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© 2001 American Society for Clinical Oncology Duration of Hospitalization as a Measure of Cost on Children’s Cancer Group Acute Lymphoblastic Leukemia StudiesFrom the Department of Pediatric Hematology-Oncology, Childrens Hospital, Los Angeles, CA; Division of Hematology-Oncology, Children’s Hospitals and Clinics, Minneapolis, MN; Department of Pediatrics, Hematology-Oncology, University of Michigan, Ann Arbor, MI; Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA; Department of Pediatric Hematology-Oncology, University of Chicago, Chicago, IL; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; Children’s Cancer Group, Arcadia, CA; and Department of Preventive Medicine, University of Southern California, Los Angeles, CA. Address reprint requests to Paul S. Gaynon, MD, The Children’s Cancer Group, Attention: Lucia Noll, PO Box 60012, Arcadia, CA 91066-6012.
PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children’s Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.
POSTINDUCTION INTENSIFICATION, termed delayed intensification (DI), has been a consistently successful strategy for improving event-free survival (EFS) and survival outcome on pediatric trials for acute lymphoblastic leukemia (ALL) conducted by the Children’s Cancer Group (CCG).1-5 The 6-year EFS rate for the overall cohorts of patients with ALL treated between 1983 and 1988 and between 1988 and 1995 increased from 64% to 74%. Building on the seminal work of the Berlin Frankfurt Münster (BFM) group,6,7 Tubergen et al4 demonstrated the specific benefit of DI for a subset of National Cancer Institute (NCI)-defined8 standard-risk patients treated on the CCG-105 trial.4 In more recent CCG studies (1988 to 1995), longer and stronger postinduction intensification was examined for standard- and higher-risk patients. In each study, the regimen with a longer or stronger postinduction intensification resulted in a superior outcome.1-4 Longer or stronger postinduction intensification, which involves additional doxorubicin, cyclophosphamide, cytarabine, dexamethasone, thioguanine, L-asparaginase, and vincristine, is also associated with an increased burden of therapy: morbidity and cost. Of all patients who receive the newer, more effective, more morbid therapy, only a minority benefit. Most patients would achieve the same good outcome with less noxious therapy, and for some, the newer therapy is still not sufficient. Future gains in outcome with increasingly burdensome regimens will likely benefit even a smaller fraction of patients. Thus, careful assessment of the total burden of therapy, even successful therapy, is imperative to choose an optimal clinical strategy. The best method for assessing morbidity and cost of therapy is unclear. Conventional measures of morbidity, such as adverse drug reactions, toxicity matrices, and major complications, have significant limitations. Reporting of morbidity may be affected by increased awareness3,9 as well as by the frequency and methodology with which a determination is made, for example, blood cultures.10 Comparison of morbidity across studies is confounded by different monitoring frequencies and reporting criteria. Duration of hospitalization, resulting from both inpatient treatment and management of the complications of treatment, provides an objective measure of burden of therapy, because it is easily verifiable and independent of the frequency of monitoring and reporting threshold issues that confound conventional data. By the NCI definition, an occurrence resulting in hospitalization or prolongation of hospitalization constitutes a serious adverse event.11 Although hospitalization may result from inpatient anticancer therapy as well as inpatient management of complications, previous studies suggest that duration of hospitalization is tightly linked to morbidity and medical cost.12-14 Therefore, to weigh improvements in EFS for particular regimens on recent CCG trials against the concomitant increase in burden of therapy, we have used a cost-effectiveness analysis in which duration of hospitalization is used as a surrogate for cost and effectiveness is based on the EFS at 5 years.
