Dexrazoxane-Associated Risk for Acute Myeloid Leukemia/Myelodysplastic Syndrome and Other Secondary Malignancies in Pediatric Hodgkin's Disease

  1. Cindy L. Schwartz
  1. From the Children's Oncology Group, Statistics and Data Center, Arcadia, CA; Tampa Children's Hospital, Tampa; Children's Oncology Group, Statistics and Data Center, University of Florida, Gainesville, FL; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; St Jude Children's Research Hospital, Memphis, TN; University of Rochester Medical Center, Rochester, NY; Children's Hospital, Los Angeles, CA; and Brown Medical School, Providence, RI
  1. Address reprint requests to Cindy L. Schwartz, MD, Brown Medical School, RIH/Hasbro Children's Hospital, Multiphasic Building 117, 593 Eddy St, Providence, RI 02903; e-mail: cindy_schwartz{at}brown.edu, cc: pubs{at}childrensoncologygroup.org
 
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Abstract

Purpose Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs).

Patients and Methods Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low-dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ (n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes.

Results Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors (osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% ± 1.0% with DRZ versus 0.85% ± 0.6% in the non-DRZ group (P = .160). For any SMN, the CIR for DRZ was 3.43% ± 1.2% versus CIR for non-DRZ of 0.85% ± 0.6% (P = .060). Among patients receiving DRZ, the standardized incidence rate (SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ (P = .0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ (P = .0231).

Conclusion DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.

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INTRODUCTION

Cure of Hodgkin's disease (HD) has been achieved in more than 90% of afflicted children and adolescents,1,2 but at the expense of potentially significant long-term toxicity.3 Alkylating agents, anthracyclines, and radiation share the etiologic spotlight for late toxicities that limit long-term survival and reduce quality of life. High-dose radiotherapy increases the risk of second malignant neoplasms (SMNs). The regimen of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) is associated with alkylating-agent–associated secondary leukemia and infertility.4-10 Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) virtually eliminates these risks,4,6,11 but it adds its own set of long-term toxicities,11-13 particularly cardiopulmonary. Since children are at a particularly high risk of such complications, reduction of toxicity by limiting exposure to radiotherapy and chemotherapy has been a major focus of efforts to improve pediatric and adolescent HD therapies.

Pediatric Oncology Group (POG) 9426 and 9425 were designed for the treatment of newly diagnosed low- and advanced-stage HD, respectively.14,15 The doxorubicin, bleomycin, vincristine, and etoposide (ABVE) was developed by modification of ABVD, using etoposide to replace dacarbazine and vincristine to replace vinblastine in an effort to provide greater dose-intensity.15 For advanced-stage HD disease, ABVE was intensified by adding prednisone and cyclophosphamide (POG 9425) and administering therapy every 3 weeks.14 Based on POG 8725 demonstrating that early therapeutic response predicted an improved outcome,16 POG 9425 and 9426 limited cumulative chemotherapy cycles for early responders to reduce the potential for long-term toxicities. Recognizing that slow responders were at risk of late adverse cardiopulmonary outcomes, patients were randomly assigned between receiving and not receiving dexrazoxane (DRZ) to evaluate its efficacy as a cardiopulmonary protectant.

DRZ is a chelating agent that limits formation of anthracycline-iron complexes believed to generate myocyte-damaging free radicals. DRZ reduces cardiac toxicity in adults treated with anthracyclines17,18 and in children with sarcoma.19 Free radicals induced by the bleomycin-Fe+3 complex are thought similarly to cause bleomycin-induced pulmonary fibrosis. DRZ reduced pulmonary fibrosis in bleomycin-treated mice.20 These data led to the primary hypotheses of POG 9425 and 9426 that DRZ in the context of ABVE or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC) might reduce risk of cardiopulmonary toxicity, overcoming the major long-term toxicity of ABVD-like regimens. While these end points require longer-term follow-up, we report on an early unexpected adverse outcome—an increased SMN risk in patients assigned to receive DRZ.

