Radioiodine and Its Relationship to Hematologic ...

JOURNAL OF CLINICAL ONCOLOGY

C O R R E S P O N D E N C E

Radioiodine and Its Relationship to Hematologic Malignancy: The Confounding Role of Supraphysiologic Thyroxine TO THE EDITOR: Molenaar et al1 have calculated an increased risk of hematologic malignancies in patients who received 131I (radioiodine [RAI]) after thyroid surgery. Of interest, the standardized incidence ratio (SIR) of 155 as quoted by Molenaar et al for patients who received RAI and surgery was greater than that for patients who received surgery alone; however, it was also interesting to note that even those patients who underwent surgery had an increased SIR of 119. Overall risk still seems to be low, and we understand this is why such analyses of big data are so vital. As all patients with differentiated thyroid cancer have an increased SIR, does this mean that having a well-differentiated thyroid is a risk factor on its own? An increased incidence of hematologic malignancies has been reported in adolescents and young adults who have been treated for solid cancer, a similar demography to many patients with differentiated thyroid cancer, but this was thought to be primarily related to chemotherapy or external beam radiotherapy, both of which are not widely used in differentiated thyroid cancer.2 There may be yet another explanation. Looking at the two patient groups, it is not surprising that 74% of patients who underwent surgery alone had limited localized disease compared with 49% of those who were treated with RAI. In the surgery alone group, 24% of patients had regional or distant metastases compared with 51% who received additional RAI; therefore, it is almost certain that those patients who received RAI were in a higher-risk group. It has been the practice postablation in these higher-risk patients to administer supraphysiologic doses of thyroid-replacement

therapy to suppress thyroid-stimulating hormone as recommended in the latest American Thyroid Association guidelines.3 It has been previously recognized that exposure to such supraphysiologic thyroxine levels, whatever the source, can in itself result in a three-fold increase in the relative risk of leukemia.4 We believe that Molenaar et al must reanalyze the data and that an adjustment must be made to account for the additional risk of leukemia as a result of another dependent variable of thyroxine suppression to which the majority of RAI-treated patients will be exposed under current practice. At the present time, these patients should be given optimal treatment for their thyroid cancer stratified by risk.

John Buscombe Cambridge University Hospitals, Cambridge, United Kingdom

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] https://doi.org/10.1200/ JCO.2017.75.0232 2. Keegan THM, Bleyer A, Rosenberg AS, et al: Second primary malignant neoplasms and survival in adolescent and young adult cancer survivors. JAMA Oncol 3:1554-1557, 2017 3. Haugen BR, Alexander EK, Bible KC, et al: 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133, 2016 4. Moskowitz C, Dutcher JP, Wiernik PH: Association of thyroid disease with acute leukemia. Am J Hematol 39:102-107, 1992

DOI: https://doi.org/10.1200/JCO.2018.78.0395; published at jco.org on May 3, 2018.

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© 2018 by American Society of Clinical Oncology

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Corresponding author: John Buscombe, MD, Nuclear Medicine, Box 170, Cambridge University Hospitals, Hills Rd, Cambridge CB2 0QQ, United Kingdom; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

Correspondence


Radioiodine and Its Relationship to Hematologic Malignancy: The Confounding Role of Supraphysiologic Thyroxine The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. John Buscombe Consulting or Advisory Role: Norgine Speakers’ Bureau: Bayer



Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.


Power of Absolute Values to Avoid Data Misinterpretations: The Case of Radioiodine-Induced Leukemia and Myelodysplasia TO THE EDITOR: Molenaar et al1 investigated 148,215 patients with differentiated thyroid cancer (DTC), 79,033 (53%) of whom received surgery alone and 68,374 (47%) of whom received surgery plus radioiodine (RAI). The authors report that RAI was associated with the risk of developing a secondary hematologic malignancy (SHM) with a hazard ratio (HR) of 1.43 (95% CI, 1.20 to 1.69; P 5 .001). Furthermore, Molenaar et al found an elevated risk for acute myeloid leukemia (AML; HR, 1.79; 95% CI, 1.13 to 2.82; P 5.01) and chronic myeloid leukemia (HR, 3.44; 95% CI, 1.87 to 6.36; P , .001). The authors also reported standardized incidence ratios after RAI that were significantly higher for AML and chronic myeloid leukemia, acute and chronic lymphatic leukemia, and nonHodgkin lymphoma. We have several concerns about the study by Molenaar et al. First, SHMs were observed in 360 of 558,912 (incidence rate, 64 3 100,000 person-years [PYs]) patients who were treated with RAI and in 410 of 733,056 (56 3 100,000 PYs) patients who were treated with surgery alone. The small difference in SHM incidence between patients with DTC who received RAI or not (8 3 100,000 PYs), which is not adjusted by the more advanced stage of disease, seems negligible and unreliable. Indeed, when considering that the actual incidence of DTC in the general population is approximately 14 per 100,000 PYs,2 the anticipated difference in incidence rate of SHMs as a result of RAI should be one per 100,000,000 PYs. We are also convinced that the analyses which compare cancer rates of the general population and then compare SIRs between RAI and surgery alone suffer from an unacceptable risk of residual confounding—that is, adjustment is only for sex, age, and year of diagnosis. With regard to competing risk models, we doubt the reliability of the results. Molenaar et al found a significant association between male sex and acute lymphatic leukemia, chronic lymphatic leukemia, multiple myeloma, and non-Hodgkin lymphoma, as well as with SHMs overall. HR for developing SHMs for a male was 1.53 (95% CI, 1.28 to 1.84; P , .001). Although this HR is slightly higher than that of RAI (1.43), Molenaar et al do not discuss the risk of any male developing an SHM. In addition, patients with DTC with a tumor diameter . 2 cm had an overall lower risk of developing SHMs (HR, 0.81; 95% CI, 0.68 to 0.97; P 5 .02), and the principal risk factor for developing AML in patients with DTC was not the RAI but the presence of locoregional involvement. Finally, patients with DTC who were treated with RAI showed a lower risk of developing multiple myeloma (HR, 0.65; 95% CI, 0.44 to 0.97; P 5 .04). These strange and unexpected findings,


the pathophysiologic basis of which is difficult to fathom in the context of known radiobiology, were not coherently explained in the discussion by Molenaar et al. Furthermore, two important issues were not addressed to plausibly prove a causal relationship between RAI and the occurrence of SHMs. First, the analysis did not consider the RAI activities administered to patients; however, the risk of developing second malignancies should be related to the administered activity and dose exposure. Indeed, as reported by the authors, patients who were treated with RAI presented with a significantly higher number of locoregional and distant metastases compared with those who were treated with surgery alone. Therefore, these patients could have undergone more than one RAI treatment or a treatment with higher administered activities of RAI. Second, Molenaar et al do not examine whether a latency time exists (and its extent), which should be expected to be present between RAI and the development of SHMs if there is a causal relationship. Finally, on an entirely different but no less important point, we would like to address an issue of ethics with the article by Molenaar et al. A paper from the same group simultaneously appeared in Leukemia, reporting on the same data.3 Splitting a single research project into multiple publications is in conflict with academic ethics in publishing, particularly when a simultaneous submission is not clearly indicated by the authors. In conclusion, we take issue with the conclusion of Molenaar et al that RAI could induce a clinically significant increase in the occurrence of SHMs. As we have explained above, the data presented by the authors do not at all justify such a far-reaching conclusion when other, even more significant effects are ignored, the basics of a causal relationship are not examined, and the absolute increase in incidence seems to be in the order of one case per 100,000,000 PYs. Raising the alarm on RAI, which is the only validated curative therapy in patients with DTC who experience failure with surgery and the only adjuvant therapy for patients with thyroid cancer, is not appropriate given the weaknesses of the presented data and analyses.

Arnoldo Piccardo and Matteo Puntoni Ente Ospedaliero Ospedali Galliera, Genoa, Italy

Frederik A. Verburg and Markus Luster University Hospital Marburg, Marburg, Germany, and European Association of Nuclear Medicine, Vienna, Austria

Luca Giovanella Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, and European Association of Nuclear Medicine, Vienna, Austria

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at jco.org.