Patients The present analysis involved 4,986 children with newly diagnosed ALL enrolled onto CCG risk-adjusted protocols between 1988 and 1995. Children 2 to 9 years of age with WBC counts less than 10,000/µL (low-risk ALL) were enrolled onto CCG-1881; children 2 to 9 years of age with WBC counts 10,000 to 49,999/µL and children 12 to 23 months of age with WBC counts less than 50,000/µL (intermediate-risk ALL) were enrolled onto CCG-1891. After completion of these studies, patients with low- or intermediate-risk ALL were enrolled onto a single protocol, CCG-1922, for standard-risk ALL (ages 1 to 9 years with WBC counts < 50,000/µL) on the basis of NCI criteria.8 Children ages 1 to 9 years with WBC counts of 50,000/µL or greater and children ages 10 years or older (NCI poor-risk group)8 were assigned to CCG-1882. Children with lymphomatous features15 were enrolled onto CCG-1901. Outcomes for individual trials have been reported elsewhere.2,3,16,17 EFS and overall survival estimates at 6 years from study entry for the entire cohort of patients treated on this series of trials were 74% (SD = 1%) and 84% (SD = 1%), respectively. All protocols were approved by the NCI and the local institutional review boards of the participating CCG-affiliated institutions. Informed consent was obtained from parents, patients, or both according to the guidelines of the Department of Health and Human Services.
Therapy on CCG Studies (1988 to 1995)
High-risk patients on CCG-1882 received chemotherapy on the basis of the BFM 76/79, CCG-193P, and CCG-106 trials,6,18-20 consisting of induction, consolidation, interim maintenance, and maintenance phases. Patients with a rapid early response to induction therapy ( Patients with lymphomatous features15 treated on CCG-1901 were randomized at study entry to receive New York (NY) I or NY II therapy. Both of these intensive regimens were based on therapy originally used for treatment of non-Hodgkin’s lymphoma.21-23 NY I therapy consisted of intensive induction, consolidation, and maintenance phases, as previously described.20 The NY II regimen is a modified version of NY I regimen. It includes additional early intensification and lesser cumulative exposure to anthracyclines and alkylating agents by substituting continuous infusion daunomycin for bolus Adriamycin and substituting standard oral 6-mercaptopurine and oral methotrexate maintenance for all but the first five 8-week intensive maintenance courses. The CCG-1941 trial for early bone marrow relapse included a 5-week reinduction with etoposide, ifosfamide, dexamethasone, vincristine, L-asparaginase, IV methotrexate, and intrathecal triple therapy consisting of methotrexate, hydrocortisone, and cytarabine. Additional details of therapy will be reported elsewhere. Similar therapy was used on the CCG-1951 trial for extramedullary relapse. During the 1989 to 1995 era, there was no specific trial for treatment of patients with a late bone marrow relapse. However, such patients generally received therapy similar to that of the CCG-1882 augmented regimen, as described above.
Statistical Methods
Mean duration of hospitalization for particular regimens on frontline studies was determined by enumeration of hospital days per patient as reported by institutions over the course of therapy. A conservative, weighted estimate of the duration of hospitalization for treatment of relapse for a sample group of 100 patients was calculated using available hospitalization data from the CCG-1941 and CCG-1951 trials for early bone marrow relapse and extramedullary relapse, respectively. On the CCG-1941 trial, the mean duration of hospitalization was 29 days per patient during induction plus an additional 50 days per patient for the 70% of patients who achieved remission and received intensification therapy. Thus, hospitalization for an early marrow relapse was estimated as 29 days + (0.7 x 50) = 64 days. Hospitalization data from the CCG-1951 study is not yet available, but the remission induction rate was 100% and patients received therapy similar to that of CCG-1941. Thus, the mean duration of hospitalization was estimated from the CCG-1941 data to be 29 days during induction + (1 x 50 days during intensification) = 79 days. Patients with a late bone marrow relapse were not treated on a specific trial but generally received therapy similar to the augmented BFM regimen described for CCG-1882, which had a mean of 48 hospital days (see Results and Table 1). On the basis of data from previous CCG trials,25 early bone marrow, late bone marrow, and extramedullary relapses accounted for 45%, 25%, and 30% of all relapses, respectively. Thus, the weighted average duration of hospitalization was (64 x 0.45) + (48 x 0.25) + (79 x 0.30) = 65 days/relapse. This value represents an underestimate of the duration of hospitalization for relapse, because it excludes hospitalization for patients who undergo an additional reinduction attempt after failure to achieve CR2 or who receive additional therapy after subsequent relapses. Thus, we also have used a less-conservative value of 90 days for comparison.