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PATIENTS AND METHODS

Patients

Patients 21 years or younger with HD were eligible for these studies at POG institutions. Informed consent was obtained according to institutional review board standards. Eligibility criteria for POG 9426 included stage I, II, or III 1A without bulk (peripheral nodal tissue > 6 cm or ratio of mass/thoracic diameter [M/T ratio] > 0.33). Lymphocyte-predominant HD was excluded from POG 9426 during the early years of the study. During the final year of accrual, all Children's Oncology Group institutions were permitted to enroll in POG 9426. Eligibility for POG 9425 included stages IIA (with bulk), IB, IIB, III (except III1A without bulk), and IV. From October 2000 through completion in March 2001, POG 9425 enrollment was restricted to disease stages IIB, IIIB, or IV.

Therapy

Patients received two ABVE cycles (POG 9426) or three ABVE-PC cycles (POG 9425) before early response evaluation (8 to 9 weeks from therapy initiation; Fig 1). Early responders (≥ 50% two-dimensional reduction in tumor size, M/T ratio < 0.33, and negative gallium scan) proceeded to radiation therapy of 25.5 Gy to involved fields (POG 9426) or 21 Gy to regional fields (POG 9425). Two additional chemotherapy cycles were given to slow responders before radiation. Granulocyte colony-stimulating factor 5 μg/kg/d was used to maintain dose intensity. Patients were randomly assigned to receive or not receive DRZ (300 mg/m2 intravenously) on any day that doxorubicin or bleomycin was administered. Since the DRZ half-life is 10 to 21 minutes with a terminal elimination of 2 to 3 hours, etoposide and DRZ were separated by 3 hours to minimize direct interactions.

Fig 1.
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Fig 1.

Treatment of Hodgkin's disease: Pediatric Oncology Group (POG) 9426 and 9425. RT, radiation therapy; ABVE, doxorubicin, bleomycin, vincristine, and etoposide; ABVE-PC, dose-intensified ABVE with prednisone and cyclophosphamide; DRZ, dexrazoxane; G-CSF, granulocyte colony-stimulating factor; CYC, cyclophosphamide.

Statistical Methods

Analyses were performed for the baseline comparability of the randomly assigned treatment groups. For categoric variables sex, race, and stage, the treatment groups were compared using a two-sided Fisher's exact test. For continuous variables age and follow-up time, a t test was used to compare groups.

Cumulative incidence rates were calculated considering competing relapses and deaths. These rates are expressed as rate ± SE. The time to an event was calculated from date of enrollment until first occurrence of relapse, progressive disease, SMN, death, or until last contact if no event occurred. SMN was calculated from the enrollment date until the date of SMN or last contact if no SMN was reported. Treatment comparisons of Cumulative incidence rates were made using a modified χ2 test, with P values of less than .05 considered statistically significant.21

Standardized incidence ratios (SIRs) of observed to expected malignancies were calculated using race-, age-, and sex-specific incidence rates of the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (Bethesda, MD).22 For the secondary analysis of SMN as a first event, patients were considered at risk of SMN from enrollment date until first occurrence of a relapse, progressive disease, SMN, death, or until last contact if no event occurred.23 For a given diagnosis (either acute myeloid leukemia [AML] and myelodyspastic syndrome [MDS], papillary carcinoma, or osteosarcoma), the incidence of SMN was standardized by comparison to the incidence of those diagnoses in the general population (Appendix, online only). Otherwise, the SIRs were calculated by standardizing in comparison to the incidence of any malignant diagnosis. Treatment comparisons of SIRs were made using a log-linear model (Poisson regression model with a log-link function), and P values of less than .05 were considered statistically significant.24

Excess absolute risk was calculated as an additional indicator of the impact of cancer diagnosis and therapy on the cohort compared with the general population. Excess absolute risk, expressed per 1,000 person-years, was determined by subtracting the number of SMN expected from the number of SMN observed, dividing the difference by person-years of follow-up and multiplying that number by 1,000.

