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Double-Blind, Placebo-Controlled Study of Quality of Life, Hematologic End Points, and Safety of Weekly Epoetin Alfa in Children With Cancer Receiving Myelosuppressive Chemotherapy

Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner, Denise Williams, Wayne R. Rackoff

From the St Jude Children's Research Hospital, Memphis, TN; Children's Hospital Medical Center of Akron, Akron, OH; Texas Children's Cancer Center, Houston, TX; Children's Hospital Oakland, Oakland, CA; and Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ

Address reprint requests to Bassem I. Razzouk, MD, 332 N Lauderdale St, Mail Stop 721, Memphis, TN 38105; e-mail: bassem.razzouk{at}stjude.org

	ABSTRACT

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PURPOSE: To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer.

METHODS: Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS).

RESULTS: One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P .238; P .081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = .002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P = .010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but was not in the placebo group (r = 0.086; P = .430). Adverse events were comparable between treatment groups.

CONCLUSION: This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer.

	INTRODUCTION

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In adults with cancer, improving hemoglobin (Hb) has been shown to affect health-related quality of life (HRQOL).¹ Many children with cancer are anemic, but little evidence supports the use of epoetin alfa (EPO) in anemic children with cancer who are receiving chemotherapy. Several studies assessed the effect of EPO in anemic pediatric patients with cancer and reported that Hb increased while blood transfusion requirements decreased.^2-10 However, a randomized, controlled study of 323 anemic children with cancer reported hematologic benefits of once-weekly EPO only among children with acute lymphoblastic leukemia (ALL).¹¹ None of the studies evaluated how HRQOL was affected by or how it correlated with hematologic end points. The Pediatric Quality of Life Inventory Generic Core Scales 4.0 (PedsQL-GCS; J.W. Varni, PhD, College Station, TX) have been shown to discriminate between HRQOL in healthy children and those with cancer.^12,13 The objective of this clinical study was to test the tolerability and effects of once-weekly EPO on patient-reported HRQOL, Hb levels, and blood transfusion requirements in anemic children with malignancies who were receiving myelosuppressive chemotherapy.

	METHODS

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This randomized, double-blind, placebo-controlled study was conducted at 27 sites. It began as two studies with identical designs—one of patients with solid tumors or Hodgkin's disease and the other of patients with ALL or non-Hodgkin's lymphoma (NHL). Both studies were designed to enroll 220 patients, but due to slow enrollment they were combined into a single study that was then stratified according to tumor type (either solid tumors/Hodgkin's disease or ALL/NHL). At the time the studies were combined, 78 patients were enrolled in the solid tumors/Hodgkin's disease study and 61 in the ALL/NHL study.

Participants
Table 1 lists eligibility criteria. Institutional review boards reviewed study materials, and the study was conducted in accordance with the Declaration of Helsinki. Patients or their legal guardian provided written informed consent for participation; the patients provided assent when appropriate.

Outcome Measures
Patients rated HRQOL at baseline and at study visits on age-appropriate PedsQL-GCS consisting of 23 questions that assessed physical, emotional, social, and school functioning (Appendix); scores from all domains were added up to provide the total score.¹⁴ Patients also completed an age-appropriate PedsQL 3.0 Cancer Module (Appendix; J.W. Varni, PhD, College Station, TX) at baseline, after 8 or 9 weeks, and at the final visit.¹³ One parent or caregiver completed parent versions of the instruments (Appendix); the same person was to complete these instruments throughout the study. The PedsQL-GCS assesses general HRQOL, regardless of underlying health, and the PedsQL Cancer Module specifically assesses HRQOL in children with cancer. Hb was measured within 24 hours of the HRQOL assessment. Patients or parents were not to be told blood count results before completion of the HRQOL instruments. Vital signs, transfusion history, and adverse events were recorded at each visit.

Statistical Analysis
The primary end point was mean change from baseline in patient-reported PedsQL-GCS total score. The sample size for each of the original studies was calculated to detect an effect size difference in PedsQL-GCS total score of at least 0.4, where effect size was defined as the mean change from baseline divided by the standard deviation of the change.¹⁵ A sample size of 100 per group was needed for 80% power at = .05. An enrollment goal of 110 per group was set to allow for attrition and was maintained after the studies were combined.