Cost-effectiveness calculations were based on a model group of 100 patients for each regimen. The cost-effectiveness ratio26 was defined as the total hospital stay (days) divided by the estimated number of event-free survivors (EFSVs) at 5 years (patient). The marginal cost-effectiveness ratio27 (hospital days per additional EFSV) was defined as the difference in total duration of hospitalization for two regimens divided by the difference in number of EFSVs at 5 years for the two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline plus relapse therapy divided by the difference in number of EFSVs at 5 years on the frontline therapy for two regimens. The duration of hospitalization attributable to relapse was estimated using the weighted average (see above) for patients with any type of relapse on each regimen. Details of these calculations are given in Appendix A.
Duration of Hospitalization on Frontline Trials Between 1988 and 1995, a total of 4,986 children were entered onto the frontline CCG trials included in this analysis. The mean (median) duration of hospitalization during induction was similar for regimens that used similar three-drug induction with vincristine, prednisone or dexamethasone, and L-asparaginase. For example, standard and DI regimens on the low-risk CCG-1881 study incurred 9.5 days (8 days) and 10.2 days (8 days) during induction, respectively (P = .25). Similarly, the DI, VPI, and DDI regimens on the CCG-1891 intermediate-risk study incurred 12.4 (10 days), 12.5 days (10 days), and 12.5 days (10 days) during induction, respectively (P = .94). On the CCG-1922 study for standard-risk patients, the prednisone and dexamethasone regimens incurred 11 days (10 days) and 11 days (9 days) during induction, respectively (P = .98). The mean and median duration of hospitalization during a DI phase also was similar for regimens that used similar or identical DI phases within a particular study. For example, the mean (median) number of hospital days during the first DI phase was 5.4 days (3 days), 5.8 days (4 days), and 6.2 days (4 days) for the DI, VPI, and DDI regimens on CCG-1891, respectively (Wilcoxon P = .32). The mean (median) number of hospital days during the dexamethasone-containing DI phase on CCG-1922 was 5.3 days (3 days) and 4.9 days (3 days) for the dexamethasone and prednisone arms, respectively (Wilcoxon P = .74). The mean (median) number of hospital days during the first DI phase for patients with a rapid early response treated with and without CRT on CCG-1882 was 6.6 days (4 days) and 7.1 days (4 days), respectively (Wilcoxon P = .91). The mean (median) number of hospital days during the first DI phase for slow early response patients treated with standard or augmented therapy on CCG-1882 was 7.5 days (5 days) and 7.6 days (3 days), respectively (Wilcoxon P = .56). Total duration of hospitalization from study entry and from treatment randomization for individual regimens on the five frontline studies included in this analysis is shown in Table 1. Statistical comparisons between regimens were done using duration of hospitalization from the time of randomization. On the CCG-1881 low-risk study, duration of hospitalization was significantly longer for the regimen using postinduction intensification, ie, DI, than for the standard regimen (P = .0001). On the CCG-1891 intermediate-risk study, duration of hospitalization was longer on the regimen that used longer postinduction intensification, ie, DDI, compared with shorter postinduction intensification, ie, the DI and VPI regimens (P = .0001). On the CCG-1922 standard-risk study, which used one DI phase for all patients, duration of hospitalization was similar for patients treated with dexamethasone or prednisone (P = .78) and for those treated with oral or IV 6-mercaptopurine (P = .61). Among high-risk patients with a slow early response to induction therapy on CCG-1882, duration of hospitalization was greater for those treated with longer and stronger postinduction intensification on the augmented regimen than for those treated with standard postinduction intensification (P = .001). In contrast, duration of hospitalization was similar for CCG-1882 rapid early responders treated with standard postinduction intensification and either CRT or additional intrathecal methotrexate (P = .58). Among higher-risk patients with lymphomatous features treated on CCG-1901, those treated with the NY II regimen had a significantly greater duration of hospitalization than those treated with the NY I regimen (68 v 47 days; P = .0001). The difference may be attributable in part to the continuous-infusion daunomycin and cytarabine on NY II that was usually given in an inpatient setting.
