) Number cycles per patient 5 (1 – 59) 4 (1 – 42) Duration of first remission, 5.3 (0.1 – 50.0) 3.0 (0.4 – 85.9) months Number of prior regimens for 3 (0 – 8) 2 (0 – 7) persistent/recurrent disease Time from last prior treatment for 1.47 (0.1 – 21.3) 1.07 (0.2 – 28.3) recurrent/persistent disease, months Dose intensity, mg/m2 per week 497 (129 – 685) 1.64 (1.0 – 2.3)
a b
All values in parentheses represent range of costs. P = 0.001 for the comparison of mean cost per cycle per patient.
direct costs per cycle per patient found topotecan to be significantly more expensive than gemcitabine ( P = 0.001). The average per patient cost for a course of drug was calculated utilizing the definition of a course as the time period from the time of start of drug plus 5 days prior, until the time of cessation of drug due to progression of disease or unacceptable toxicity plus 30 days after cessation to capture all treatment-related costs. The average per patient cost for recurrent/persistent ovarian cancer was $13,937.28 for a course of gemcitabine and $28,098.10 for a course of topotecan (Table 2). When the individual cost components were examined, it was found that the highest percentage of total cost was attributable to chemotherapy drug cost/drug delivery in both cohorts of patients, accounting for 46% of the total costs in each group. In the gemcitabine cohort, the next major cost component was hospitalization, comprising 22%, while inpatient and outpatient physician charges accounted for 15% of total costs. The percentage attributable to physician costs was higher in the topotecan group, and amounted to 21% of the total cost, while hospitalization costs were less, at 16%. Response and survival Among the 56 patients who received gemcitabine, 13 (23.2%; 95% confidence interval [CI], 11.9 –34.5%) displayed clinical benefit while undergoing treatment. This included 10 (17.8%) patients who had an objective clinical response and three patients who achieved stable disease. The median time to progression was 1.8 months (Fig. 1), with a median overall survival of 8.2 months (Table 3). Of the 51 patients who received topotecan, follow-up data on response could be obtained for 50 patients. Twenty-eight (56%, 95% CI, 42.0 – 70.0%) patients showed clinical benefit, and 24 (48%) had an objective clinical response. Four patients had stable disease, and the median time to progression for the entire topotecan cohort was 3.6 months (Fig. 2), with a median overall survival of 16.8 months. Predictors of response
a
All values represent median (range). Total number of cycles of gemcitabine = 415. c Total number of cycles of topotecan = 264. b
Potential predictors of response were evaluated for possible associations with the outcomes of clinical benefit,
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Fig. 1. Progression-free survival—gemcitabine.
time to progression, and overall survival. Patient age, number of prior salvage chemotherapy regimens, time from last prior treatment for recurrent/persistent disease, and duration of first clinical remission were all tested for possible association with clinical outcomes. There were no significant associations between any of these variables and clinical benefit, time to progression, or overall survival for either gemcitabine or topotecan. In the gemcitabine group, however, increasing time from last prior treatment for recurrent/persistent disease approached significance in association with an increased time to progression and greater overall survival, with P = 0.05 and 0.06, respectively. Toxicity and growth factor use Overall, grade 3 or 4 toxicity was observed in 31/56 (55.4%) patients receiving gemcitabine and 27/51 (52.9%) patients receiving topotecan. Severe anemia (23/51, 45.1%) and myelosuppression (16/51, 31.4%) were most commonly seen with topotecan, with 47.1% (24/51) of patients receiving erythropoietin and 84.3% (43/51) receiving G-CSF. Neutropenia was the most common grade 3 or 4 toxicity observed in the gemcitabine group (17/56, 30.4%). However, few of these patients received growth factor, with
Table 3 Treatment outcomes of gemcitabine or topotecan as second-line therapy or greater for platinum-resistant ovarian cancer Chemotherapy
Outcome
Value (95% CI)
Gemcitabine
Clinical benefit
Topotecan
Median survival (months) Median time to progression (months) Clinical benefit
13/56 = 23.2% (11.9% – 34.5%) 8.2 (range, 5.9 – 12.1) 1.8 (range, 1.5 – 2.6)
Median survival (months) Median time to progression (months)
28/50 = 56% (42.0% – 70.0%) 16.8 (range, 13.9 – 24.9) 3.6 (range, 3.0 – 5.5)
Fig. 2. Progression-free survival—topotecan.