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RESULTS

Patients

From October 1996 through September 2000, POG 9426 enrolled 294 patients, with 262 eligible. From March 1997 through February 2001, POG 9425 enrolled 219 patients, with 216 eligible. Table 1 presents clinical characteristics of patients by enrollment and DRZ assignment.

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Table 1.

Demographics of Patients Treated on POG Protocols 9426 and 9425 by ± DRZ

Analyses of baseline comparability found no differences between DRZ-positive and DRZ-negative groups in terms of sex (P = .9253), race (P = .1652), stage at diagnosis (P = .9233), age (P = .2710), or follow-up time (P = .3299). In addition, there was no statistically significant difference in proportion with early response (P = .2466) or event-free survival rates (P = .4128) between DRZ groups.

Secondary AML/MDS

Five patients developed AML, and three developed MDS on POG 9425 and 9426 (Table 2), with a median time to AML/MDS of 26 months (range, 12 to 48 months). Cytogenetic abnormalities were known in six of the patients. These involved chromosome 16 (inv16, t[16;18] and t[16;21]), t(10;17) t(9;11), trisomy 8, and monosomy 7 (Table 2). With a median follow-up of 58 months, the 4-year cumulative incidence rate of AML/MDS was 2.55% ± 1.0% with DRZ versus 0.85% ± 0.6% without DRZ (P = .160) (Table 3).

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Table 2.

SMN After Treatment for Hodgkin's Disease

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Table 3.

Occurrence of SMNs by Treatment Group

In comparison to the general population, there was an elevated risk for AML/MDS in this study population (SIR of 406.89; 95% CI, 175.67 to 801.73; Table 4). Moreover, the risk of AML/MDS was higher among those treated with DRZ (SIR = 613.6; 95% CI, 225.2 to 1,335.6) as compared with those not treated with DRZ (SIR = 202.37; 95% CI, 24.5 to 731.0; P = .0990; Table 3).

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Table 4.

Observed and Expected Rates of SMN

All Secondary Malignant Neoplasms

In addition to the eight patients with AML/MDS, there were two solid tumors reported: papillary thyroid carcinoma occurring within the radiation field (35.4 months postdiagnosis) and an osteosarcoma occurring outside the radiation field (38.9 months postdiagnosis). Overall, there were eight with SMN (six with AML/MDS and two with solid tumors) with DRZ, compared with two (one with AML and one with MDS) without DRZ. With median follow-up of 58 months, the 4-year cumulative incidence rate of any SMN was 3.43% ± 1.2% with DRZ versus 0.85% ± 0.6% without DRZ (P = .060; Table 3; Fig 2A).

Fig 2.
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Fig 2.

(A) Cumulative incidence rates (CIR) for all second malignant neoplasms (SMNs) by treatment group: dexrazoxane (DRZ; n = 239) v non-DRZ (n = 239; P = .060). (B) CIR for all events within DRZ patients (n = 239). (C) CIR for all events within non-DRZ patients (n = 239). The one with SMN was myelodysplastic syndrome (MDS), so the acute myeloid leukemia (AMS)/MDS curve is equivalent to the SMN curve displayed.

Figures 2B and 2C show cumulative incidence rates of events within the treatment group (DRZ and non-DRZ, respectively). In Figure 2B (DRZ), the six with AML/MDS are plotted in a separate curve as well as included in the curve for the eight total SMNs. For Figure 2C, the two SMNs in the non-DRZ group were AML and MDS, so the AML/MDS curve is equivalent to the SMN curve displayed.

Observed and expected numbers of all subsequent malignancies are shown (Table 4). There were elevated risks for all three types of SMN reported in this cohort, with an SIR of 406.89 (95% CI, 175.7 to 801.7) for AML/MDS, 30.37 (95% CI, 0.77 to 169.18) for papillary carcinoma, 63.70 (95% CI, 1.61 to 354.90) for osteosarcoma, and 20.55 (95% CI, 8.87 to 40.49) for the occurrence of any type of malignancy. Among DRZ patients, the SIR for any SMN was 41.86 × that of the general population and statistically significantly higher than the SIR of 10.08 in the non-DRZ group, after age, sex, and race standardization (95% CI, 18.07 to 82.48 and 1.22 to 36.44, respectively; P = .0231; Table 3).