Cost-Effectiveness Analysis for Frontline Trials
Duration of Hospitalization and Cost-Effectiveness Ratios for Relapsed ALL
Relapse-Adjusted Cost of Frontline Therapy As described in the Statistical Methods and listed in Table 3, a conservative weighted average duration of hospitalization incurred for relapse was calculated to be 65 days/patient. Hospitalization after a second relapse was not included. This weighted average was used to calculate a relapse-adjusted cost for superior frontline treatment regimens. As listed in Table 4, the relapse-adjusted marginal cost of frontline therapy was decreased compared with the unadjusted marginal costs listed in Table 2. The relapse-adjusted marginal costs of DI therapy on CCG-1881 and DDI therapy on CCG-1891 were 68 days per additional EFSV and 52 days per additional EFSV, respectively. By comparison, dexamethasone-based therapy on CCG-1922 and augmented therapy for higher-risk, slow early responders on CCG-1882 saved a marginal 82 days per additional EFSV and 16 days per additional EFSV, respectively. Use of a second, less-conservative estimate of 90 days per relapse results in relapse-adjusted marginal costs of 43 days per additional EFSV for DI for lower-risk patients and 27 days per additional EFSV for DDI for intermediate-risk patients and savings of 107 days per additional EFSV for dexamethasone for standard-risk patients and 38 days per EFSV for augmented therapy for the higher-risk slow early response patients.
Hospital days are an important medical resource, accounting for 45% of pediatric healthcare expenditures in the United States in 1980.28 Bloom et al29 found that inpatient costs accounted for 78% of direct medical costs for children with ALL, whereas room, board, and standard nursing care accounted for one half of inpatient costs. Similarly, adult studies have demonstrated that hospital days and hospital-based claims accounted for 48% and 70%, respectively, of the medical costs of treatment for non–small-cell lung cancer12 and that charges associated with prostatectomy were determined primarily by the duration of hospitalization rather than by the intensity of services provided.14 Kukull et al13 found that duration of hospital stay was the primary determinant of charges in a study of 103 selected Veterans Administration Hospital admissions. Thus, duration of hospitalization may provide a basis for useful cross-study comparisons of cost, burden, or therapy. We examined hospital stays for nearly 5,000 children with ALL treated in more than 100 CCG institutions over a 7-year period. Duration of hospitalization during specific phases of treatment was similar for patients treated with similar induction or intensification therapies. Hospitalization practice may vary over time. However, comparing earlier CCG data from 1983 to 1988 with more recent data from 1989 to 1995, we found that the mean duration of hospitalization was similar for corresponding regimens in corresponding populations, namely, 27 and 29 days for DI therapy for intermediate-risk patients on CCG-1054 and CCG-1891 and 40 and 36 days for standard intensive therapy for higher-risk patients on CCG-10620 and CCG-1882. Hospital stays differed, however, between more- or less-aggressive regimens within a study, such as single DI versus standard therapy for lower-risk patients, DDI versus DI for intermediate-risk patients, augmented versus standard intensive therapy for higher-risk patients, and NY II versus NY I therapy for patients with lymphomatous ALL (see Table 1). Similarly, on CCG trials conducted between 1983 and 1988 for intermediate-risk ALL, lymphomatous syndrome, and higher-risk ALL, more aggressive, experimental therapies also incurred increased hospitalization.4,20,30 The cost of preventing a relapse on frontline trials must be evaluated in light of the cost of treating a relapse. Relapse-adjusted marginal cost-effectiveness calculations revealed a net reduction in costs for the dexamethasone-based regimen on CCG-1922 and the augmented regimen on CCG-1882. By this measure, augmented therapy improved EFS by 17 percentage points and decreased costs by 275 days per 100 patients, resulting in a relapse-adjusted marginal savings of 16 hospital days per additional EFSV. Similarly, substitution of dexamethasone for prednisone improved EFS by 6 percentage points and decreased costs by 490 days, with a relapse-adjusted marginal savings of 82 hospital days per additional EFSV. On CCG-1881, single DI improved EFS by 6 percentage points and increased hospitalization by 410 days, resulting in a relapse-adjusted marginal cost of 68 additional hospital days per additional EFSV. Similarly, for intermediate-risk patients on CCG-1891, DDI improved EFS by 6 percentage points and increased costs by 310 days, resulting in a relapse-adjusted marginal cost of 52 additional hospital days per additional