16.1% (9/56) and 33.9% (19/56) of patients receiving GCSF and erythropoietin, respectively.
Discussion There is currently no standard therapy for patients with persistent or recurrent, platinum-resistant epithelial ovarian cancer. Few phase II clinical trials have focused specifically on assessing chemotherapy efficacy among patients with both platinum- and paclitaxel-resistant disease who have previously received multiple other salvage chemotherapy regimens. Clinicians are thus faced with the difficult task of extrapolating from phase II studies conducted in less resistant and nearly always less heavily pretreated patients to make decisions regarding further salvage treatment for this ovarian cancer population. The data presented here suggest that topotecan and gemcitabine are both active as single agents and associated with moderate rates of objective clinical response and clinical benefit in heavily pretreated platinum- and paclitaxel-resistant patients. We sought to examine costs of salvage treatment as well as treatment outcomes outside the clinical trial setting in the current study, thus approximating many clinicians’ practices. In a previous study by our institution, a cost analysis of liposomal doxorubicin was performed and its efficacy was examined in a similar group of heavily pretreated patients [13]. The reported costs associated with liposomal doxorubicin administration were a mean total direct cost per cycle per patient of $5763 and a mean per patient cost per course of $16,173. It thus appears that gemcitabine was least expensive, with an average cost of $13,937 per course delivered, while topotecan had an average cost per patient of $28,098 per course and was most expensive among the three chemotherapeutic agents to administer in the salvage setting to patients with platinum- and paclitaxel-resistant ovarian cancer. The major cost driver was the drug acquisition/delivery cost, which accounted for 46% of the total
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costs in each cohort. This is consistent with previous data on liposomal doxorubicin costs in which the major cost drivers were chemotherapy drug costs (43%) and hospitalizations (29%) [13]. Outpatient and inpatient physician visit costs comprised 21% of the topotecan costs, compared to 15% with gemcitabine and 11% with liposomal doxorubicin. In addition, hospitalization cost was a major contributor, comprising 22% and 16% of total costs of treatment in the gemcitabine and topotecan cohorts, respectively. The increase in the percentage of physician costs in the topotecan group is possibly due to the high level of grade 3 and 4 anemia and myelosuppression associated with its administration in the 5-day schedule, thus requiring close monitoring and frequent physician visits. In the current study, the 5-day regimen of topotecan was utilized every 21 days. There are reports that support the use of topotecan as a 3-day regimen [14] or at a reduced dosage [15], resulting in a more convenient treatment schedule with lower toxicity. These factors could potentially decrease the costs associated with topotecan while maintaining drug efficacy in the salvage setting. If efficacy were maintained with lower doses, the need for growth factor support could also be reduced and may thus contribute to a reduction of the total cost of delivering topotecan. Weekly dosing of topotecan is emerging as a possible alternative to the 5-day and 3-day regimens; however, an optimal dosing schedule has not yet been identified and efficacy has not been firmly established in phase II trials [16,17]. Furthermore, it is unclear if the weekly dosing of topotecan will be beneficial for patients with platinum- and paclitaxel-resistant disease. If the weekly dosing is found to be effective in this patient population, potential cost benefits should be studied, since the costs of higher doses of drug utilized in the weekly setting may offset the cost benefits derived from decreased delivery times and potentially fewer hospitalizations due to less toxicity. Gemcitabine has been shown to have response rates of 11– 22% when administered as a second-line agent [3,4,18]. Our data concur with the previously reported rates, showing that 17.8% of patients displayed an objective clinical response by CT scan or CA-125 level reduction. The cohort that received topotecan had an unexpectedly high objective clinical response rate of 48%, supporting the idea that topotecan is non-cross-resistant to paclitaxel, as all patients were resistant to both platinum and paclitaxel [10]. Our observed response rate for topotecan was considerably higher than the rates of 12.4% to 17.8% [5– 8] that have been reported from phase II trials. This may be due to several factors including the relatively low number of prior salvage regimens, a selection bias in choosing which patients received topotecan, the use of CA-125 reduction as a measurement of response [12], as well as a nonstandard method of response measurement by CT scan as opposed to the more standard WHO criteria used in phase II trials. In addition, a large percentage of patients received G-CSF support during topotecan treatment, and this may have