Baseline data were compared between treatment groups with t tests and ² tests. Efficacy analyses included patients who received at least one dose of study medication and had at least one postrandom assignment HRQOL evaluation (a modified-intent-to-treat population). Analyses of change from baseline to final visit used the last observation carried forward.

The primary efficacy end point of the change from baseline to final visit in PedsQL-GCS total score used an analysis of covariance (ANCOVA) with study treatment, site, and tumor type (solid tumors/Hodgkin's disease or ALL/NHL) as factors, and baseline score as a covariate. Parent-reported PedsQL-GCS total scores, patient- and parent-reported PedsQL-GCS total scores according to age strata, and patient- and parent-reported scores among all patients for each domain of the PedsQL Cancer Module were compared between treatment groups at the final visit using similar ANCOVA methods. Repeated-measures analyses were performed to evaluate the overall change from baseline for each measure of HRQOL using generalized estimating equations with autoregressive covariance structures and baseline scores as covariates. Pearson correlation coefficients were determined between patient- and parent-reported HRQOL scores within groups for the total score and component scores of the PedsQL-GCS and the individual domains of the PedsQL Cancer Module.

Mean change in Hb from baseline was compared between groups using ANCOVA methods for the final visit (with baseline Hb as a covariate), as well as repeated-measures analysis of all reported Hb values. Hb responders were defined as patients who had a Hb increase of 2 g/dL or higher from baseline at any time after 4 weeks, independent of RBC transfusion within the previous 28 days. Hb response was evaluated for the efficacy population and separately by age strata.

The percentage of patients in each group who received any blood transfusions and the percentage who were transfusion free after 4 weeks were compared between treatment groups with Fisher's exact tests. Kaplan-Meier estimates of the time to first blood transfusion were analyzed using a log-rank test.

To examine the transfusion-independent effects of study treatment, the statistical analyses of HRQOL and Hb were repeated censoring data collected within 28 days after a RBC transfusion.

Pearson coefficients were calculated posthoc to evaluate the correlation between Hb and PedsQL-GCS total score at baseline (for all patients in both treatment groups combined) and for the changes from baseline (within each treatment group); coefficients for changes from baseline were compared between groups based on the normal distribution with Fisher's Z-transformation.¹⁶

Safety analyses included all patients who received at least one dose of study medication. Treatment-emergent adverse events were summarized by their frequency and seriousness. Thrombotic vascular events (intravenous thrombus, chest pain, edema, thrombosis, disseminated intravascular coagulation, cerebral infarction, and pulmonary thrombosis) were summarized by seriousness and clinical relevance.

	RESULTS

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Study Participants
From September 2000 through September 2003, 224 patients were randomly assigned to receive EPO (n = 113) or placebo (n = 111). The efficacy population included 111 patients in each treatment group; patients in the EPO group were slightly older, heavier, and taller at baseline (Table 2). PedsQL-GCS scores at baseline were comparable between treatment groups. The safety population included 112 patients in the EPO group and 110 patients in the placebo group because one patient in the latter group inadvertently received a single dose of EPO during study.

HRQOL
Mean patient-reported PedsQL-GCS total score at the final visit, adjusted for baseline differences, was not significantly different between the EPO and placebo groups (74.9 v 75.5; P = .763). Mean patient-reported PedsQL-GCS total score at the final visit was significantly greater in the EPO group among patients 5 years to 7 years of age (88.0 v 78.1; P = .043), but not among patients 8 years to 12 years of age (73.1 v 77.1; P = .328) or 13 years to 18 years of age (74.9 v 75.7; P = .791).

Mean scores at the final visit were not significantly different between treatment groups for the summary components of the PedsQL-GCS or for the individual domains of the PedsQL Cancer Module (Table 3). Repeated-measures analysis confirmed these findings (Table 3).

Hb
Mean change in Hb from baseline was not significantly different between the EPO and placebo groups at the final visit (1.3 v 1.0 g/dL; P = .129). Repeated-measures analysis determined that EPO was associated with significantly greater increases in Hb than placebo overall (P = .002; Table 3).