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Corresponding author: Luca Giovanella, MD, Department of Nuclear Medicine and Competence Center for Thyroid Diseases, Oncology Institute of Southern Switzerland, Via Ospedale 12, 6500 Bellinzona, Switzerland; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] https://doi.org/10.1200/JCO.2017.75.0232 2. Lim H, Devesa SS, Sosa JA, et al: Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA 317:1338-1348, 2017

3. Molenaar RJ, Pleyer C, Radivoyevitch T, et al: Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine. Leukemia 32:952-959, 2018


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Power of Absolute Values to Avoid Data Misinterpretations: The Case of Radioiodine-Induced Leukemia and Myelodysplasia The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Arnoldo Piccardo No relationship to disclose Matteo Puntoni No relationship to disclose Frederik A. Verburg Consulting or Advisory Role: Eisai, Genzyme Speakers’ Bureau: Genzyme, Diasorin

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Markus Luster Consulting or Advisory Role: Genzyme, GE Healthcare, Sanofi, Bayer, Ipsen, Novartis, AstraZeneca, Eisai Research Funding: Bayer (Inst) Luca Giovanella No relationship to disclose




Selective Focus on Rare Hematologic Malignancies Misleads Risk-Benefit Assessment of Radioiodine Therapy of Thyroid Cancer TO THE EDITOR: Molenaar et al1 have studied secondary hematologic malignancies (SHMs) in patients who were treated for well-differentiated thyroid cancer (WDTC) and reported that radioactive iodine (RAI) treatment was associated with a significantly increased risk of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). On the basis of this risk assessment, the authors have stressed the importance of avoiding RAI treatment in patients with WDTC with low-risk or intermediate-risk disease in whom RAI has demonstrated no or questionable benefit. Molenaar et al also recommended using the least effective dose to treat patients who have high-risk features to avoid excess bone marrow exposure, as the risk of SHM is dose dependent. In addition, the authors recommended monitoring blood counts to detect the development of myeloid malignancies for patients who receive high doses of RAI. It is indeed important to perform such a risk-benefit analysis; however, using relative risk of rare cancers to infer the risk from treatments may not be appropriate, as such relative risks may not be representative of the overall risk of treatments. For example, in a study of cancer mortality rates in patients with hyperthyroidism who were treated with RAI, higher mortality rates were observed for cancers of the thyroid and small bowel, but reduced mortality rates were noted for cancers of the bronchus and trachea, and the overall cancer mortality rate was significantly lower than that in the standardized general population.2 Considering increased thyroid cancers alone would have misrepresented the overall risk of RAI treatment. Although the observed reduction of some cancers and overall cancers after exposure to an increased radiation dose from RAI treatment of hyperthyroidism is puzzling, there is indeed an explanation that is based on radiobiology and evidence. It is well

Table 1. Standardized Incidence Ratio for Cancers After Radioactive Iodine Treatment of Patients With Well-Differentiated Thyroid Cancer Compared With Patients Not Treated With Radioactive Iodine

Cancer Type

Expected Cases, No.

Observed Cases, No.

AML CML MM Solid tumors All cancers

39 15 74 4,412 4,773

59 40 44 3,827 4,193

Standardized Incidence Ratio (95% CI) 1.52 2.72 0.59 0.87 0.88

(1.13 (1.88 (0.42 (0.84 (0.85

to to to to to

1.90) 3.56) 0.77) 0.89) 0.91)

NOTE. Data are from the Data Supplement in Molenaar et al.1 Cancer types for which standardized incidence ratios are significantly different from 1 are shown. Abbreviations: AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MM, multiple myeloma.


known that there would be greater DNA damage, mutations,3 and cancers from exposure to high doses of radiation4; however, after exposure to low radiation doses, there would be enhanced defenses, such as an increase in antioxidants and DNA repair enzymes, which results in reduced DNA damage and mutations,5 as has been reported in studies of Drosophila melanogaster and mice,6,7 and reduced cancers, as has been observed in human studies.8,9 RAI treatments would result in high doses to some organs (for example, the thyroid), whereas other organs would receive medium and low radiation doses. Organs that receive high radiation doses would be subject to increased DNA damage and mutations, which results in a greater likelihood of secondary cancers. Organs exposed to low radiation doses would have reduced DNA damage and mutations as a result of the enhancement of the defense systems, which leads to lower than expected rates of cancer. Indeed, Molenaar et al1 also report finding a decreased risk of multiple myeloma in RAI-treated patients compared with those treated with surgery alone, whereas the risk of AML and CML increased. Examination of the data in the supplement included by Molenaar et al1 revealed a markedly lower standardized incidence ratio (SIR) of solid tumors in the RAI group compared with the surgery alone group (Table 1). SIR for all cancers was also significantly less than 1 for patients who were treated with RAI. Highlighting the increase in SIR in AML and CML but not taking into account the much larger reduction of solid cancers misrepresents the risk from RAI treatments. A proper risk assessment for RAI treatments should include consideration of the effect of the treatment on all cancers. The above discussion notwithstanding, I agree with the precautions proposed by Molenaar et al with regard to RAI treatments, such as administering treatment with the lowest effective activity and monitoring for possible SHMs. In summary, I agree that a comprehensive risk-benefit analysis should be performed for medical procedures, such as RAI treatments for patients with WDTC; however, focusing on the increased incidence of a few rare cancers while ignoring the reduction of other more frequently occurring cancers and overall cancers grossly misrepresents the risk of the treatments.

Mohan Doss Fox Chase Cancer Center, Philadelphia, PA


Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] doi:10.1200/JCO.2017.75.0232 2. Franklyn JA, Maisonneuve P, Sheppard M, et al: Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: A population-based cohort study. Lancet 353:2111-2115, 1999 3. Klug WS, Cummings MR, Spencer CA: Concepts of Genetics (ed 8). Upper Saddle River, NJ, Prentice Hall, 2006


Corresponding author: Mohan Doss, PhD, Department of Diagnostic Imaging, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111-2497; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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4. Ozasa K, Shimizu Y, Suyama A, et al: Studies of the mortality of atomic bomb survivors, report 14, 1950-2003: An overview of cancer and noncancer diseases. Radiat Res 177:229-243, 2012 5. Feinendegen LE: Evidence for beneficial low level radiation effects and radiation hormesis. Br J Radiol 78:3-7, 2005 6. Koana T, Tsujimura H: A U-shaped dose-response relationship between x radiation and sex-linked recessive lethal mutation in male germ cells of Drosophila. Radiat Res 174:46-51, 2010 7. Osipov AN, Buleeva G, Arkhangelskaya E, et al: In vivo g-irradiation low dose threshold for suppression of DNA double strand breaks below the spontaneous level in mouse blood and spleen cells. Mutat Res 756:141-145, 2013

8. Sutou S, Doss M, Tanooka H (eds): Evidence against the linear no-threshold hypothesis in the atomic bomb survivor cancer data and other data and reasons for a change in the radiation safety paradigm, in Fukushima Nuclear Accident: Global Implications, Long-Term Health Effects and Ecological Consequences. New York, NY, Nova Science Publishers, 2015, pp 61-75 9. Sanders CL: Radiobiology and Radiation Hormesis: New Evidence and Its Implications for Medicine and Society. New York, NY, Springer, 2017 https://doi. org/10.1007/978-3-319-56372-5


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Selective Focus on Rare Hematologic Malignancies Misleads Risk-Benefit Assessment of Radioiodine Therapy of Thyroid Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Mohan Doss No relationship to disclose