EFSV. These results exclude any hospitalization after second relapse. By comparison, the estimated average cost-effectiveness for treating any relapse was 250 days per EFSV. Thus, use of more aggressive therapy on frontline trials seems to have been cost-effective. Dexamethasone on CCG-1922 and DDI on CCG-1891 each showed a statistically significant advantage for EFS. Benefit may not be additive. However, dexamethasone provided a net decrease in relapse-adjusted hospital stay. Therefore, current CCG standard-risk trial CCG-1991 builds on dexamethasone as the less-burdensome intervention and re-examines the value of DDI in that context rather than the converse. We found no apparent EFS benefit for NYII compared with NYI therapy for patients with lymphomatous ALL treated on CCG-1901, but the NYII regimen incurred significantly more hospital days. The continuous-infusion daunomycin and cytarabine on NYII therapy required hospitalization in many hospitals not equipped to deliver this treatment on an outpatient basis. NYII therapy was designed with the aim of reducing long-term risk of anthracycline-induced cardiac toxicity and alkylator-induced second malignant neoplasms. Neither of these benefits is measured by duration of hospitalization. Our BFM-based and NY-based intensive regimens provide a similar EFS, but the BFM-based regimens require at least 20 hospital days per patient fewer than NY II. Anthracycline exposure and alkylator exposure are similarly limited, providing justification for pursuit of our BFM-based strategies on the current higher-risk trial, CCG-1961. On the basis of data of Pui et al,31 who estimated the average cost of hospitalization for children with ALL to be more than $1,500 per day, an estimate of true monetary cost (on the basis of relapse-adjusted marginal cost-effectiveness calculation) of intensive therapy is $102,000 per additional EFSV for DI on CCG-1881 and $78,000 per additional EFSV for DDI on CCG-1891. The savings afforded by dexamethasone-based therapy on CCG-1922 and augmented therapy on CCG-1882 would be $117,000 per additional EFSV and $24,000 per additional EFSV, respectively. It is noteworthy that whereas adult studies may report costs of $20,000 to $30,000 per year of life saved with various medical interventions, successful therapy for pediatric ALL may save more than 50 years of life for an individual.32 Duration of hospitalization may also be useful for comparing the burden of therapy incurred on different studies within specific patient subgroups. For example, intermediate-dose IV methotrexate–based therapy for treatment of standard-risk ALL9,33 was reported to incur a median of 39 hospital days during postinduction therapy. By comparison, postinduction mean duration of hospitalization for lower-risk patients treated with DI, intermediate-risk patients treated with DDI, or NCI standard-risk patients treated with dexamethasone (calculated from total hospitalization minus induction hospitalization) was 16 to 17 days. Similar EFS was reported for all of these studies. Thus, on the basis of hospitalization, DI and dexamethasone-based therapy may be more cost-effective than high-dose IV methotrexate. Other considerations, such as expected late effects, also play a role in regimen selection. Assessment of a treatment strategy does not stop with relapse. Treatment after relapse may contribute substantially to the burden of therapy. Considered in isolation, the augmented regimen costs 41 hospital days per relapse prevented. However, when the relapse experience is included, the result is a net savings in hospital days. Ineffective cancer treatment remains the most expensive cancer treatment. Treatment failure leads to additional therapy, which is usually more morbid, more expensive, and ultimately less successful than primary therapy. Simple enumeration of hospital days does not include important elements of burden of therapy, such as days in the intensive care unit, operative procedures, radiographic studies, laboratory tests, and consultations. Hospital stay may not reflect outpatient expenses, families’ indirect expenses, or the intangible benefits and burdens of treatment, nor does it reflect the possible late adverse effects of therapy. Nevertheless, hospital stay represents a reproducible, accurate, and feasible estimate of utilization of medical resources. Hospital stay may be used as an internal check for incompletely reported morbidity. Data forms describing prolonged hospitalization without adequate explanation might be flagged for review. Taken together, the findings described above suggest that duration of hospitalization may be useful for determining if a regimen with superior outcome has an acceptable cost burden and directing treatment choices when outcomes are similar. Hospitalization experience is an informative element in reports of clinical trials.
