Annals of Oncology Advance Access originally published online on December 12, 2006
Annals of Oncology 2007 18(3):529-534; doi:10.1093/annonc/mdl420
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© 2006 European Society for Medical Oncology
hematologic malignancies |
Cost-effectiveness of postremission intensive therapy in patients with acute leukemia
1 Division of Hematology and Oncology, Department of Medicine, Taipei-Veterans General Hospital
2 Department of Medicine, School of Medicine, National Yang-Ming University
3 Information Service Center, Taipei-Veterans General Hospital
4 Division of Transfusion Medicine, Department of Medicine, Taipei-Veterans General Hospital
5 Institute of Physiology, School of Medicine, National Yang-Ming University; Taipei, Taiwan, Republic of China
* Correspondence to: Dr H.-C. Hsu, Division of Hematology and Oncology, Department of Medicine, Taipei-Veterans General Hospital, Shih-Pai Road, Taipei, Taiwan 11217, Republic of China. Tel: +886-2-2871-2121 ext. 3865; Fax: +886-2-6610-9119; E-mail: hchsu{at}vghtpe.gov.tw
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: We assessed the cost-effectiveness of high-dose arabinoside (HiDAC)-based and allogeneic stem-cell transplantation (alloSCT)-based therapy in patients with acute leukemia.
Patients and methods: We analyzed the outcome, cost and cost-effectiveness of 106 patients treated from January 1994 to January 2002 [94 acute myelogenous leukemia (AML)/12 acute lymphoblastic leukemia (ALL)]. Forty-two young patients at either intermediate or unknown cytogenetic risk received postremission intensive therapy (24 HiDAC-based/18 alloSCT-based therapy).
Results: After a median follow-up of 50 months, the estimated 7-year overall survival for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%, P = 0.1452). The HiDAC-based group spent a significantly lower total cost ($US51 857 versus 75 474, P = 0.004) than the alloSCT-based group. Cost-effectiveness analysis showed that the mean cost per year of life saved for the HiDAC-based group is considerably less expensive than the alloSCT-based group ($US11 224 versus 21 564). The reduced total cost for the HiDAC-based group originated from lower cost in room fees, medication, laboratory and procedure, but not in blood transfusion and professional manpower fees.
Conclusion: For the postremission therapy in young AML patients at either intermediate or unknown cytogenetic risk, cost-effectiveness of HiDAC-based therapy compares favorably with that of alloSCT-based therapy, which deserves further clinical trials.
Key words: acute myelogenous leukemia, allogeneic stem-cell transplantation, cost-effectiveness, high-dose arabinoside, postremission therapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Postremission intensive therapy is definitely required for the treatment of acute myelogenous leukemia (AML) in order to achieve long-term, disease-free survival; the possible approaches include high-dose arabinoside (HiDAC), autologous stem-cell transplantation (ASCT) and allogeneic stem-cell transplantation (alloSCT) [1]. AlloSCT has been established as a potentially curative treatment of patients with AML, but its role remains controversial because a definitive survival advantage has not been shown in a number of controlled studies [2–5]. This may be the result of a combination of high transplantation-related mortality during alloSCT treatment and continuous improvements in non-alloSCT strategies. Numerous studies have identified the impact of cytogenetic risk on the patients' outcome and this further stratifies AML patients into favorable, intermediate and unfavorable groups [5–8]. In the last decade, the standard approach to the young AML patient has been adjusted towards risk-adapted postremission therapy, that is HiDAC-based therapy for those at favorable risk and alloSCT for those with unfavorable cytogenetics [1, 9–11]. The best postremission therapy, however, for AML patients with either intermediate or unknown cytogenetic risk is still a controversial issue.