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Inconclusive Analysis of the Connection Between Secondary Hematologic Malignancies and Radioiodine Treatment TO THE EDITOR: The analysis by Molenaar et al1 in their article in Journal of Clinical Oncology is of great interest; however, the data seem to be flawed. Results are presented in a one-sided manner and the conclusion, to a large extent, is not supported by the data. The codes for selecting patients are listed in Appendix Table A1 of their article. Of the 15 codes, at least three (8130, 8450, and 8452) are for clearly nonthyroid cancer entities, that is, 8452 is used to classify pancreatic tumors. It remains unclear whether the data from those patients were excluded from additional analysis because of non–well-differentiated thyroid cancer histology (n 5 10,785; Fig 1 in Molenaar et al). If so, why were the codes included in first place? If the data were not excluded, the effect of these erroneous codes has to be questioned. Moreover, different numbers for the same groups are mentioned in different sections of the article. Under Patient Characteristics in the Results section, the authors state that, “Among the survivors of well-differentiated thyroid cancer, a total of 783 nonsynchronous [secondary hematologic malignancies] were identified, 417 after surgery alone and 366 after surgery plus [radioiodine].”1 These numbers are discrepant to Fig 1 in Molenaar et al, which states 76 cases of secondary hematologic malignancy (SHM) in the surgery only group within 1 year and another 410 cases thereafter (n 5 486 cases). The number of SHMs in the surgery and radioiodine (RAI) group in Fig 1—56 after 1 year and 360 in the following years (n 5 416) —also does not match the number in the results section (n 5 366). The authors mention that low- and intermediate-risk patients were defined per the latest American Thyroid Association guidelines as T1-2N0 tumors that are # 4 cm in size or T13N1 tumors in patients older than age 45 years. There is no statement about the respective M-status, which would automatically put the patient into a high-risk group. Neither is the R-status mentioned, which is known to be an important risk factor for relapse of disease.2 In addition to ablation of thyroid tissue and treatment of microscopic and macroscopic tumor deposits, RAI enables highly sensitive and specific whole-body staging via post-therapeutic imaging. There are robust data that demonstrate changes in risk stratification (. 20%) as a result of findings in post-therapeutic single-photon emission computed tomography/computed tomography.3,4 Even smaller lymph node metastases may be treated with high efficacy.5 Hence, the two groups of patients analyzed are not only different in terms of exposure to RAI, but also in terms of the staging applied.


As Molenaar et al correctly point out in the discussion, the induction of SHM is dose dependent; however, the authors do not provide any information concerning the amount of radioactivity used, nor whether chemotherapy or other proleukemic drugs or conditions were administered subsequently. There are two scenarios when RAI is used for therapy. First, in high-risk cases to cure the patient or to achieve a long-lasting disease stabilization with high doses, with the awareness that toxicities will occur. Second, in intermediate-risk or low-risk cases as adjunct to ablate thyroid remnants, treat (occult) residual disease, and perform highly specific and sensitive post-therapeutic imaging. Most patients in this group will receive a low cumulative dose of RAI; however, as there is no information on the R and M status of the patients studied, and knowing that post-therapeutic imaging leads to an upstaging in a relevant number of patients, it is likely that some of the patients in this group received higher doses of RAI for a valid reason and had a higher risk for SHM. The statement in the Discussion that mentions a “. . . relatively homogenous treatment exposure” for the reasons given above is likely wrong and cannot be made as there are no corresponding data presented. For the above-mentioned reasons and in consideration of retrospective study design, we disagree with the statement that RAI should be avoided in low-risk and intermediate-risk patients. The data are not strong and/or clean enough to support such a statement. Remarkably, patients with No acute myeloid leukemia, but also no chronic myeloid leukemia, seem to have better survival after RAI (Figs 3A and 3B in Molenaar et al). It would be appropriate to show the survival curves for patients (stratified into risk groups) who have received RAI and who have not, so that readers can make up their own minds.

Michael C. Kreissl University Hospital Magdeburg, Otto-von-Guericke University, Magdeburg, Germany

Enrique Grande MD Anderson Cancer Center, Madrid, Spain


Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] https://doi.org/10.1200/JCO. 2017.75.0232 2. Haugen BR, Alexander EK, Bible KC, et al: 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133, 2016 3. Kohlfuerst S, Igerc I, Lobnig M, et al: Post-therapeutic 131I SPECT-CT offers high diagnostic accuracy when the findings on conventional planar imaging are inconclusive and allows a tailored patient treatment regimen. Eur J Nucl Med Mol Imaging 36:886-893, 2009


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Corresponding author: Michael C. Kreissl, MD, Department of Radiology and Nuclear Medicine, University Hospital Magdeburg, Otto-vonGuericke University Magdeburg, Leipziger Str 44, 39120 Magdeburg, Germany; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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4. Schmidt D, Szikszai A, Linke R, et al: Impact of 131I SPECT/spiral CT on nodal staging of differentiated thyroid carcinoma at the first radioablation. J Nucl Med 50: 18-23, 2009 5. Ilhan H, Mustafa M, Bartenstein P, et al: Rate of elimination of radioiodine-avid lymph node metastases of differentiated thyroid carcinoma by

postsurgical radioiodine ablation. A bicentric study. Nucl Med (Stuttg) 55: 221-227, 2016


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Inconclusive Analysis of the Connection Between Secondary Hematologic Malignancies and Radioiodine Treatment The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Michael C. Kreissl Stock or Other Ownership: Endocyte, Progenics Honoraria: Sanofi, GE Healthcare Consulting or Advisory Role: AstraZeneca, Bayer, Ipsen, Sanofi, Eisai, GE Healthcare Research Funding: AstraZeneca, Sanofi, GE Healthcare (Inst)

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Enrique Grande No relationship to disclose




Risk of Hematologic Malignancies After Radioactive Iodine Treatment of Thyroid Cancer: An Unjustified Warning TO THE EDITOR: Although increased risk of second malignancies in patients with well-differentiated thyroid cancer (WDTC) has been accepted, the role of radioactive iodine (RAI) treatment in second malignancies remains controversial.1 Molenaar et al2 used SEER data to compare the risk of second hematologic malignancies in 79,033 patients with WDTC who were treated with surgery alone and 68,374 patients who were treated with surgery plus RAI. In multivariable analysis, RAI treatment was associated with an increased risk of acute myeloid leukemia (AML; hazard ratio [HR], 1.79) and chronic myeloid leukemia (CML; HR, 3.44), and reduced risk of multiple myeloma (HR, 0.65).2 Several issues need to be considered to avoid misinterpretations. Considering the findings as radiation induced rather than mere association would require demonstrating a dose-response relationship; however, SEER data lack information on 131I administered activity. Therapy-related CML is a rare clinical entity.3 Figure 3D in Molenaar et al shows that RAI-treated patients with CML had better survival than matched control patients with de novo CML,2 which supports early detection or overascertainment bias as likely explanations. Neither the small number of cases (Appendix Table A2 in Molenaar et al),2 nor the current excellent prognosis of CML,3 would justify the warning against RAI therapy. Ten-year cumulative risks of AML were 0.08% after surgery alone and 0.12% after surgery plus RAI.2 An increase in AML incidence has been reported for patients with distant metastases that required repeated RAI therapy; however, this has to be weighed against the beneficial effect of RAI therapy for these groups of patients who carry a high risk of death.4 RAI-treated patients may need additional external beam radiation therapy (for example, to bone metastases)5; however, SEER data do not capture delayed radiation.2 In a study of 1,497 patients who were treated with 131I only, no case of leukemia was observed, whereas three cases occurred among 449 patients who received additional external beam radiation therapy.6 Genetic predisposition can also be a confounding factor.1 In assessing the surgery alone group, regional involvement was present at WDTC diagnosis in 47% of patients who later developed AML compared with 21% of those who did not (P 5 .0002; Appendix Table A3 in Molenaar et al).2 As the decision to administer RAI depends on disease stage, a higher level of genomic instability (mutations in NRAS, TERT promoter, and so on) might explain the increased AML risk.7,8 Molenaar et al recommend against adjuvant therapy in lowrisk and intermediate-risk WDTCs,2 emphasizing that in these