Patients in the EPO group were more likely than those in the placebo group to be Hb responders, defined as a Hb increase of at least 2 g/dL from baseline (56.5% v 34.9%; P = .002). Among patients age 5 years to 7 years, 12 (92.3%) of 13 in the EPO group and 14 (41.2%) of 34 in the placebo group were Hb responders.

Blood Transfusions
During the study, 72 patients (64.9%) in the EPO group and 86 patients (77.5%) in the placebo group received an RBC transfusion. The median time to first transfusion was 15.0 days and 14.5 days in the EPO and placebo groups, respectively (P = .254). Approximately one half of the patients in both groups received an RBC transfusion during the first 4 weeks on study treatment (Fig 1). After week 4, patients in the EPO group were significantly more likely than those in the placebo group to remain transfusion-free (38.7% v 22.5%; P = .010). The median time to first RBC transfusion after week 4 was 71 days in the EPO group and 53 days in the placebo group (P = .03).

View larger version (11K): [in this window] [in a new window]   Fig 1. Use of RBC transfusions. *P = .002 versus placebo. P = .036 versus placebo.

Censoring Hb values for 28 days after RBC transfusion did not result in significantly greater increases in Hb from baseline in the EPO group than in the placebo group at the final visit (1.6 g/dL v 1.3 g/dL; P = .098), but the difference in the overall change was statistically significant with repeated-measures analysis (P = .007; Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 2. Mean (SE) hemoglobin (Hb) by treatment week. Within each treatment group, mean Hb was similar whether values within 28 days of blood transfusion were included (solid lines) or censored (dotted lines). Between-group P values from repeated-measures analyses: P = .002 for all values; P = .007 excluding post-transfusion Hb.

A similar proportion of patients in the EPO and placebo groups (22.3% and 22.7%, respectively) had at least one thrombotic vascular event during treatment. These events primarily included clotted lines (9.8% and 9.1% of patients in the EPO and placebo groups, respectively) or chest pain or edema (8.9% and 11.8%, respectively). Clinically relevant thrombotic vascular events were reported for six patients (5.4%) in the EPO group and two patients (1.8%) in the placebo group (Table 5). No deaths due to thrombotic vascular events were reported.

	DISCUSSION

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This is the first large-scale, randomized, placebo-controlled study of EPO in anemic children with cancer and the first to measure the effect of EPO on HRQOL. The hypothesis was that the amelioration of anemia with EPO would result in improvement in HRQOL. Hematologic effects and the tolerability of intravenous administration of EPO in this study were similar to those reported previously in adults—better Hb response and a reduction in RBC transfusion occurred in the EPO group as compared with the placebo group, and adverse events were comparable between treatment groups.¹⁷ Changes in HRQOL scores were comparable between the EPO and placebo groups. A significant correlation was observed between improvement in Hb and improvement in HRQOL in the EPO group, but not in the placebo group. The correlations were not significantly different between treatment groups. These findings are similar to correlation analyses reported by Witzig et al¹⁷ among adult cancer patients.

The lack of a significant difference in HRQOL between treatment groups was not likely due to insensitivity of the PedsQL-GCS and PedsQL Cancer Module. Both are reliable, validated measures of HRQOL for children ranging from 2 years to 18 years of age.^12,13 Correlations between patient-reported scores and parent-reported scores were comparable with previously reported correlation values.¹³ The mean patient-reported PedsQL-GCS total scores before study treatment (69.7 in the EPO group and 69.0 in the placebo group) were also similar to the value of 68.9 previously reported for children receiving treatment for newly diagnosed cancers.¹³ Different versions of the PedsQL-GCS were used according to the age of the patient, and a significant difference favoring the EPO group was observed among the youngest patients, 5 years to 7 years of age, although this subset result must be interpreted with caution.

EPO was administered intravenously to gain acceptance for the use of placebo injections. Previous studies of 3-times per week dosing in children that permitted the use of either intravenous or subcutaneous administration^2-4 generally reported a lesser Hb response to EPO than studies that mandated subcutaneous dosing.^5-9 However, the overall change in Hb from baseline was significantly different between the EPO and placebo groups with intravenous administration in this study. Therefore, the lack of difference in HRQOL between the groups was probably not due to the route of administration.

