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Osteonecrosis in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

Nina S. Kadan-Lottick, Irina Dinu, Karen Wasilewski-Masker, Sue Kaste, Lillian R. Meacham, Anita Mahajan, Marilyn Stovall, Yutaka Yasui, Leslie L. Robison, Charles A. Sklar

From the Section of Pediatric Hematology-Oncology, Yale University School of Medicine, New Haven, CT; Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta; Emory Children's Center, Atlanta, GA; Department of Epidemiology and Cancer Control and Division of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; and Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada

Corresponding author: Nina S. Kadan-Lottick, MD, Yale University School of Medicine, 333 Cedar St, LMP 2073, PO Box 208064, New Haven, CT 06520; e-mail: Nina.Kadan-Lottick{at}Yale.Edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Osteonecrosis (ON) is a potentially serious complication of therapy in survivors of childhood cancer. Our goals were to describe the incidence of ON and identify patient and treatment characteristics associated with elevated risk.

Patients and Methods The rate of self-reported ON was determined for 9,261 patients enrolled onto the Childhood Cancer Survivor Study, a cohort of 5-year survivors of childhood cancer diagnosed from 1970 to 1986, and compared with the rate in a random sample of 2,872 siblings of survivors. Survivors with positive responses were reinterviewed to confirm the diagnosis.

Results Fifty-two cancer survivors reported ON in 78 joints, yielding 20-year cumulative incidence of 0.43% and a rate ratio (RR) of 6.2 (95% CI, 2.3 to 17.2) compared with siblings, adjusted for age and sex; 44% developed ON in a previous radiation field. The RR was greatest among survivors of stem-cell transplantation for acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (RR = 26.9, 66.5, and 93.1, respectively). Nontransplantation patients with ALL (RR = 6.5; 95% CI, 2.2 to 19.4), AML (RR = 11.2; 95% CI, 2.1 to 61.2), and bone sarcoma (RR = 7.3; 95% CI, 2.0 to 26.2) were at higher risk for ON. Older age at diagnosis, shorter elapsed time, older treatment era, exposure to dexamethasone (± prednisone), and gonadal and nongonadal radiation were independently associated with ON.

Conclusion ON among long-term survivors of childhood cancer is rare. However, compared with siblings, childhood cancer survivors have a significantly increased relative rate of ON, particularly those who were older at diagnosis and who received dexamethasone or radiation therapy. Future studies are needed to better delineate our findings, particularly the increased risk after gonadal radiation.

	INTRODUCTION

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Currently, approximately 80% of children with cancer will be cured and become long-term survivors.¹ Osteonecrosis (ON) is an extremely rare disorder in the general population that can be a devastating outcome of therapy in children with cancer. The pathophysiology has not been well elucidated, but the end result is necrosis of one or more bone sites, usually at weight-bearing joints.² Other terms for ON include avascular necrosis and aseptic ON. Patients experience a spectrum of symptoms that range from mild discomfort to decreased mobility, severe pain at rest, joint swelling, and articular collapse.³ Some young childhood cancer survivors require surgical joint decompression or replacement.

Previously identified risk factors for ON include glucocorticoid therapy, radiation, and adolescent age at cancer diagnosis.^4-8 Early case series recognized an association between radiation of the femoral head or jaw and ON.⁹ However, ON has predominantly been studied and reported in patients exposed to substantial doses of glucocorticoids, often concurrently with other therapies. These studies include mainly children with acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, and history of stem-cell transplantation. There is a paucity of data on the risk of ON in patients with nonhematologic conditions and the independent contribution of other patients and treatment factors.