patients, “RAI treatment was the only factor in Fine-Gray competing risk regression analyses that was significantly associated with the development of AML (HR, 2.87; P 5 .002).”2 However, it is surprising to note that tumor stage (regional v localized) was excluded from univariable and multivariable analyses (Appendix Tables A18 and A19 in Molenaar et al).2 This is extremely concerning, as patients who received RAI had a much higher rate of regional disease than did those who received surgery alone (35% v 12%; Appendix Table A17 in Molenaar et al), and regional disease was highly associated with AML risk for the whole cohort (Table 2 in Molenaar et al).2 The choice of the observation period ($ 1 to 20 years after WDTC diagnosis) might also have affected the relative risk analysis. Of importance, in the surgery alone group, no AML case occurred beyond 10 years (118,470 person-years follow-up), whereas 6.9 cases were expected on the basis of background incidence (Appendix Table A30 in Molenaar et al).2 As the probability for no AML cases during this period is low (Fisher’s exact test, P , .04), how can the authors exclude any potential error in registration? Recommending against 131I adjuvant therapy in thyroid cancer would have required strong evidence that the risks outweigh the benefits. Appropriate use of RAI therapy permits the early diagnosis and treatment of regional and distant metastases and reduces the risk of recurrence and potential mortality. In a recent multivariable analysis in 21,870 patients with intermediate-risk (T3/N0 and T1-3/N1) papillary thyroid cancer, RAI was associated with a 29% reduction in the risk of death (P , .001).9 The conclusions of Molenaar et al and their distinctly different recommendations from the current clinical management of WDTC are unsupported by the data presented. Finally, Molenaar et al chose to report separately on myelodysplastic syndromes (MDS).10 This also causes a methodologic problem. The authors state “RAI treatment for WDTC is associated with increased risk of MDS with short latency and poor survival”10; however, some of the mortality from MDS is likely a result of the transformation to AML, but SEER has been reporting progression of MDS to AML only since 2010 (Supplemental Methods in Molenaar et al).2 It is then unclear how mortality from AML and mortality from MDS transformed to AML were differentiated in these studies, not to be counted twice, as this causes confusion regarding the actual risk from RAI. The authors’ clarification of the issues outlined above would be highly appreciated.

Elif Hindié

ˆ ´ eque, ˆ Bordeaux University Hospitals, Hopital Haut-Lev Pessac, France

Christian Récher and Slimane Zerdoud Institut Universitaire du Cancer de Toulouse–Oncopole, Toulouse, France

Laurence Leenhardt

ˆ ere ` University Hospital, Paris, France Pitie´ Salpetri

Anca M. Avram University of Michigan, Ann Arbor, MI


Corresponding author: Elif Hindié, MD, Service de Médecine Nucléaire, Hôpital Haut-Lévêque, Avenue Magellan, 33604 Pessac, France; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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Correspondence


Disclosures provided by the authors are available with this article at jco.org.

REFERENCES 1. Hirsch D, Shohat T, Gorshtein A, et al: Incidence of nonthyroidal primary malignancy and the association with 131I treatment in patients with differentiated thyroid cancer. Thyroid 26:1110-1116, 2016 2. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] doi:10.1200/JCO.2017. 75.0232 3. Iriyama N, Tokuhira M, Takaku T, et al: Incidences and outcomes of therapyrelated chronic myeloid leukemia in the era of tyrosine kinase inhibitors: Surveillance of the CML Cooperative Study Group. Leuk Res 54:55-58, 2017 4. Durante C, Haddy N, Baudin E, et al: Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 91:2892-2899, 2006

5. Hindie´ E, Zanotti-Fregonara P, Keller I, et al: Bone metastases of differentiated thyroid cancer: Impact of early 131I-based detection on outcome. Endocr Relat Cancer 14:799-807, 2007 6. de Vathaire F, Schlumberger M, Delisle MJ, et al: Leukaemias and cancers following iodine-131 administration for thyroid cancer. Br J Cancer 75:734-739, 1997 7. Melo M, Gaspar da Rocha A, Batista R, et al: TERT, BRAF, and NRAS in primary thyroid cancer and metastatic disease. J Clin Endocrinol Metab 102: 1898-1907, 2017 8. Johnson DB, Smalley KS, Sosman JA: Molecular pathways: Targeting NRAS in melanoma and acute myelogenous leukemia. Clin Cancer Res 20: 4186-4192, 2014 9. Ruel E, Thomas S, Dinan M, et al: Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer. J Clin Endocrinol Metab 100:1529-1536, 2015 10. Molenaar RJ, Pleyer C, Radivoyevitch T, et al: Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine. Leukemia 32:952-959, 2018


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Risk of Hematologic Malignancies After Radioactive Iodine Treatment of Thyroid Cancer: An Unjustified Warning The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Elif Hindié No relationship to disclose Christian Recher Honoraria: Sunesis, Amgen, Novartis, Celgene, Jazz Pharmaceuticals Consulting or Advisory Role: Sunesis, Amgen, Novartis, Celgene, Astellas Pharma, AbbVie, Otsuka, Jazz Pharmaceuticals Research Funding: Sunesis, Amgen, Novartis, Celgene, Chugai Pharmaceuticals Travel, Accommodations, Expenses: Novartis, Amgen, Sanofi

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Slimane Zerdoud Honoraria: Genzyme Travel, Accommodations, Expenses: Genzyme Laurence Leenhardt Honoraria: Bayer, Eisai, Genzyme Anca M. Avram No relationship to disclose




Concerns About the Risk of Myeloid Malignancies After Radioiodine Therapy in Thyroid Cancer TO THE EDITOR: Molenaar et al1 aimed to assess the associative effect of radioactive iodine (RAI) in the development of hematologic malignancies (HMs). The authors found that patients with differentiated thyroid cancer (DTC) who were treated with RAI had an increased risk of developing myeloid leukemia compared with patients who were treated with surgery alone. An increased risk of second cancers, including HMs, has previously been reported in patients who were treated with RAI2-6; however, the association between thyroid cancer and other cancers, including lymphoma and leukemia, has been reported irrespective of which cancer occurred first, which indicates that their occurrence cannot be entirely attributed to the treatment.4,7 Consequently, some issues raised in the study by Molenaar et al need to be more closely examined. For the purpose of the study, International Classification of Diseases for Oncology, Third Revision, codes were used to search for patients in the SEER registries; however, some codes listed in Table 1 of the Data Supplement in Molenaar et al identify tumors that do not belong to DTC (8130, urinary system; 8450, genitals; and 8452, pancreas/ovary). It is not possible to estimate the effect of these errors. The authors also report that they stratified patients into low, intermediate, and high risk according to criteria reported in the latest version of the American Thyroid Association guidelines8; however, as mentioned in the study limitations, the SEER registries did not contain some data (for example, completeness of tumor resection) that are necessary to categorize patients according to these criteria. Moreover, there are many inconsistencies in the numbers between Figure 1, the text, and the Data Supplement. In addition to the choice of factors included in the multivariable analysis, errors in numbers may have affected the statistical analysis. Confounding factors that are known to be associated with an increased risk of HM,9 administered activity, and number of cycles should also be considered. Data on RAI administrations are not reported in the SEER registries, which makes it impossible to identify how many patients who received more than one cycle were included in the analysis. The authors briefly acknowledge that this could have affected their results, but additional considerations need to be made concerning this specific issue. Hypothetically, most patients in the RAI group could have received more than one cycle, which would negatively affect the study results, as the risk of developing an HM is dose dependent.2,5,6 It is reasonable to hypothesize that patients with metastatic disease (twice in the RAI group) received more than one RAI cycle, but it is impossible to speculate further on the overall percentage of patients who were treated with multiple RAI, so its effect cannot be estimated. In addition, the decade of treatment should be considered, given that the administered activities of RAI were generally higher in the past and the association between


RAI and second cancers has been found to vary according to the decade of treatment.5 An additional important point is that the authors quantified only the risk of a second HM and failed to examine the potential benefit of RAI therapy, despite the availability of these data in the cohort. In surveillance series and many single-institution experiences, RAI has been reported to improve recurrence and mortality rates compared with surgery alone,3 although it should be acknowledged that these studies were retrospective. On the basis of more recent evidence from long-term follow-up studies,3 RAI is not routinely recommended after thyroidectomy in patients with low-risk DTC.8 Therefore, some comments concerning low-risk patients and their exposure to unjustified treatment within the Discussion are inapplicable today. In contrast, use of RAI is not questionable in patients with high-risk DTC.3,8 The data provided on solid cancer would have been more interesting were it not for potential flaws as a result of the methodologic issues mentioned above. The authors found a higher occurrence of solid tumors in patients who were treated with surgery alone than in the RAI group (P , .001 using the Z-score calculator for two population proportions). An extrapolated calculation per 100,000 cases would have revealed an interesting observation. RAI was responsible for an additional 66 cases of myeloid leukemia while reducing the occurrence of solid cancers by 856 cases. This emphasizes the importance of comparing the entirety of the risks with the entirety of the benefits. Finally, a relevant article was simultaneously published by Molenaar et al10 in Leukemia, and the intention to report this cohort separately should at least have been mentioned. These limitations, as well as the possible sources of bias, should be taken into account by readers of Journal of Clinical Oncology before drawing any conclusions on the risk of myeloid malignancies after RAI therapy in thyroid cancer.