Overall, the excess absolute risk was 4.79 excess malignancies per 1,000 person-years of patient follow-up. The excess absolute risk was the highest for AML/MDS (3.83 excess absolute risk for AML/MDS, 0.46 excess absolute risk for papillary thyroid cancer, and 0.47 excess absolute risk for osteosarcoma per 1,000 person-years of patient follow-up).

Analysis of AML/MDS and SMN As First Events

A secondary analysis of the six with AML/MDS that occurred as a first event (excluding the two with AML/MDS that occurred after relapse and salvage therapy) was performed. This analysis was performed because the two patients with AML/MDS occurring after HD recurrence had received additional therapies (eg, five cycles of MOPP) before the diagnosis of AML/MDS. The 4-year cumulative incidence of AML/MDS as a first event was 2.10% ± 0.9% with DRZ (n = 239) versus 0.42% ± 0.4% without DRZ (n = 239; P = .1052; Table 3).

A secondary analysis of the eight with SMNs occurring as a first event (excluding two with SMN occurring after relapse and salvage therapy) was performed. The 4-year cumulative incidence of SMN as a first event was 2.98% ± 1.1% with DRZ (n = 239) versus 0.42% ± 0.4% without DRZ (n = 239), P = .0355 (Table 3).

Association With Cumulative Chemotherapeutic Exposures

Of the eight with SMN who received DRZ, five were slow responders and three were rapid responders to chemotherapy. Slow responders received more chemotherapy cycles, resulting in higher cumulative-dose doxorubicin, etoposide, and bleomycin. Slow reponders on POG 9425 also received more cyclophosphamide. Therefore, we analyzed the risk of SMN conferred by the number of chemotherapy cycles. In a test for association between exposure to these agents and risk of SMN, although with limited statistical power because of the small number of SMN in each group, the number of cycles was not statistically significantly predictive of SMN (P = .4910). Similarly, the cyclophosphamide did not appear to confer increased risk as there were four SMN in POG 9425 (included cyclophosphamide) and four SMN on POG 9426 (no cyclophosphamide).

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DISCUSSION

Recent studies have shown that long-term toxic effects of therapy significantly impact outcome. Twenty years from diagnosis, mortality related to cardiac effects, SMN, and other late toxicities is nearly as great as the likelihood of having died of the disease itself.3 Clinical trials in HD must therefore aim to minimize long-term toxicity as much as they strive to increase therapeutic efficacy. POG 9425 and 9426 represented a new paradigm, focused primarily on reduction of long-term toxicity by (1) enhancing early response by intensified drug delivery in the context of a response-based therapeutic intervention, thus maximizing the number of patients who receive minimal therapy, and by (2) using DRZ to minimize cardiopulmonary toxicity of a doxorubicin/bleomycin-based regimen.

Second malignancies after Hodgkin's disease are well-recognized. Leukemia has been associated with alkylating-agent exposure, with mechlorethamine the most leukemogenic agent.25-29 Strategies to decrease risk include substitution of cyclophosphamide for mechlorethamine in MOPP,28 or use of ABVD, a regimen with less than 1% risk of secondary leukemia.4 ABVE and ABVE-PC have no or minimal alkylating agents to avoid risks of sterility and secondary leukemia. Low-dose radiotherapy decreases the risk of second solid tumors reported in HD survivors as compared to higher-dose radiotherapy.30-37 Protection from cardiopulmonary effects with DRZ would mitigate the most significant remaining long-term adverse consequence of HD therapy.