The published incidence of ON varies widely in children with cancer^3-5,10-14 and even among studies restricted to patients with ALL. Mattano et al⁴ reported that 9.3% of 1,409 children with high-risk ALL treated between 1989 and 1995 developed ON within 3 years. In contrast, Arico et al¹³ found the 5-year cumulative incidence to be 1.6% in ALL patients treated with intensive chemotherapy between 1995 and 1999 based on a chart review for symptoms suggestive of ON. The different findings may be a result of differences in the cumulative dosages of glucocorticoids and/or differences in the types of glucocorticoids (ie, dexamethasone v prednisone).¹⁰ The toxicity burden of dexamethasone is important to elucidate because of the increased use of dexamethasone in current therapeutic regimens for hematologic malignancies based on promising data from recent clinical trials.^15,16

Past studies of ON, although provocative, generally have included small patient samples, have focused on one cancer diagnosis, or were based on single-institution experiences. The Childhood Cancer Survivor Study (CCSS) is a 26-site retrospective cohort study of 14,363 childhood cancer survivors, with a wide distribution of cancer diagnoses and treatment exposures. Because of the availability of detailed, high-quality data on chemotherapy and radiation treatment exposure for participants, the CCSS cohort provides a unique sample to further study ON. In this study, we seek to describe the overall incidence of ON among a diverse group of cancer survivors and to identify patient and treatment factors associated with an elevated risk of ON.

	PATIENTS AND METHODS

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Patients
The CCSS is a multisite, retrospectively ascertained cohort with prospective follow-up designed to study the late effects of childhood cancer therapy. Inclusion criteria include diagnosis of leukemia, CNS malignancy, Hodgkin's disease, non-Hodgkin's lymphoma, malignant kidney tumor, neuroblastoma, soft tissue sarcoma, or bone tumor; diagnosis and initial treatment at one of the 26 collaborating centers between January 1, 1970 and December 31, 1986; age younger than 21 years at diagnosis; and alive 5 years from the date of diagnosis.

Beginning in August 1994, participants completed an extensive baseline questionnaire about their demographic, medical, and psychosocial status. Three subsequent follow-up surveys have been administered thus far to obtain updated information. For participants who returned a signed medical release, data were abstracted from the medical record regarding their initial cancer treatment, treatment for any relapse, and preparatory regimens for bone marrow transplantation. Data regarding exposure to 42 chemotherapeutic agents were abstracted from the medical record; cumulative doses were abstracted for 22 of these agents. Cumulative data for glucocorticoids were not available, and glucocorticoid history for nononcologic conditions was not abstracted. Data were also obtained on the site of the tumor and on fields and doses of radiation therapy. The study design and cohort characteristics have been described previously,¹⁷ and further details, together with the study documents, are available at http://www.stjude.org/ccss. All CCSS protocol and contact documents were reviewed and approved by the human subjects committee at each participating institution.

Of the 20,691 patients eligible for participation, 17,633 were successfully located, and 14,363 (81.5%) completed the baseline questionnaire. Of the 14,363 initial participants, 9,261 completed the second follow-up questionnaire, which included questions relating to the occurrence of ON. A random sample of participating survivors (n = 6,005) was asked to contact their sibling closest in age for participation in the study; 3,839 siblings completed the baseline questionnaire, and 2,872 siblings completed the second follow-up questionnaire, including the questions regarding ON.

Assessment of ON
Participants were asked if they were ever diagnosed with ON or "avascular necrosis... a condition in which blood supply to the bone or joints becomes interrupted, causing that part of the bone to die," the date of diagnosis, and what treatment, if any, they received. Survivors who reported a history of ON were administered a brief additional survey by telephone clarifying the exact location(s) of the joints affected, how the diagnosis was made, and the presence of current symptoms and limitations related to the ON. Questions regarding the symptom burden of ON were derived from the Functional Study Index instrument.¹⁸

Data Analysis
Body mass index was calculated as weight (kg)/height (m)² as described by the Centers for Disease Control and Prevention, with a body mass index 25 corresponding to overweight status. Because hormone levels were not available, threshold radiation doses were used as surrogates, consistent with previous studies. Radiation 24 Gy to the hypothalamic- pituitary region was used to categorize patients at high risk for low growth hormone production.^19-21 Radiation of 10 Gy²² to the ovary and 20 Gy to the testes²³ was used to define hypogonadism in females (ie, ovarian failure) and males (ie, Leydig cell insufficiency), respectively.