Martina Sollini Humanitas University, Milan, Italy

Arturo Chiti Humanitas University and Humanitas Clinical and Research Hospital, Milan, Italy


Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] 10.1200/JCO. 2017.75.0232 2. Rubino C, de Vathaire F, Dottorini ME, et al: Second primary malignancies in thyroid cancer patients. Br J Cancer 89:1638-1644, 2003 3. Andresen NS, Buatti JM, Tewfik HH, et al: Radioiodine ablation following thyroidectomy for differentiated thyroid cancer: Literature review of utility, dose, and toxicity. Eur Thyroid J 6:187-196, 2017 4. Ronckers CM, McCarron P, Ron E: Thyroid cancer and multiple primary tumors in the SEER cancer registries. Int J Cancer 117:281-288, 2005


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Corresponding author: Martina Sollini, MD, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

Correspondence

5. Brown AP, Chen J, Hitchcock YJ, et al: The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 93:504-515, 2008 6. Teng C-J, Hu Y-W, Chen S-C, et al: Use of radioactive iodine for thyroid cancer and risk of second primary malignancy: A nationwide population-based study. J Natl Cancer Inst 108:djv314, 2015 7. Sandeep TC, Strachan MWJ, Reynolds RM, et al: Second primary cancers in thyroid cancer patients: A multinational record linkage study. J Clin Endocrinol Metab 91:1819-1825, 2006 8. Haugen BR, Alexander EK, Bible KC, et al: 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and

differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133, 2016 9. American Cancer Society: Learn about cancer: Cancer resources. https:// www.cancer.org/cancer 10. Molenaar RJ, Pleyer C, Radivoyevitch T, et al: Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine. Leukemia 32:952-959, 2018


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Correspondence


Concerns About the Risk of Myeloid Malignancies After Radioiodine Therapy in Thyroid Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Martina Sollini Travel, Accommodations, Expenses: Genzyme, Ion Beam Applications, GE Healthcare

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Arturo Chiti Honoraria: GE Healthcare, Sirtex Consulting or Advisory Role: Advanced Accelerator Applications, Blue Earth Diagnostics Research Funding: Sanofi





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Questionable Relevance of Leukemia Risk After Radioiodine Ablation of Thyroid Cancer TO THE EDITOR: The article by Molenaar et al1 concludes that I radioiodine ablation should not be performed in patients with differentiated thyroid cancer with low-risk or intermediate-risk disease. This conclusion is based on their claim to have found a slight increase in the risk of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) after surgery plus 131I ablation when compared to surgery alone. The reported increased incidence of these leukemias at first glance seems impressive—12.5% greater than expected for the surgery alone group (deemed statistically insignificant) and 49.1% for surgery plus 131I. But these are rare cancers. What percentage of treated patients actually developed AML or CML? For surgery alone, it was 0.519%, and for surgery plus 131I, it was 0.527%. In other words, patients who received 131I after surgery were just 0.008% more likely to develop AML or CML. This is a microscopically small risk. To put it in perspective, the risk of dying in a car accident during the roughly 9 years of follow-up was approximately 0.1%, or more than 10 times as likely.2 For this, must we abandon 131I ablation, which has produced excellent outcomes in patients with thyroid cancer for many decades? Of more importance, what about all of the other diseases that afflict humans? Might not some of these be reduced after 131I ablation? There are plausible biophysical and cellular mechanisms and animal and human data to support such radiation hormesis, reviewed in Siegel et al.3 In fact, the authors themselves report that multiple myeloma incidence was significantly reduced in patients who were treated with 131I compared with those treated with surgery alone. Solid tumor incidence was also lower in the 131

I group, although the statistical significance of this was not thoroughly evaluated (6.45% of surgery-only patients v 5.60% of surgery plus 131I patients, but surgery patients were observed a little longer on average). Even a tiny reduction in solid tumors would more than offset the reported small increase in the two leukemias, and this is only part of the story. When weighing the value of any therapy for any disease, one must include all of the risks and benefits. Molenaar et al look only at the risk of two leukemias and assume there is no benefit whatsoever to 131I ablation in terms of killing residual or metastatic thyroid cancer cells. The decision to treat or not (with any type of therapy) should rest on two factors only: Do the treated patients live longer? And do the treated patients have a better quality of life? These issues are simply not addressed in the article by Molenaar et al. The conclusion to discard 131I ablation in patients with low-risk or intermediate-risk disease is not supported by the evidence presented.

Ronald Fisher Houston Methodist Hospital, Baylor College of Medicine, Houston, TX


Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] doi:10.1200/JCO.2017.75.0232 2. Wikipedia: List of motor vehicle deaths in US by year. https://en.wikipedia. org/wiki/List_of_motor_vehicle_deaths_in_U.S._by_year 3. Siegel JA, Pennington CW, Sacks B: Subjecting radiologic imaging to the linear no-threshold hypothesis: A non sequitur of non-trivial proportion. J Nucl Med 58:1-6, 2017


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Corresponding author: Ronald Fisher, MD, Houston Methodist Hospital, Departments of Radiology and Neuroscience, Baylor College of Medicine, 6565 Fannin St, Houston, TX 77030; e-mail: rfi[email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

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Correspondence


Questionable Relevance of Leukemia Risk After Radioiodine Ablation of Thyroid Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Ronald Fisher No relationship to disclose






Risk of Hematologic Malignancies After Radioiodine Treatment of WellDifferentiated Thyroid Cancer TO THE EDITOR: The primary end point of the article by Molenaar et al1 is presumably that which is indicated in the title, “Risk of Hematologic Malignancies Following Radioiodine Treatment.” Molenaar et al demonstrate an additional increase in these malignancies after radioiodine therapy, which they attributed to radioiodine therapy rather than a pretherapy predisposition to second malignancies following thyroid cancer. The raw probability of hematologic malignancies was not higher in the entire group of patients treated with radioiodine than in those who underwent surgery only, and detailed statistical modeling was used to justify this claim. However, I note that neither the stage of cancer nor the size of the primary tumor were incorporated into this model, and as patients with more advanced stages and larger cancers are more likely to receive radioiodine (as demonstrated in Appendix Table A17 in Molenaar et al), it is possible that a greater postradioiodine likelihood of developing a second hematologic malignancy is simply a result of the higher thyroid tumor stage. I understand the reason for not incorporating tumor stage and size, as it was not statistically significant in the univariable analysis. It nevertheless may still be a factor in the risk model of second malignancies probability. I also note that the total secondary hematologic malignancies were not increased (to a statistically significant degree) in patients with low-risk and intermediate-risk thyroid cancer but was only more common in the total cohort, which included high-risk patients who received higher cumulative radioiodine doses. The secondary end point—that of AML and CML—was statistically

significantly increased in the intermediate-risk and low-risk groups, although this was not clearly stated in the results. However, subgroup analysis requires correction for multiple comparisons, and this does not seem to have been done, so it is hypothesis generating, not practice changing. Furthermore, the conclusion presented in the Abstract states that radioiodine should not be used for low-risk and intermediaterisk patients on the basis of the risk of hematologic malignancy; however, the decision to use radioiodine is not based solely on the rare (.06%) increased risk of AML demonstrated in this group. This is especially so when improved overall survival with adjuvant radioiodine was demonstrated for intermediate-risk thyroid cancer in a database study of 21,870 patients.2 No analysis of total solid malignancies was attempted, but the raw numbers indicate a decrease in solid malignancy after radioiodine therapy compared with nonradioiodine therapy. I would welcome the authors’ reply to my reservations and suggestions.