Although etoposide has significant activity in HD,1 secondary myeloid leukemia is a recognized risk. Translocations occur at the 11q23 locus,38-45 which are attributed to inhibition of DNA repair by a catalytic complex formed by etoposide with topoisomerase II. Duration of drug administration (thus duration of DNA repair inhibition) and cumulative dose have been implicated in the evolution of AML, but differing schedules for etoposide administration make risk assessments difficult.42 Nonetheless, the low doses of etoposide in HD regimens have not been associated with a high secondary leukemia risk. No SMNs occurred in 61 patients treated with ABVE (etoposide 2.5 g/m2) on pilot study POG 922646 nor were any SMN attributable to etoposide reported in the 452 boys given OEPA (vincristine, etoposide at 1 g/m2, prednisone, and doxorubicin) on GPOH-HD 95.1 Landman-Parker et al47 reported a 0.9% cumulative incidence of secondary AML in 202 low-stage patients treated with 2 g/m2 of etoposide47 (one patient with French-American-British M5 AML had an 11q23 translocation attributable to etoposide; another with M2 AML without cytogenetic abnormality had received procarbazine). The cumulative incidence of secondary AML/MDS on our non-DRZ arm was similar to that reported for chemotherapy regimens including etoposide.40-42 One AML (after an alkylating-agent–based treatment of recurrent HD) was reported on POG 9426 and one MDS on POG 9425.

These studies were not designed specifically for comparison of SMN between the DRZ treatment arms. We have evaluated these events in two ways. First, we drew a conventional comparison of SMN in all enrolled patients including those who recurred and received additional therapies. Second, we evaluated SMN/MDS as first events. Although we recognize that the analysis of first events is not conventional, two things occur at relapse that interfere with our ability to understand the impact of the protocol therapy itself: (1) other potentially mutagenic therapies are administered, and (2) the reporting of clinical outcomes becomes more limited when patients are removed from protocol therapy and may seek therapy at other institutions. For these reasons, we have presented both analyses.

The initial concerns were the secondary AML/MDS that occur early and are usually attributed to etoposide. Although the tests for showing a statistically increased risk of AML/MDS in the DRZ versus non-DRZ treatment arms were underpowered, the SIR for AML/MDS after DRZ versus non-DRZ approached statistical significance once all events were considered and reached a P = .0534 when AML/MDS that occurred as first events were considered.

Secondary solid cancers are usually attributable to radiation-induced injury and tend to occur later48 than etoposide-induced hematopoietic malignancies. However, in our study, two solid tumors emerged early at only 35.4 and 38.9 months from diagnosis. The osteosarcoma did not occur in a radiation field. Both patients had received DZR. Because this was an unusual pattern, we considered the possibility that the evolution of both AML/MDS and the secondary solid tumors could be attributable, at least in part, to the effect of combining DZR with multiple topoisomerase II inhibitors. The incidence and risk of all SMN were increased in the DZR arm compared to the non-DRZ arm, particularly when SMN as first events are considered. While we recognize that this may be attributable to chance alone, it will be important to monitor whether DRZ will impact the risk of solid tumors or the risk of alkylating-agent–induced secondary leukemia that typically occur 5 to 15 years from diagnosis.

It is important to understand how DRZ might induce a secondary malignancy. DRZ is a bisdioxopiperazine. Unlike most inhibitors of topoisomerase II that compete for the adenosine triphosphate (ATPase) -binding pocket, this class of agents blocks topoisomerase II turnover by bridging and stabilizing the ATPase region of the enzyme in its dimerized state.38 Although we intentionally separated DRZ and etoposide administration by 3 hours to avoid potential interaction, basing this interval on the t1/2 of DRZ,49 this half-life does not reflect persistence of the drug bound to the ATPase region. Combining DRZ with etoposide thus affects topoisomerase II at two distinct sites with potentially synergistic effects on DNA repair. Doxorubicin is also a weak topoisomerase II inhibitor50,51 and may further impact DNA repair. Although dexrazoxane has been used with doxorubicin without evidence of enhanced SMN,17-19 the addition of etoposide to the DRZ/doxorubicin combination could be hypothesized to exceed a threshold for topoisomerase inhibitor-induced effects.50 Alternatively, the major contribution to the enhanced risk of SMN could have been the combination of etoposide with dexrazoxane. The enhanced risk for secondary malignancy with DRZ has not been reported, but etoposide and DRZ have not been administered simultaneously in other reported trials. Our finding could be unique to the POG 9425 and 9426 regimens.