The distribution of the reported sites of ON among patients and their symptoms was described, including the prevalence of pain and limitations of ambulation. Survivors with and without ON were compared in terms of various individual and treatment characteristics using the t test for continuous variables or Fisher's exact test for categoric variables. The cumulative incidence of ON was calculated for survivors and siblings separately and by age at diagnosis among survivors. Patients who did not have ON and died before the second follow-up (1%) were censored. The relative rates of ON in childhood cancer survivors, overall and by cancer diagnosis, were calculated relative to the siblings using Poisson regression adjusting for age and sex.

Among survivors, Poisson regression was used to assess the association of patient and treatment factors with ON rates. We initially performed an unadjusted analysis for each of the patient and treatment factors of interest, followed by a multiple Poisson regression including factors that were marginally significant in the unadjusted analysis (P < .2). We tested a priori hypothesized interactions between age at diagnosis and sex, age at diagnosis and glucocorticoid exposure, and age at diagnosis and gonadal radiation. All statistical analyses were conducted using SAS Version 9.1 (SAS Institute, Cary, NC) and R 2.4.1 (http://www.R-project.org).

	RESULTS

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Description of ON Among Survivors
Overall, within the cohort, 69 individuals reported a history of ON; 58 successfully completed the additional clarification survey, resulting in 52 confirmed diagnoses of ON. A survivor was classified as having ON only if the additional telephone survey yielded confirmatory information. Survivors with ON were more likely to be older at cancer diagnosis and have a history of allogeneic stem-cell transplantation and exposure to both chemotherapy and radiation (Table 1).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative incidence of osteonecrosis among survivors and a sibling comparison group starting 5 years after diagnosis. The x-axis for a sibling represents elapsed years since the diagnosis date of his/her corresponding survivor.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Cumulative incidence of osteonecrosis among all survivors stratified by age at diagnosis.

Older age at diagnosis, glucocorticoid therapy, gonadal radiation, and shorter elapsed time since diagnosis remained independently associated with ON in multivariate analysis after adjusting for sex and treatment era. Dexamethasone therapy, with or without prednisone, conferred a higher RR of ON than prednisone alone (2.7; 95% CI, 1.2 to 6.4 v 1.5; 95% CI, 0.5 to 4.3). In testing for possible interactions, the association between age at diagnosis and rate of ON did not vary according to glucocorticoid exposure, sex, or gonadal radiation. Similarly, the association between glucocorticoid exposure and ON did not vary with sex.

	DISCUSSION

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In this large, multisite, retrospective cohort study, childhood cancer survivors were 6.2 times as likely as a sibling comparison group to report the diagnosis of ON. This corresponds to an overall cumulative incidence of 0.43% at 20 years from diagnosis and a 2.8% cumulative incidence for patients 16 years and older. Patients experienced considerable morbidity from their ON, with 57% having at least one limitation among activities of daily living. To our knowledge, this is the largest study to date to examine the risk of ON among long-term survivors of childhood cancer. Because of our large sample size and the distribution of different treatment and patient characteristics, we could examine the role of contributing factors more broadly. We found that children with a history of leukemia, lymphoma, and sarcoma are at the highest risk of developing ON. We confirmed that a history of stem-cell transplantation, radiation exposure, and glucocorticoid therapy and adolescent age at diagnosis are major risk factors for the development of ON. Furthermore, we determined that the type of glucocorticoid formulation is a determinant of risk; patients receiving dexamethasone were approximately 30% more likely to develop ON than patients who received prednisone alone. After adjusting for glucocorticoid history and age, we identified gonadal radiation as a potential independent risk factor in both males and females. Moreover, with the benefit of extended follow-up, we found that the cumulative incidence increases with time for years after treatment. Previous studies have described ON to be an acute effect of therapy and generally not reported after more than the first few years from exposure.^3,12,24