Meir Lichtenstein Royal Melbourne Hospital, Parkville, Victoria, Australia


Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] 10.1200/JCO.2017.75.0232 2. Ruel E, Thomas S, Dinan M, et al: Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer. J Clin Endocrinol Metab 100:1529-1536, 2015


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Corresponding author: Meir Lichtenstein, MD, Nuclear Medicine Service, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, Australia; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

Correspondence


Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Meir Lichtenstein No relationship to disclose





Well-Founded Recommendations for Radioactive Iodine Treatment of Differentiated Thyroid Cancer Require Balanced Study of Benefits and Harms TO THE EDITOR: Molenaar et al1 analyzed the possible hematologic harms of radioactive iodine treatment (RAIT) administered to patients with differentiated thyroid cancer (DTC). The authors found associations of RAIT with acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML). Their conclusion unequivocally states that the “results demonstrate the importance of avoiding treatment with RAI in patients with low-risk or intermediate-risk disease, in whom RAI has shown no or questionable benefit.”1 Such a statement would have been appropriate if the authors prospectively treated two well-matched DTC groups where one would receive RAIT and the other would not, showing no or questionable benefit. Instead, this was a retrospective study and only the harms were investigated. Therefore, the certainty of their conclusion was not supported by either the study design or the results. We also disagree with the assertion that “RAI has shown no or questionable benefit.”1 Molenaar et al used exclusively their interpretation of the guidelines by the American Thyroid Association2 for evaluation of the therapeutic benefits of RAIT. Our assessment of the benefits of RAIT is contrary to that of the authors, and it is based not only on the interpretation of the same guidelines, but also the primary sources and our collective experience with hundreds of thousands of patients who received RAIT for low-risk and intermediate-risk DTC. In one recent primary source, 21,870 patients with intermediate-risk disease demonstrated a significant overall survival benefit in those who received RAIT.3 It is regretful that Molenaar et al, having the large database of patients with DTC at their disposal, neglected to study the benefits of RAIT to balance them against the harms. Nevertheless, the authors serendipitously discovered a protective effect of RAIT in multiple myeloma risk, which is mentioned in one sentence of the Results and the Discussion. The authors qualify this benefit as an “interesting finding” and offer no explanation for it, writing instead that “the possible mechanism of which needs further investigation.”1 Unbiased scientific discussion would have mentioned that in other studies of RAIT, a similar protective effect on the risk of some cancers has also been reported. 4 In addition, the only applicable mechanism, termed radiation hormesis,5,6 would have also been discussed. Of more importance, Molenaar et al neglected to mention that, counterbalancing the number of AML and CML events, the RAIT group had a markedly lower number of solid cancers according to Appendix Table A2.1 Solid tumors were found in 5,100 (6.45%) of 79,033 patients who were treated with surgery alone, but a significantly lower percentage in 3,827 (5.60%) of 68,374 patients was found in patients treated with surgery plus RAIT ( P , .001 using z score calculator for two population proportions). An extrapolated calculation to 100,000 treated cases with RAIT would have resulted in 66 cases of combined AML and CML in the RAIT group while at the same time reduced solid cancers by 856 cases. We realize that the


above extrapolation lacks multivariable analysis, but that is all that was possible on the basis of what the authors supplied. Molenaar et al should have performed a comprehensive analysis of the possible positive effects of RAIT in solid cancers, as they have done for the few, albeit serious, but rare hematologic malignancies. Patients in the RAIT group had more advanced tumors according to Table 1 in Molenaar et al and would be more likely to receive supraphysiologic thyroid hormone doses to prevent the recurrence of DTC, maintaining them in mild iatrogenic thyrotoxicosis according to current treatment guidelines.2 The authors neglected to consider that thyrotoxicosis is an independent risk factor for leukemia7,8 (ie, the confounding variable). It is near certain that patients who underwent RAIT were also more commonly treated with supraphysiologic thyroid hormone replacement, possibly developing AML and CML as a result of the risk conferred by the thyrotoxicosis instead of the RAIT. Finally, Molenaar et al applied hypothetical dose-response analysis to the same database, evaluating the relationship of RAIT and chronic myeloid neoplasms.9 Whereas all other analyses in the two synchronous papers were identical, it is puzzling not to find a similar attempt at confirming the presumed dose-response relationship of their findings in this closely related publication. In conclusion, the study is severely hampered by exclusive focus on the harms of RAIT, paying minimal attention to possible benefits and neglecting an important confounding variable (thyrotoxicosis) that could have explained the increased leukemia risk in the RAIT group. Therefore, we strongly disagree with the firm conclusion that recommends withholding RAIT (the current standard of care) from the suggested patients with DTC on the basis of the small absolute risks associated with AML and CML.

Mark Tulchinsky Pennsylvania State University, Hershey, PA

Richard P. Baum Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Bad Berka, Germany

K. G. Bennet American College of Nuclear Medicine, Downers Grove, IL

Leonard M. Freeman Albert Einstein College of Medicine, Bronx, NY

Ian Jong Monash Health, Melbourne, Victoria, Australia

Kalevi Kairemo Docrates Cancer Center, Helsinki, Finland

Carol S. Marcus David Geffen School of Medicine at University of California, Los Angles, Los Angeles, CA

Renee M. Moadel Albert Einstein College of Medicine, Bronx, NY

Paritosh Suman Columbia University–Harlem Hospital Center, New York, NY


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Corresponding author: Mark Tulchinsky, MD, FACNM, Pennsylvania State University, Section of Nuclear Medicine, Department of Radiology, 500 University Dr, Hershey, PA 17033; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 3, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

Correspondence


Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] doi:10.1200/JCO.2017. 75.0232 2. Haugen BR, Alexander EK, Bible KC, et al: 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133, 2016 3. Ruel E, Thomas S, Dinan M, et al: Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer. J Clin Endocrinol Metab 100:1529-1536, 2015

4. Franklyn JA, Maisonneuve P, Sheppard M, et al: Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: A population-based cohort study. Lancet 353:2111-2115, 1999 5. Doss M: Linear no-threshold model vs. radiation hormesis. Dose Response 11:495-512, 2013 6. Yu HS, Liu ZM, Yu XY, et al: Low-dose radiation induces antitumor effects and erythrocyte system hormesis. Asian Pac J Cancer Prev 14:4121-4126, 2013 7. Jiang Y, Hu K, Xie W, et al: Hyperthyroidism with concurrent FMS-like tyrosine kinase 3-internal tandem duplication-positive acute promyelocytic leukemia: A case report and review of the literature. Oncol Lett 7:419-422, 2014 8. Moskowitz C, Dutcher JP, Wiernik PH: Association of thyroid disease with acute leukemia. Am J Hematol 39:102-107, 1992 9. Molenaar RJ, Pleyer C, Radivoyevitch T, et al: Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine. Leukemia 32:952-959, 2018


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Well-Founded Recommendations for Radioactive Iodine Treatment of Differentiated Thyroid Cancer Require Balanced Study of Benefits and Harms The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Mark Tulchinsky No relationship to disclose

Ian Jong No relationship to disclose

Richard P. Baum Stock or Other Ownership: Advanced Accelerator Applications Honoraria: Advanced Accelerator Applications, ITG Consulting or Advisory Role: Ipsen Research Funding: Advanced Accelerator Applications (Inst), ITG (Inst)