AML is an expensive disease to treat, which is due to prolonged hospital care, high-level technological medical intervention and the provision of specialized facilities. In 1989, Welch and Larson [12] first reported that the total costs for American AML patients for a period of 5 years was greater for alloSCT treatment than that for chemotherapy (193 000 versus 136 000, in 1989 USD), but that the former was more cost-effective than the latter. In 1992, Dufoir et al. [13] also reported the ‘estimated’ total costs of alloSCT, ASCT and HiDAC therapies as $US78 144; 92 986 and 56 091, respectively, (converted from 1990 French Francs) for French AML patients after the first complete remission (CR), and that alloSCT was as cost-effective as HiDAC and preferable to ASCT. Previous studies have also demonstrated the learning curve effects in the decrease of cost over time in the ASCT for patients with lymphoma due to the development of new technologies, organizational changes and the more cost-effective use of laboratory tests and pharmaceuticals [14, 15]. The best cost-effective approach, however, to postremission intensive treatment in acute leukemia has been rarely studied both over the last decade and in developing countries. We conducted this study to analyze the outcome and cost of acute leukemic patients treated with AML-type postremission intensive therapy in our single institute over the last decade. Our special objective is to analyze the cost-effectiveness of HiDAC-based therapy and alloSCT-based therapy especially among patients at either intermediate or unknown cytogenetic risk.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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From January 1994 to January 2002, 106 patients with acute leukemia were admitted to our hematological ward for treatment (Table 1). All AML patients received conventional remission induction chemotherapy with arabinoside and daunorubine (or idarubicin) [16]. Patients with acute promyelocytic leukemia received all-trans-retinoic acid and idarubicin as remission induction treatment. The acute lymphoblastic leukemia (ALL) patients received standard remission induction regimens. After achieving CR, 54 young patients (<60 years old) received postremission intensive therapy, including HiDAC, ASCT and alloSCT or a combination of these according to the in charge physician's decision. The HiDAC regimen includes arabinoside (3 g/m2) every 12 h for 3–4 days, in combination with either mitoxantrone or idarubicin for 3 days [17]. All patients treated with either ASCT or alloSCT, except one patient, received stem cells harvested from the peripheral blood. The conditioning regimen for ASCT and alloSCT was a standard busufan–cyclophosphamide regimen for the AML patients, and total body irradiation and cyclophosphamide regimen for the ALL patients. Cyclosporine and methotrexate were used for graft-versus-host disease prophylaxis. All patients received granulocyte colony-stimulating factor (G-CSF) after chemotherapy or stem-cell transplantation (SCT). No maintenance therapy was given after intensive therapy in all patients. Conventional consolidation or supportive care was given to older patients (>60 years old) or those with a poor performance after their first CR.
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cytogenetic studies
Bone marrow cells were harvested after 3 days of unstimulated culture. Metaphase chromosomes were banded by the conventional trypsin–Giemsa banding technique. Cytogenetic abnormalities were grouped according to published criteria adopted by the Southwest Oncology Group [7].
total cost analysis
All patients were admitted for chemotherapy, SCT and supportive care, including control of graft-versus-host disease or infection, blood transfusion and terminal care, over the whole treatment period. All patients except one received postremission intensive therapy in a regular single bedroom without a laminar airflow device. Payments of all 512 hospitalizations were retrieved from the administrative database. Outpatient direct medical costs, patient time costs, productivity costs and direct nonmedical costs were not included, but are expected to be low compared with direct medical inpatient costs [18]. All costs have been converted to 2003 $US (1 $US = 33.5 New Taiwan Dollars).
cost-effectiveness
To calculate cost-effectiveness, we divided the mean total cost of each treatment group by the number of saved life-years calculated by the Kaplan–Meier method, and thus cost-effectiveness was expressed in $US per additional year of life (‘life-year’) [12].