APPENDIX A
For example, on CCG-1881 standard therapy, the cost effectiveness ratio isequation
Marginal Cost-Effectiveness Ratio
For example, on CCG-1881, for DI (regimen B) and standard lower-risk therapy (regimen A), the marginal cost-effectiveness ratio of DI isequation
Relapse-Adjusted Marginal Cost-Effectiveness of Frontline Therapy The number of relapses for the 100-patient model was calculated as follows: Number of RelapsesA = number of eventsA x fraction relapsesA For example, on CCG-1881 STD therapy, EFS was 79%; thus, there were 21 events among the model group of 100 patients. Eighty-nine percent of adverse events were relapses. The fractional relapse rate was 89%. Thus, Number of RelapsesA = number of eventsA x fraction relapsesA Number of Relapses1881 STD = 21 x 0.89 = 19 relapses The number of hospital days incurred for each relapse (relapse days) was calculated from the weighted average of 65 hospital days per patient at relapse (see Statistical Methods). For example, on CCG-1881 STD therapy, the number of relapse days is 65 days x 19 relapses = 1,235 relapse days
Relapse-Adjusted Marginal Cost-Effectiveness
For example, the relapse-adjusted marginal cost-effectiveness ratio on CCG-1881 for DI (regimen B) versus standard lower-risk therapy (regimen A) isequation
APPENDIX B
Supported in part by research grants, including Children’s Cancer Group Chairman’s Grants CA-13539 and CA-60437 from the National Cancer Institute, National Institutes of Health.
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Nachman JB, Sather HN, Sensel MG, et al: Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338: 1663-1671, 1998
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Tubergen DG, Gilchrist GS, O’Brien RT, et al: Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: A Children’s Cancer Group phase III trial. J Clin Oncol 11: 527-537, 1993 5. Uckun FM, Reaman G, Steinherz P, et al: Improved clinical outcome for children with T-lineage acute lymphoblastic leukemia after contemporary chemotherapy: A Children’s Cancer Group study. Leuk Lymphoma 24: 57-70, 1996[Medline] 6. Henze G, Langermann HJ, Bramswig J, et al: The BFM 76/79 Acute Lymphoblastic Leukemia Therapy study [in German]. Klin Padiatr 193: 145-154, 1981[Medline] 7. Henze G, Fengler R, Reiter A, et al: Impact of early intensive reinduction therapy on event-free survival in children with low-risk acute lymphoblastic leukemia. Hamatol Bluttransfus 33: 483-488, 1990[Medline] 8. Smith M, Arthur D, Camitta B, et al: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14: 18-24, 1996[Abstract] 9. Mahoney DH Jr, Shuster JJ, Nitschke R, et al: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy–A Pediatric Oncology Group study. J Clin Oncol 16: 1712-1722, 1998[Abstract] 10. Aronson MD, Bor DH: Blood cultures. Ann Intern Med 106: 246-253, 1987 11. National Cancer Institute: NCI guidelines: Expedited adverse event reporting requirements for NCI investigational agents. Program CTE, National Cancer Institute, 2001