Kalevi Kairemo No relationship to disclose

K. G. Bennet No relationship to disclose

Renee M. Moadel Travel, Accommodations, Expenses: BTG

Leonard M. Freeman Consulting or Advisory Role: Jubilant DraxImage

Paritosh Suman No relationship to disclose

jco.org

Carol S. Marcus No relationship to disclose




Reply to A. Piccardo, et al, E. Hindié, et al, M. Kreissl, et al, M. Doss, J. Buscombe, R. Fisher, M. Sollini, et al, M. Lichtenstein, and M. Tulchinsky, et al Piccardo et al,1 Hindié et al,2 Kreissl and Grande,3 Doss,4 Buscombe,5 Fisher,6 Sollini and Chiti,7 Lichtenstein,8 and Tulchinsky et al9 have provided feedback seeking clarity about several aspects of our study. In the space provided, we have chosen to elaborate on the main themes distilled from these correspondences. First and foremost, our study is a risk characterization study and was not designed to evaluate treatment efficacy.10 We reported an increased risk of second hematologic malignancy (SHM) in patients with well-differentiated thyroid cancer (WDTC) who were treated with radioactive iodine (RAI), even in low-risk and intermediate-risk WDTC cases where the clinical benefit of RAI is unclear at best, as described in the American Thyroid Association treatment guidelines.11 The claim that the use of adjuvant RAI confers survival or recurrence benefits in patients with WDTC is based on anecdotal experience and expert opinion as opposed to rigorous prospective studies. We do not dispute the role of adjuvant RAI in patients with high-risk WDTC, but for low-risk tumors, no study has demonstrated any survival or recurrence benefit with adjuvant RAI. A US National Cancer Database study that showed a survival benefit with RAI in intermediate-risk tumors has been cited as definitive evidence for routine use of RAI in this cohort12; however, a systematic review that consisted of 26 studies (2008 to 2014) failed to establish treatment efficacy for RAI in patients with intermediate-risk disease.13 Available data justify the use of RAI in certain intermediate-risk subgroups characterized by advanced age, adverse histologies, or extensive locally advanced or nodal disease.11 Two randomized clinical trials in Europe—the IoN study (ClinicalTrials.gov identifier: NCT01398085) and the ESTIMABL2 study (ClinicalTrials.gov identifier: NCT01837745)—will provide clarity on the use of RAI in these cohorts. Despite the paucity of evidence pointing to a clinical benefit, increased use of RAI has paralleled the increase in incidence of low-risk WDTC (Fig 1). In National Cancer Database surveys, patient and tumor characteristics explained only 21% of the variation in the use of RAI among hospitals.14 For stage I WDTCs, the likelihood of RAI use was significantly increased if the nuclear medicine provider was the primary decision maker (compared with endocrinologist or surgeon), if there were more providers administering RAI and who had access to a tumor board.14 SEER reports on the pathologic stage of the disease—or its equivalent—but not on other disease variables, such as multifocality, vascular invasion, and R0 status that are used for risk stratification.15 Because of this inherent limitation, we selected low-risk and intermediate-risk WDTC tumors using criteria that


best matched the American Thyroid Association classification (T1-2N0/xM0/x for low risk and T1-3N1/xM0/x with age , 45 years for intermediate risk). There are several instances of flawed methodology across the correspondences, which leads the authors to results that are incongruent with our findings— calculating absolute risk using unadjusted rates, direct risk comparison between treatment cohorts using standardized incidence ratios (SIRs), and interpretations on the basis of crude incidence numbers. We developed our methodology to avoid these shortcomings and adequately compare risks between treatment groups from SEER data. We used Fine-Gray competing risk regression (CRR) analysis to compare patients with WDTC who were treated with surgery and RAI with those who were treated with surgery alone, controlling for other covariates, including WDTC risk.10 SIRs were calculated to compare SHM incidence rates in patients with WDTC with the background population (United States) and are analyses that should be interpreted only in that context, not used to directly compare the WDTC treatment groups head-to-head. We additionally performed SHM risk analysis using Cox proportional hazards regression (the preferred approach of prior published studies) and the results were unchanged, which further validates our findings. At the suggestion of Hindié et al,2 we incorporated WDTC risk as a covariate in multivariable CRR analysis of SHM risk in low-risk and intermediate-risk WDTC. The higher risk of acute myeloid leukemia (AML) in intermediate-risk disease was not surprising considering the likelihood that these patients received higher cumulative doses of RAI compared with those with low-risk disease. This is consistent with the known dose-dependent leukemogenic effect of RAI.16 Even after adjusting for WDTC risk in the multivariable CRR model, RAI receipt (yes or no) was independently associated with a significantly increased risk of AML. As SHM includes several different hematologic malignancy entities that are biologically heterogeneous with disparate natural histories, interpreting the risk of the individual SHM entity is clinically more relevant. In response to the question by Piccardo et al1 of significant associations of SHMs with male sex as shown in Table 2 of the article,10 the findings are not surprising, as the rates of these cancers are higher in males than in females.15 Although we observed a lower risk of developing multiple myeloma with RAI exposure, the upper limit of the hazard ratio for multiple myeloma approached 1 (95% CI, 0.44 to 0.97). Whereas Doss and Tulchinsky et al9 hypothesize that this may be the result of radiation hormesis, we have refrained from speculation with regard to an explanation for this borderline significant but likely not clinically meaningful result. To clarify the question by Hindié et al2 on how death from AML was differentiated from death from myelodysplastic syndrome that progressed to AML in patients with WDTC, we used death from any cause and not disease-specific mortality in our primary survival analysis. In reply to questions raised by Tulchinsky et al,9 Lichtenstein,8 Fisher,6 Doss,4 and Sollini and Chiti7 regarding the risk of second solid tumors after RAI, we show significantly elevated SIR for solid © 2018 by American Society of Clinical Oncology

Corresponding author: Sudipto Mukherjee, MD, PhD, MPH, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: [email protected]. Downloaded from ascopubs.org by Penn State Milton S Hershey Medical Center on May 4, 2018 from 150.231.246.001 Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

1

A

B Incidence per 100,000 PYs

15

Total Low risk Intermediate risk

10

5

0 1985

1990

1995

2000

2005

2010

Patients With WDTC Treated With RAI (%)

Correspondence

100

Total Low risk Intermediate risk

80

60

40

20

0 1985

1990

1995

2000

2005

2010

Year of PY Accrual

Year of PY Accrual

D

C

Total

0.25

100

Mortality per 100,000 PYs

Patients Attaining 5-Year Survival (%)

Low risk

95

90

85

Total Low risk

Intermediate risk

0.20

0.15

0.10

0.05

Intermediate risk

0.00

80 1985

1990

1995

2000

2005

2010

Year of PY Accrual

1985

1990

1995

2000

2005

2010

Year of PY Accrual

Fig 1. (A) Incidence of well-differentiated thyroid cancer (WDTC) per 100,000 person-years (PYs) shown on the y-axis by disease risk. (B) Percentage of patients with WDTC who were treated with radioactive iodine on the y-axis by disease risk. (C) Percentage of patients with WDTC who survived at least 5 years by disease risk. (D) Mortality per 100,000 PYs on the y-axis by disease risk. Data are from 1973 through 2014 and derived from all 18 SEER registries.

tumors with RAI exposure (SIR, surgery alone, 1.00 [95% CI, 0.97 to 1.04]; P 5 1.00; surgery and RAI, 1.14 [95% CI, 1.10 to 1.18]; P , .001; attributable risk from RAI, 1.14 [95% CI, 1.08 to 1.19]; P , .001). RAI was also associated with a significantly elevated risk for solid tumors in multivariable CRR analysis (hazard ratio, 1.21 [95% CI, 1.14 to 1.28]; P , .0001; Table 1). The table by Doss that lists SIRs is erroneous as the SIR calculations were performed without adjusting the incidence rates to the background population or the follow-up duration in each treatment group. SEER reports on RAI that is received as an initial course of treatment but does not have information on RAI dose or the date of administration, delayed RAI, post-RAI therapy scans, or thyroid hormone–suppressive doses. As requested by the correspondents, to account for overascertainment bias in the RAI group—higher detection as a result of rigorous follow-up—we excluded all SHMs that were detected within 24 months of WDTC diagnosis before assessment of SHM risk. AML and chronic myeloid leukemia risks remained significantly elevated. Our findings show increased risk 2


even with lower RAI doses. The presence of clonal hematopoiesis of indeterminate potential–associated somatic mutations at the time of diagnosis of first cancer and higher prevalence of inherited mutation in patients with cancer (8.5% to 12.6%) compared with noncancer individuals (1% to 2.7%) suggest this is biologically plausible.17,18 RAI, even at lower doses, may thus be the last hit—that is, somatic mutation—needed to induce myeloid malignancy. The role of supraphysiologic thyroxine doses or clonal hematopoiesis of indeterminate potential in the promotion of leukemogenesis in RAItreated patients with WDTC cannot be answered using SEER registries and must be investigated in prospective studies. Sollini and Chiti7 and Kreissl and Grande3 questioned the inclusion of WDTCs identified by International Classification of Diseases for Oncology, Third Revision, codes 8130, 8450, and 8452. These are all WDTCs per the SEER official Site/Histology Validation List. Correspondents pointed out discrepancies between Figure 1 and the text which were a result of typographical errors and have been corrected in the errata. It is regrettable that some JOURNAL OF CLINICAL ONCOLOGY