statistical analysis
All analyses were carried out using the SPSS statistical package software. Actuarial probability of survival was calculated by the method of Kaplan and Meier [19]. Comparisons of the use of resources and costs were carried out by the Mann–Whitney test and Fisher's exact test. A value of P <0.05 was considered statistically significant.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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treatment outcome and cost in all patients with acute leukemia
A total of 106 patients with acute leukemia were included in this study, including 94 patients with AML and 12 patients with ALL. The mean age of our patients was 45.5 ± 18.5 years, and 30 patients were >60 years old. Ten patients were in poor general condition and did not receive any chemotherapy. A total of 111 courses of remission induction chemotherapy were carried out during the study period, including 15 patients who underwent a second induction course after relapse. Among these patients, 70 entered CR (63.1%), 20 patients had refractory disease (18%) and 21 patients had treatment-related mortality (<30 days, 18.9%). After the first CR, 54 patients received intensive therapy and 14 patients received conventional consolidation. After a median follow-up of 14 months (range 0.5–142 months), 25 patients remained alive and the estimated 5-year overall survival (OS) rate was 24%. Further analysis showed that younger age (<60 years versus >60 years, P < 0.0001), cytogenetic risk (favorable versus intermediate versus unfavorable; P = 0.0437) and intensive therapy (P < 0.0001, Figure 1) were associated with higher OS. Sex and disease type (AML versus ALL), however, had no effect on the survival rate.
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The 54 patients who received intensive therapy had a significantly higher 5-year OS than those who did not (43% versus 2.5%, P < 0.0001, Figure 1) and they were associated with a significantly younger age (34.0 ± 10.9 years versus 57.5 ± 17.3 years; P < 0.0001; Table 1), but without any difference for disease type and karyotype. Ninety-six courses of intensive therapy were carried out, in which treatment-related mortalities (<30 days after the start of treatment) for HiDAC, ASCT and alloSCT were 7.7%, 0% and 15.1%, respectively (Table 2).
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From diagnosis to the end of the treatment, either cure or mortality, all patients need a median of 4.0 hospitalizations (range 1–15) and a median total of 117 days (4–377 days) of in-hospital care. The median cost for the entire treatment across the 106 patients was $US43 418 (range $US1494–172 332). The costs for drugs, room fee, blood transfusion, laboratory, procedure, professional manpower fee and private cost were 35%, 21%, 13%, 11%, 14%, 4% and 2% of the total cost, respectively. Patients receiving intensive treatment needed 47.3% more hospital-care days and showed a 57.3% higher total cost than those without intensive treatment (Table 1). Among the intensive therapies, alloSCT resulted in a higher cost than HiDAC or ASCT (P < 0.05 and P < 0.05, respectively), and also needed more hospital-care days (Table 2). The cost of HiDAC treatment was higher than ASCT; however, the cost of peripheral blood stem-cell mobilization and processing was included in the cost of the HiDAC treatment.
HiDAC-based versus alloSCT-based intensive therapy in patients regardless of their cytogenetic risk group
We further divided the 54 patients who underwent intensive therapy into HiDAC-based and alloSCT-based groups for further analysis (Table 3). There were 33 patients who underwent HiDAC-based therapy, of whom nine patients received additional ASCT immediately after HiDAC and three patients received alloSCT after relapse from the previous HiDAC therapy. All patients received alloSCT-based treatment during their first CR. After a median follow-up of 44 months (range 3–142 months), the estimated 5-year OS for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%, P = 0.1452). Further analysis showed that alloSCT-based group included significantly more patients with an unfavorable karyotype (P = 0.047) and ALL type (P = 0.009). We further analyzed the role of ASCT after HiDAC in nine patients, but there was no associated survival benefit detected compared with the 21 HiDAC-only treatment patients (P = 0.649). Similarly, HiDAC therapy before alloSCT therapy (nine patients) in the alloSCT-based group was not associated with a survival benefit compared with those receiving only alloSCT therapy (12 patients, P = 0.488).