The only patient with the well-defined etoposide-associated 11q23 translocation did not receive DRZ. However, Inv(16) and t(16;21) noted in two patients have been associated with topoisomerase-associated secondary leukemia.52-57 Agents in the same class of drugs as DRZ have been associated with AML, including several with similar chromosomal aberrations: (1) AML with inversion 16 after cyclophosphamide and razoxane58 and (2) AML involving t(15;17) in eight patients, t(8,21) in four patients, and del(7q) in one patient after bimolane for psoriasis.59 The POG 9426 and 9425 patients developed similar chromosomal abnormalities. The monosomy 7 and trisomy 8 are unusual for etoposide-associated malignancy; they are usually associated with alkylating agents and emerge after 5 or more years.

Our results suggest a need for caution when planning regimens that might use dexrazoxane with multiple topoisomerase II inhibitors. We have not observed this cohort long enough to know whether DRZ provided cardiopulmonary protection, nor were these studies designed for statistical comparison of leukemia and SMN risk. Nonetheless, the incidence of and the time of onset of the specific leukemias and solid tumors noted after DRZ with doxorubicin and etoposide heightens our concern about using DRZ to reduce long-term cardiopulmonary toxicity in the context of ABVE-based therapy. Because DRZ may be of benefit for those who receive a high cumulative dose doxorubicin, careful monitoring and further study is recommended.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

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AUTHOR CONTRIBUTIONS

Conception and design: Cameron K. Tebbi, Wendy B. London, Debra Friedman, Pedro A. De Alarcon, Louis S. Constine, Nancy Price Mendenhall, Richard Sposto, Allen Chauvenet, Cindy L. Schwartz

Provision of study materials or patients: Cameron K. Tebbi, Debra Friedman, Pedro A. De Alarcon, Louis S. Constine, Nancy Price Mendenhall, Allen Chauvenet, Cindy L. Schwartz

Collection and assembly of data: Cameron K. Tebbi, Wendy B. London, Debra Friedman, Doojduen Villaluna, Pedro A. De Alarcon, Louis S. Constine, Nancy Price Mendenhall, Richard Sposto, Allen Chauvenet, Cindy L. Schwartz

Data analysis and interpretation: Cameron K. Tebbi, Wendy B. London, Debra Friedman, Doojduen Villaluna, Pedro A. De Alarcon, Louis S. Constine, Richard Sposto, Allen Chauvenet, Cindy L. Schwartz

Manuscript writing: Cameron K. Tebbi, Wendy B. London, Debra Friedman, Doojduen Villaluna, Pedro A. De Alarcon, Richard Sposto, Allen Chauvenet, Cindy L. Schwartz

Final approval of manuscript: Cameron K. Tebbi, Wendy B. London, Debra Friedman, Doojduen Villaluna, Pedro A. De Alarcon, Louis S. Constine, Nancy Price Mendenhall, Richard Sposto, Allen Chauvenet, Cindy L. Schwartz

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Appendix: List of Codes From the International Classification of Diseases for Oncology, Third Edition, to Which Each Diagnosis in Table 4 Was Standardized

Acute myeloid leukemia/myelodysplastic syndrome: 9800, 9801, 9805, 9840, 9860, 9861, 9866, 9867, 9871 to 9874, 9891, 9895 to 9897, 9910, 9920, 9931, 9945, 9946, 9948, 9975, 9980, 9982 to 9987, 9989

Thyroid cancer (papillary carcinoma): 8330 to 8333, 8335, 8337, 8340 to 8347, 8290, 8050, 8260, 8010

Osteosarcoma: 9180 to 9187, 9191 to 9195, 9200, 9210, 9250

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Footnotes

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

  • Received April 13, 2005.
  • Accepted November 20, 2006.
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  1. doi: 10.1200/JCO.2005.02.3879 JCO vol. 25 no. 5 493-500
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