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allowed for maintenance of greater dose intensity, perhaps leading to an improved chance of response. We specifically report the response, including indices such as dose intensity, and survival outcomes associated with each drug to show that these drugs can be administered in doses approximating those of phase II trials and that they remain active even in heavily pretreated patients with platinum and paclitaxel resistance. The overall survival rates for patients who received topotecan, gemcitabine, or liposomal doxorubicin in the salvage setting suggest that all three agents display efficacy in this patient population. The median overall survival for patients receiving liposomal doxorubicin was previously reported to be 9.6 months, with a median time to progression of 2.2 months [13], similar to what is seen with gemcitabine and seemingly worse in terms of overall survival compared to topotecan. We did not compare response or survival data between different chemotherapies in this study because of the variability in our patient population as shown in Table 4. When the number of prior therapies in each chemotherapy group was examined, it was found that 80% (45/56) of the patients who received gemcitabine were undergoing fourth-line therapy or greater, and only 2% (1/56 patients) received gemcitabine as second-line therapy. Similarly, liposomal doxorubicin was given to 8% (5/62) of patients as second-line therapy and to 64% (40/62) of patients as fourth-line therapy or greater. Topotecan, on the other hand, was given to 22% (11/51) of patients as second-line therapy and 51% (26/51) as fourthline therapy or greater. It is likely that the high response rates observed with topotecan are actually a reflection of the earlier time point in the disease process in which the drug was administered rather than an intrinsic effect of the drug itself. Further support of this is the fact that median time to progression for each of the three drug regimens is similar, suggesting similar efficacy as salvage agents. Over 50% of the patients in both the topotecan and gemcitabine cohorts experienced grade 3 or 4 toxicity. The most common toxicities were hematologic and were reversible with dose and schedule adjustments. An increase in the use of growth factors in the future for ovarian cancer patients undergoing salvage therapy may aid in decreasing the severity of hematologic toxicity but is likely to impact overall survival. The limitations of this study are related to its retrospective design and to the examination of salvage therapy in the nonclinical-trial setting. Although the definitions of clinical response and benefit are accepted in most clinical practices, Table 4 Number of prior chemotherapy regimens for persistent/recurrent disease Line of therapy
Gemcitabine (n = 56)
Topotecan (n = 51)
Liposomal doxorubicin (n = 62) [13]
2nd 3rd 4th 5th or greater
1 (2%) 10 (18%) 11 (20%) 34 (60%)
11 14 12 14
5 17 15 25
(22%) (27%) (24%) (27%)
(8%) (27%) (24%) (40%)
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they are not typically used in formal, prospective phase II trials. In addition, there were no strict criteria employed for dosage adjustments or for growth factor use. The cost analysis shows that these drugs are expensive and that topotecan is significantly more expensive than gemcitabine in the salvage setting. It may be that these differences in costs are less pronounced than was seen upon retrospective examination, and this question could be further explored by the inclusion of formal cost data in prospective trials. A true cost-effectiveness analysis of the drugs would require a prospective, randomized comparison of these agents in the salvage setting. Because any potential survival advantage is likely to be small, assessment of quality of life for patients receiving salvage therapy would be equally important. The nonclinical-trial setting of this study most closely resembles the majority of clinicians’ practices. Our data suggest that in this ‘‘real-world’’ setting, single-agent administration of topotecan or gemcitabine, although expensive, results in clinical benefit with acceptable toxicity for heavily pretreated patients with relapsed platinum- and paclitaxel-resistant epithelial ovarian cancer.
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