The cause of the markedly elevated relative rate of ON among recipients of allogeneic stem-cell transplantation has been specifically correlated with long-term glucocorticoid therapy, which is used to treat chronic graft-versus-host disease (GVHD). In a case-control study of 43 children after allogeneic transplantation, Faraci et al²⁵ found that both TBI and GVHD were independently associated with ON in multivariate analysis. In a retrospective analysis by Socié et al⁸ of 4,388 patients who had undergone an allogeneic bone marrow transplantation, ON was associated with GVHD but not radiation. Later, Socié et al²⁶ confirmed these findings in 316 patients with chronic myeloid leukemia and 172 patients AML who had been randomly assigned to either cyclophosphamide (CY) and TBI or busulfan and CY. In multivariate analysis, the relative risk of ON was increased among patients with chronic GVHD and not CY/TBI. These latter data suggest that glucocorticoid therapy is a more important determinant of ON than radiation exposure among transplantation patients.

Although hypogonadism and ON are both possible treatment-related complications after cancer, to the best of our knowledge, hypogonadism has not been previously reported as a risk factor for ON. Our observation that gonadal radiation is an independent risk factor for ON has at least two potential explanations. First, it is possible that the ON is a direct result of radiation-induced damage to a bone/joint within the radiation field (eg, the hip).^27,28 Alternatively, this could be an indirect effect of radiation-induced gonadal damage and insufficient production of sex steroids. This latter explanation is supported by the increased RR of ON associated with alkylator therapy, another gonadotoxic therapy, in unadjusted analysis. We know that both estrogen and testosterone deficiencies are associated with reduced bone density.^29,30 We hypothesize that reduced gonadal sex steroids could also affect the risk of ON by a similar or separate mechanism(s). This finding will need to be verified in future studies that include hormonal measurements.

The majority of past studies included only patients with ALL. Overall estimates for the incidence of ON have ranged from approximately 1%^3,31 to 9%,⁴ when based on clinical presentation, to approximately 15%, when based on magnetic resonance imaging (MRI) screening.⁷ Caution should be used when comparing our risk estimates based on patients treated from 1970 to 1986 to more recently treated patients. Because our study relied on self-report, as opposed to the medical record or MRI screening, we may have underestimated the incidence of ON. However, our rate may be a reasonable reflection of the true burden of disease, rather than acute toxicity, because the major morbidities resulting from ON are unrelieved discomfort and decreased ambulatory mobility. These are symptoms that are amenable to self-report.^18,32 Karimova et al³³ have found that only larger lesions occupying more than 30% of the femoral head volume were associated with joint collapse or need for arthroplasty, suggesting that not all lesions detected by MRI are clinically significant. Furthermore, one would expect any underestimation to be the same across treatment exposures and diagnoses.

Previous investigators have been concerned about possible additional toxicity of dexamethasone on joints compared with prednisone based on clinical trials with different glucocorticoid schedules. Mattano et al⁴ noted a higher rate of ON in patients who received higher doses of dexamethasone (23% v 16% in patients who received lower doses) in the delayed intensification phase for high-risk ALL, but the results were not statistically significant. Later, Mattano et al¹⁰ observed lower rates of ON in patients who received discontinuous dexamethasone (10 mg/m²/d on days 0 through 6 and days 14 through 20) versus higher dose continuous dexamethasone (10 mg/m²/d on days 0 through 20). These previous studies, as well as ours, support that dexamethasone is associated with a greater relative risk of ON compared with prednisone.

Our analysis concludes that older age at cancer diagnosis is associated with a higher RR of ON in an incremental fashion. This age association has been noted by others.^4,6-8,34 Unlike Mattano et al⁴ and Arico et al,¹³ females in our large cohort did not have a higher rate of ON, even in analyses restricted to patients with ALL and in the adolescent age range. This may be because our method of ascertainment was patient self-report, rather than prospective physician assessment. However, other investigators have similarly concluded that sex is not an important contributing factor.^6,35 In past reports, white race^4,7 and high body mass index³⁶ were independent risk factors for ON, none of which were significant in our study.