The dose of EPO may also influence response. Nearly 60% of patients required a dose increase after 3 weeks to 4 weeks of treatment, and significant differences were observed between groups for several hematologic end points thereafter. A higher starting dose may be warranted in future studies of intravenous EPO therapy in pediatric populations.

Inadequate utilization of iron supplementation in this study may have impaired the response to EPO.¹⁸ Investigators used clinical judgment to identify patients with iron-deficiency anemia and exclude them from study, but patients with a low iron level could enroll if the investigator thought it did not contribute to the anemia. Although 19.6% of patients in the EPO group had transferrin saturation levels less than 20% during follow-up, only 7.2% received iron supplementation. Three prior pediatric studies required iron supplementation in all pediatric patients with subcutaneous administration of EPO⁵ or with either subcutaneous or intravenous administration of EPO,^3,4 and significantly greater hematologic response to EPO than control was reported in each study.

Finally, the Hb response rate of 34.9% and the mean Hb increase of 1.0 g/dL in the placebo group were inconsistent with hematologic outcomes with placebo administration in some previous studies of pediatric patients.^4,6 The relatively common use of RBC transfusion (> 75% of patients) in the placebo group was higher than in previous studies and may have influenced the outcomes. However, analyses that censored Hb and HRQOL values for 28 days after a blood transfusion resulted in similar changes to those observed when all values were included. In a posthoc analysis, patients in the placebo group were also less likely to receive high-intensity chemotherapy, potentially influencing Hb response.

In summary, intravenous administration of EPO increased Hb and reduced transfusion use relative to placebo, and EPO was tolerated well by anemic children with cancer receiving myelosuppressive chemotherapy, although clinically relevant thrombotic vascular events were reported more often in the EPO group than in the placebo group. However, the use of EPO did not result in a statistically significant effect on HRQOL scores compared with placebo. Importantly, increased Hb was correlated with increased HRQOL in the EPO group but not in the placebo group. Future studies that address some of the described issues present in this study, particularly those that influence Hb response to erythropoietic therapy (such as proper iron supplementation), might be more successful in demonstrating a positive effect of EPO on HRQOL in anemic children with cancer.

	Appendix

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The principal investigators for the study were as follows (listed alphabetically by surname): Anne Angiolillo, Washington, DC; Julie Blatt, Chapel Hill, NC; Emmett Broxson, Dayton, OH; Richard Drachtman, East Brunswick, NJ; Ronald Dubowy, Syracuse, NY; Abbas Emami, Kansas City, MO; James Feusner, Oakland, CA; Andrew Freiberg, Hershey, PA; Julia Glade Bender, New York, NY; Richard Gorlick, New York, NY; Jay Greenberg, Fairfax, VA; Marilyn Hockenberry, Houston, TX; Jeffrey D. Hord, Akron, OH; Sima Jeha, Houston, TX; Javier R. Kane, San Antonio, TX; Michael G. Levien, Cleveland, OH; Carole Paley, New Hyde Park, NY; Ramesh Patel, Long Beach, CA; John J. Quinn, Los Angeles, CA; Bassem I. Razzouk, Memphis, TN; Susan Rheingold, Philadelphia, PA; A. Kim Ritchey, Pittsburgh, PA; Philip M. Rosoff, Durham, NC; Kimo C. Stine, Little Rock, AR; Joel Weinthal, Dallas, TX; and James Whitlock, Nashville, TN.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Bassem I. Razzouk Ortho Biotech (B) Jeffrey D. Hord Ortho Biotech (B) Ortho Biotech (B) Marilyn Hockenberry Ortho Biotech (B) Pamela S. Hinds Ortho Biotech (B) James Feusner Ortho Biotech (A) Denise Williams Ortho Biotech (N/R); Johnson & Johnson Pharmaceutical Research & Development (N/R) Johnson & Johnson (B) Wayne R. Rackoff Johnson & Johnson (N/R) Johnson & Johnson (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner, Wayne R. Rackoff Financial support: Wayne R. Rackoff Provision of study materials or patients: Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner Collection and assembly of data: Bassem I. Razzouk, Marilyn Hockenberry, Pamela S. Hinds, Denise Williams, Wayne R. Rackoff Data analysis and interpretation: Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner, Denise Williams, Wayne R. Rackoff Manuscript writing: Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner, Denise Williams, Wayne R. Rackoff Final approval of manuscript: Bassem I. Razzouk, Jeffrey D. Hord, Marilyn Hockenberry, Pamela S. Hinds, James Feusner, Denise Williams, Wayne R. Rackoff