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HiDAC-based versus alloSCT-based therapy in patients at either intermediate or unknown cytogenetic risk
We further determined the impact of the intensive treatment modality on the outcome and cost for the 16 patients at intermediate risk and the 26 patients without cytogenetic data (Table 4). After a median follow-up of 50 months (range, 5–142 months), the estimated 7-year OS in the HiDAC-based group showed a tendency to be higher than that in the alloSCT-based group (54% versus 34%, P = 0.1563, Figure 2). Table 4 shows that across the 24 patients who received HiDAC-based therapy, less was spent in terms of total cost (P = 0.004), out-of-pocket money (P = 0.004) and hospital days (P = 0.067). The reduced total cost for the HiDAC-based group originated from a lower total room fee (P = 0.003), medication (P = 0.003), laboratory tests cost (P = 0.001) and procedure costs (P = 0.031), but not from blood transfusion costs (P = 0.741) and professional manpower fees (P = 0.195).
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The cost-effectiveness analysis showed that the estimated length of survival of patients at 7 years was 4.62 years for the HiDAC-based group and 3.5 years for the alloSCT-based group (Figure 2). Thus, at 7 years, the mean cost per year of life saved was $US11 224 for the HiDAC-based group, but was much higher at $US21 564 for the alloSCT-based group.
We also analyzed the effect of treatment period (1994–1997 versus 1998–2002) on the total cost. In the latter period, the total cost decreased 0.1% in patients with HiDAC-based therapy, but increased 9.3% in those with alloSCT-based group. The percent contributions of the seven cost-drivers, however, remained similar between the two treatment periods in both treatment modalities.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Taiwan is a developing country with a population of about 24 million, in which the majority of people (
96%) are covered by the National Health Insurance. Our study demonstrates that the total cost of treating young AML patients with intensive therapy in Taiwan is far less expensive than that in the United States and European countries [12, 13]. Expressed on the basis of the corresponding national Annual Average Income of Household (AAIH), the total cost of treating a young AML patient with either alloSCT-based or HiDAC-based postCR therapy was 2.4 times and 1.6 times the AAIH in Taiwan (2001), respectively, but was 4.6 times and 3.2 times for the United States (USA Census Bureau, 1986–1988), respectively [12]. Similarly, the mean cost of alloSCT procedure alone in our study ($US29 208, between 1996 and 2001) is much lower than that among the Western countries (France: 
76 237, between 1998 and 2000 [20]; United States: $US105 300, between 1994 and 1997 [21]), which can be represented as 0.9 times relative to the Taiwanese AAIH (2001) and 2.5 times relative to the United States AAIH (1997) [21]. Besides undercompensated by our National Health Insurance compared with Western countries, the lower treatment cost of our AML patients mainly originated from the marked decrease in the room fee. The latter occupied 22% of the total cost in our study, but occupied 56%–81% of total cost in the Western countries [22, 23]. Our patients under SCT or HiDAC therapy were treated in a regular single bedroom, with the average daily room fee of $US73. The average daily cost of the special High Efficiency Particulate Air filtered bone marrow transplantation (BMT) facilities, however, was $US1196 and 1089 in the American and French hospitals, respectively [13, 21]. Different from the previous study [14], the reduced total cost in our study is unlikely due to learning curve effect because the recently developed medications and technology such as G-CSF and peripheral blood SCT had been applied from the beginning of this study and no major organizational change during the whole study period. The central finding in our study is that HiDAC-based therapy is a more cost-effective approach than alloSCT-based therapy in the AML patients at either intermediate or unknown cytogenetic risk. In AML patients with all-risk cytogenetic risk groups, two studies, carried out two decades ago, reported alloSCT to be as cost-effective as HiDAC and preferable to conventional consolidation during postremission treatment [12, 13]. The superior cost-effectiveness of HiDAC-based therapy in our study was derived from both a higher survival rate (54% versus 34% at 7 years) and a lower total cost ($US51 857 versus $US75 474), when compared with the alloSCT-based therapy. Our results are consistent with previous studies that there was a marginal advantage in terms of OS for HiDAC compared with alloSCT during postremission therapy for AML patients [5, 7]. The Medical Research Council AML-10 trial showed that alloSCT was associated with better survival than the intermediate dose arabinoside therapy among AML patients in the intermediate risk group [6]. Compared with patients undergoing alloSCT-based therapy, the reduced total cost in our HiDAC-based group was derived mostly from, first, less total hospital-care days (median 118 days versus 175 days) due to the shorter duration of the HiDAC therapy (median 27.5 days versus 48 days in alloSCT) and less terminal care (45% versus 67% in the alloSCT-based group) and, secondly, less cost for medication, laboratory tests and procedures. It is unlikely that the cost for alloSCT-based group is relatively high in our study because the median duration of the in-hospital care days for alloSCT in our study (48 days) was comparable to that in Western countries (39–62 days) and most patients received alloSCT without a laminar airflow device, which also reduces the cost of alloSCT [13, 21].