Several limitations of our study need to be kept in mind. The study design was retrospective, not prospective. Although patients in our cohort generally received the same types of chemotherapeutic agents that are currently used, some of the treatments may not be applicable to the experience of children treated with more modern regimens. The schedule and exact dosage information for the glucocorticoids were not available for our analysis. Specifically, it is not known whether survivors received glucocorticoids for nononcologic diagnoses. In addition, the power for detecting factors that modified the rate of ON was limited as a result of the relatively small number of events, despite the large total number of survivors in the CCSS.

From this large, multisite, cohort study, we conclude that ON occurs in childhood cancer survivors at much higher rates than one would expect in a healthy population. Our results further highlight the considerable discomfort and impaired mobility experienced by individuals with ON. Therefore, medical providers caring for cancer survivors should question their patients about pain and mobility problems in joints and monitor for progression and disability. Focused screening is especially important in stem-cell transplantation recipients and patients who were older at diagnosis. Radiation therapy and glucocorticoids, particularly dexamethasone, confer greater risk. Furthermore, our data suggest that patients who received gonadotoxic therapies may also be at high risk of ON; future studies will be required to confirm this latter observation.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Nina S. Kadan-Lottick, Yutaka Yasui, Leslie L. Robison, Charles A. Sklar

Financial support: Leslie L. Robison

Administrative support: Leslie L. Robison

Provision of study materials or patients: Lillian R. Meacham, Marilyn Stovall, Leslie L. Robison

Collection and assembly of data: Nina S. Kadan-Lottick, Leslie L. Robison, Charles A. Sklar

Data analysis and interpretation: Nina S. Kadan-Lottick, Irina Dinu, Sue Kaste, Anita Mahajan, Marilyn Stovall, Yutaka Yasui, Leslie L. Robison, Charles A. Sklar

Manuscript writing: Nina S. Kadan-Lottick, Irina Dinu, Karen Wasilewski-Masker, Sue Kaste, Lillian R. Meacham, Anita Mahajan, Marilyn Stovall, Yutaka Yasui, Leslie L. Robison, Charles A. Sklar

Final approval of manuscript: Nina S. Kadan-Lottick, Irina Dinu, Karen Wasilewski-Masker, Sue Kaste, Lillian R. Meacham, Anita Mahajan, Marilyn Stovall, Yutaka Yasui, Leslie L. Robison, Charles A. Sklar

	Appendix

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The Childhood Cancer Survivor Study (CCSS) is a collaborative, multi-institutional project, funded as a resource by the National Cancer Institute (NCI), of individuals who survived 5 or more years after diagnosis of childhood cancer.

CCSS is a retrospectively ascertained cohort of 20,346 childhood cancer survivors diagnosed before age 21 between 1970 and 1986 and approximately 4,000 siblings of survivors, who serve as a control group. The cohort was assembled through the efforts of 26 participating clinical research centers in the United States and Canada. The study is currently funded by a U24 resource grant (NCI Grant No. U24 CA55727) awarded to St. Jude Children's Research Hospital. Currently, we are in the process of expanding the cohort to include an additional 14,000 childhood cancer survivors diagnosed before age 21 between 1987 and 1999. For information on how to access and use the CCSS resource, visit www.stjude.org/ccss.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Cumulative incidence of osteonecrosis among acute lymphoblastic leukemia patients stratified by age at diagnosis.

	NOTES

 
Supported by Grant No. U24-CA-55727 (L.L.R., Principal Investigator) from the Department of Health and Human Services, funding to the University of Minnesota from the Children's Cancer Research Fund, and funding to St. Jude Children's Research Hospital from the American Lebanese Syrian Associated Charities. This publication was made possible by Clinical and Translational Science Award Grant No. Number KL2 RR024138 from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of National Center for Research Resources or National Institutes of Health (NIH). Information on Re-engineering the Clinical Research Enterprise can be obtained from the NIH website: http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.

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

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Submitted October 15, 2007; accepted March 17, 2008.

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