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Hillner BE, McDonald MK, Desch CE, et al: Costs of care associated with non–small-cell lung cancer in a commercially insured cohort. J Clin Oncol 16: 1420-1424, 1998 13. Kukull WA, Koepsell TD, Conrad DA, et al: Rapid estimation of hospitalization charges from a brief medical record review: Evaluation of a multivariate prediction model. Med Care 24: 961-966, 1986[Medline] 14. Litwin MS, Kahn KL, Reccius N: Why do sicker patients cost more? A charge-based analysis of patients undergoing prostatectomy. J Urol 149: 84-88, 1993[Medline] 15. Steinherz PG, Siegel SE, Bleyer WA, et al: Lymphomatous presentation of childhood acute lymphoblastic leukemia: A subgroup at high risk of early relapse. Cancer 68: 751-758, 1991[Medline] 16. Bostrom B, Gaynon PS, Sather H, et al: Dexamethasone (DEX) decreases central nervous system (CNS) relapse and improves event-free survival (EFS) in lower risk acute lymphoblastic leukemia (ALL). Proc Am Soc Clin Oncol 17: 527a, 1998 17. Nachman J, Sather HN, Cherlow JM, et al: Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: A report from the Children’s Cancer Group. J Clin Oncol 16: 920-930, 1998[Abstract] 18. Gaynon PS, Steinherz PG, Bleyer WA, et al: Intensive therapy for children with acute lymphoblastic leukaemia and unfavourable presenting features: Early conclusions of study CCG-106 by the Childrens Cancer Study Group. Lancet 2: 921-924, 1988[Medline] 19. Gaynon PS, Bleyer WA, Steinherz PG, et al: Modified BFM therapy for children with previously untreated acute lymphoblastic leukemia and unfavorable prognostic features: Report of Children’s Cancer Study Group study CCG-193p. Am J Pediatr Hematol Oncol 10: 42-50, 1988[Medline]
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Gaynon PS, Steinherz PG, Bleyer WA, et al: Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: A follow-up report of the Childrens Cancer Group study CCG-106. J Clin Oncol 11: 2234-2242, 1993 21. Duque-Hammershaimb L, Wollner N, Miller DR: LSA2-L2 protocol treatment of stage IV non-Hodgkin’s lymphoma in children with partial and extensive bone marrow involvement. Cancer 52: 39-43, 1983[Medline]
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Anderson JR, Jenkin RD, Wilson JF, et al: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin’s lymphoma: A report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11: 1024-1032, 1993 23. Anderson JR, Wilson JF, Jenkin RD, et al: Childhood non-Hodgkin’s lymphoma: The results of a randomized therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2). N Engl J Med 308: 559-565, 1983[Abstract] 24. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 25. Gaynon PS, Qu RP, Chappell RJ, et al: Survival after relapse in childhood acute lymphoblastic leukemia: Impact of site and time to first relapse. The Children’s Cancer Group experience. Cancer 82: 1387-1395, 1998[Medline] 26. Weinstein MC, Stason WB: Foundations of cost-effectiveness analysis for health and medical practices. N Engl J Med 296: 716-721, 1977[Abstract] 27. Maynard A: The design of future cost-benefit studies. Am Heart J 119: 761-765, 1990[Medline] 28. Perrin JM, Homer CJ, Berwick DM, et al: Variations in rates of hospitalization of children in three urban communities. N Engl J Med 320: 1183-1187, 1989[Abstract] 29. Bloom BS, Knorr RS, Evans AE: The epidemiology of disease expenses: The costs of caring for children with cancer. JAMA 253: 2393-2397, 1985[Abstract] 30. Steinherz PG, Gaynon PS, Breneman JC, et al: Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: Randomized controlled trial from the Children’s Cancer Group. Cancer 82: 600-612, 1998[Medline]
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Mahoney DH Jr, Shuster J, Nitschke R, et al: Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: A Pediatric Oncology Group phase III trial. J Clin Oncol 16: 246-254, 1998 Submitted August 8, 2000; accepted December 27, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25% marrow blasts on day 7)