Our results only enrolled a limited number of patients, although this number is similar to that analyzed in the previous two cost-effectiveness studies [12, 13]. Cytogenetic data were available for only 50% of patients in our study because of technical failure and because it is not reimbursed by our insurance system, which was higher than many large cooperative clinical studies for AML patients in Western countries (17%–23%) [6–8]. Our analysis therefore targeted the data from patients without cytogenetic data and at intermediate risk, grouping these patients for specific study because optimal postCR intensive therapy for these patients is still not clear for either group. The better survival outcome of the HiDAC-based group in our study is unlikely to be due to the enrollment of more patients with a favorable risk profile because the latter only constitutes less than one fourth of all AML patients [6–8]. In spite of these limiting factors in our study, our data represent the most up-to-date cost-effective analysis in the treatment of AML. There is also strength in our single-institute experience because the same medical team was in charge of the patients during all stages of treatment using the same equipment, facilities and charging system for all patients. This makes both treatment groups comparable and without institutional bias effects, which can easily occur with multicenter trials. Our data will encourage more prospective clinical trials to enroll larger number of patients and address more fully the cost-effectiveness issue.
It is not clear whether our results can be extrapolated to either Western countries or to multicenter clinical trials. Several controversial issues still exist relative to the postremission treatment of AML, such as the optimal number of cycles of HiDAC and nonmyeloablative SCT. A previous study conducted by the Cancer and Leukemia Group B in AML patients with a normal karyotype demonstrated that fewer cycles of HiDAC gave a similar survival to either four cycles of HiDAC or one cycle of HiDAC followed by ASCT [24]. This was because of positive salvage SCT in relapse patients with less cycles of HiDAC [24]. From this standpoint, more cycles of HiDAC therapy will further increase total treatment cost, but without a definite improvement in survival. Recently, studies have also demonstrated that there is no difference in cost between myeloablative and nonmyeloablative SCT in AML patients, and between allogeneic BMT and allogeneic peripheral blood SCT [23, 25]. Matched unrelated BMT further increases treatment cost compared with matched sibling BMT (151 754 versus 98 334), although the cost can be reduced by T-cell depletion (from $US155 000 to $US113 000) [25, 26]. It is unlikely that the cost of alloSCT will decrease in the near future, except for a selected group of patients who can benefit from the substantial cost savings of an outpatient-based BMT program [27].
Recently, many somatic mutations have been detected in AML patients with a normal karyotype such as FMS-like tyrosine kinase 3 (FLT3), mixed lineage leukaemia (MLL), Brain and Acute Leukemia (BAALC), CCAAT/enhancer-binding protein 
(CEBPA) and nucleophosmin and these have been associated with different prognostic effects [28]. Unfortunately, molecular information is not available at most hospitals that lack a research laboratory. It is likely that patients with certain molecular abnormalities may benefit from specific postremission treatments, although the specific nature of these is currently unknown. We conclude that, for the postremission therapy in the young AML patients at either intermediate or unknown cytogenetic risk, cost-effectiveness of the HiDAC-based therapy compares favorably with that of alloSCT-based therapy, which deserves further prospective clinical trials.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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We thank Pui-Ching Lee and Muh-Hwa Yang for their help with the statistical analysis. This study was supported by grant NSC 94-2314-B-010-13 and a grant from the Taipei-Veterans General Hospital.
Received for publication July 10, 2006. Revision received September 16, 2006. Accepted for publication October 12, 2006.
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