 

	ACKNOWLEDGMENTS

 
We acknowledge the principal investigators (online-only Appendix), the patients and their families who volunteered for this study, the people who care for these children, and Helen Varsos and her colleagues on the clinical team at Ortho Biotech Clinical Affairs LLC. Jonathan N. Latham provided editorial assistance on behalf of Ortho Biotech Clinical Affairs LLC.

	NOTES

 
Sponsored by Ortho Biotech Clinical Affairs LLC, Bridgewater, NJ; B.I.R. and P.S.H. supported in part by National Cancer Institute Cancer Center support Grant No. P30 CA 21765 and by the American Lebanese Syrian Associated Charities (ALSAC). This protocol is identified on the ClinicalTrials.gov Web site as NCT00261677.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004 (abstract 8527); the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004 (abstract 2218); and the 30th Annual Congress of the Oncology Nursing Society, Orlando, FL, April 28-May 1, 2005 (abstract 200).

B.I.R. and J.D.H. contributed equally to this article.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
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3. Porter JC, Leahey A, Polise K, et al: Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: A randomized, double-blind, placebo-controlled trial. J Pediatr 129:656-660, 1996[CrossRef][Medline]

4. Kronberger M, Fischmeister G, Poetschger U, et al: Reduction in transfusion requirements with early epoetin alfa treatment in pediatric patients with solid tumors: A case-control study. Pediatr Hematol Oncol 19:95-105, 2002[CrossRef][Medline]

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6. Varan A, Buyukpamukcu M, Kutluk T, et al: Recombinant human erythropoietin treatment for chemotherapy-related anemia in children. Pediatrics 103:E16, 1999

7. Csaki C, Ferencz T, Schuler D, et al: Recombinant human erythropoietin in the prevention of chemotherapy-induced anaemia in children with malignant solid tumours. Eur J Cancer 34:364-367, 1998[CrossRef][Medline]

8. Buyukpamukcu M, Varan A, Kutluk T, et al: Is epoetin alfa a treatment option for chemotherapy-related anemia in children? Med Pediatr Oncol 39:455-458, 2002[CrossRef][Medline]

9. Yilmaz D, Cetingul N, Kantar M, et al: A single institutional experience: Is epoetin alpha effective in anemic children with cancer? Pediatr Hematol Oncol 21:1-8, 2004[CrossRef][Medline]

10. Beck MN, Beck D: Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer. Med Pediatr Oncol 25:17-21, 1995[Medline]

11. Henze G, Michon J, Morland B, et al: Phase III randomized study: Efficacy of epoetin alfa in reducing blood transfusions in newly diagnosed pediatric cancer patients receiving chemotherapy. Proc Am Soc Clin Oncol 21:387a, 2002 (abstr 1547)

12. Varni JW, Seid M, Kurtin PS: PedsQL 4.0: Reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 39:800-812, 2001[CrossRef][Medline]

13. Varni JW, Burwinkle TM, Katz ER, et al: The PedsQL in pediatric cancer: Reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer 94:2090-2106, 2002[CrossRef][Medline]

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15. Cohen J: Statistical Power Analysis for the Behavioral Sciences. New York, NY, Academic Press, 1988

16. Anderson TW: An Introduction to Multivariate Statistical Analysis (ed 3). Hoboken, NJ, Wiley, 2003

17. Witzig TE, Silberstein PT, Loprinzi CL, et al: Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 23:2606-2617, 2005[Abstract/Free Full Text]

18. Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 22:1301-1307, 2004[Abstract/Free Full Text]

Submitted July 28, 2005; accepted June 12, 2006.

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