Correspondence

Table 1. Multivariable Competing Risk Regression Analysis of Risk of Developing Solid Tumors in Patients With Well-Differentiated Thyroid Cancer 1-Year Cutoff

2-Year Cutoff

Covariate

HR (95% CI)

P

HR (95% CI)

P

Age, per year Race Black v white Other v white Sex Male v female Year of diagnosis, per year Stage Regional v localized Metastasized v localized Histology Follicular v papillary Tumor size, cm .2v,2 Treatment RAI v no radiation

1.05 (1.04 to 1.05)

, .001

1.04 (1.04 to 1.05)

, .001

1.07 (0.96 to 1.20) 0.81 (0.74 to 0.88)

.22 , .001

1.08 (0.95 to 1.22) 0.82 (0.75 to 0.90)

.23 .001

1.34 (1.26 to 1.42) 0.92 (0.92 to 0.93)

, .001 , .001

1.34 (1.25 to 1.43) 0.92 (0.92 to 0.92)

, .001 , .001

0.95 (0.89 to 1.01) 0.85 (0.70 to 1.02)

.08 .08

0.95 (0.88 to 1.01) 0.91 (0.75 to 1.10)

.10 .33

0.92 (0.83 to 1.02)

.11

0.94 (0.84 to 1.05)

.27

0.90 (0.85 to 0.96)

.0009

0.92 (0.87 to 0.98)

.014

1.19 (1.12 to 1.26)

, .001

1.21 (1.14 to 1.28)

, .001

NOTE. Shown are hazard ratios (HRs) and 95% CIs for developing a nonsynchronous ($ 1 year or $ 2 year after well-differentiated thyroid cancer diagnosis) second solid tumor in patients with well-differentiated thyroid cancer, calculated using Fine-Gray competing risk regression analyses. Multivariable analysis was subjected to a backward selection procedure to generate the final model. Abbreviation: RAI, radioactive iodine.

authors questioned our academic ethics by accusing us of splitting the findings of a single research project into two publications without fact finding.10,19 These are two entirely different studies analyzing completely different sets of hematologic malignancies. Of importance, the study methodology to analyze chronic myeloid neoplasms presents unique challenges because of the diagnostic complexities and reporting timeframe in SEER (only since 2001).19 We addressed this during our anonymous peer-review process, and explanations for separating the analyses are provided in the Appendix of the manuscript.10 Lastly, hematologic malignancies are rare—fewer than five to six cases per 100,000 person-years—and SHMs are even rarer, hence absolute SHM risks will be low. In the absence of incontrovertible evidence that RAI is beneficial for patients with low-risk and some intermediate-risk WDTC,11 and the overall dismal prognosis of therapy-related AML, routine use of RAI in these patients needs to be critically reassessed and avoided when possible.

Remco J. Molenaar Cleveland Clinic, Cleveland, Ohio, and University of Amsterdam, Amsterdam, the Netherlands

Surbhi Sidana Cleveland Clinic, Cleveland, Ohio, and Mayo Clinic, Rochester, MN

Tomas Radivoyevitch, Aaron T. Gerds, Hetty E. Carraway, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneed S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee Cleveland Clinic, Cleveland, Ohio

ACKNOWLEDGMENT

Supported by the American Cancer Society. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at jco.org. jco.org

REFERENCES 1. Piccardo A, Puntoni M, Verburg FA, et al: Power of absolute values to avoid data misinterpretations: The case of radioiodine-induced leukemia and myelodysplasia. J Clin Oncol doi:10.1200/JCO.2018.77.7318 ´ 2. Hindie´ E, Recher C, Zerdoud S, et al: Risk of hematologic malignancies after radioiodine treatment of thyroid cancer: An unjustified warning. J Clin Oncol doi: 10.1200/JCO.2018.78.1096 3. Kreissl MC, Grande E: Inconclusive analysis of the connection between secondary hematologic malignancies and radioiodine treatment. J Clin Oncol doi: 10.1200/JCO.2018.78.1054 4. Doss M: Selective focus on rare hematologic malignancies misleads riskbenefit assessment of radioiodine therapy of thyroid cancer. J Clin Oncol doi: 10.1200/JCO.2018.78.0981 5. Buscombe J: Radioiodine and its relationship to hematologic malignancy: The confounding role of supraphysiologic thyroxine. J Clin Oncol doi:10.1200/ JCO.2018.78.0395 6. Fisher R: Questionable relevance of leukemia risk after radioiodine ablation of thyroid cancer. J Clin Oncol doi:10.1200/JCO.2018.78.1534 7. Sollini M, Chiti A: Concerns about the risk of myeloid malignancies after radioiodine therapy in thyroid cancer. J Clin Oncol doi:10.1200/JCO.2018. 78.1419 8. Lichtenstein M: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol doi:10.1200/JCO.2018.78. 5675 9. Tulchinsky M, Baum RP, Bennet KG, et al: Well-founded recommendations for radioactive iodine treatment of differentiated thyroid cancer require balanced study of benefits and harms. J Clin Oncol doi:10.1200/JCO.2018.78.5972 10. Molenaar RJ, Sidana S, Radivoyevitch T, et al: Risk of hematologic malignancies after radioiodine treatment of well-differentiated thyroid cancer. J Clin Oncol [epub ahead of print on December 18, 2017] doi:10.1200/JCO.2017. 75.0232 11. Haugen BR, Alexander EK, Bible KC, et al: 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133, 2016 12. Ruel E, Thomas S, Dinan M, et al: Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer. J Clin Endocrinol Metab 100:1529-1536, 2015 13. Lamartina L, Durante C, Filetti S, et al: Low-risk differentiated thyroid cancer and radioiodine remnant ablation: A systematic review of the literature. J Clin Endocrinol Metab 100:1748-1761, 2015 14. Haymart MR, Banerjee M, Yang D, et al: The role of clinicians in determining radioactive iodine use for low-risk thyroid cancer. Cancer 119:259-265, 2013



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Correspondence

15. US National Cancer Institute: SEER incidence data, 1973-2014. https://seer. cancer.gov/data/ 16. Teng CJ, Hu YW, Chen SC, et al: Use of radioactive iodine for thyroid cancer and risk of second primary malignancy: A nationwide population-based study. J Natl Cancer Inst 108:djv314, 2015 17. Gillis NK, Ball M, Zhang Q, et al: Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: A proof-of-concept, case-control study. Lancet Oncol 18:112-121, 2017

18. McNerney ME, Godley LA, Le Beau MM: Therapy-related myeloid neoplasms: When genetics and environment collide. Nat Rev Cancer 17:513-527, 2017 19. Molenaar RJ, Pleyer C, Radivoyevitch T, et al: Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine. Leukemia 32:952-959, 201


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Correspondence


Reply to A. Piccardo, et al, E. Hindié, et al, M. Kreissl, et al, M. Doss, J. Buscombe, R. Fisher, M. Sollini, et al, M. Lichtenstein, and M. Tulchinsky, et al The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Remco J. Molenaar No relationship to disclose

Aziz Nazha No relationship to disclose

Surbhi Sidana Honoraria: Janssen Pharmaceuticals Consulting or Advisory Role: Janssen Pharmaceuticals

David J. Adelstein No relationship to disclose

Tomas Radivoyevitch No relationship to disclose Aaron T. Gerds Consulting or Advisory Role: Incyte (Inst), AstraZeneca (Inst), CTI BioPharma (Inst) Research Funding: CTI BioPharma (Inst), Pfizer (Inst), Incyte (Inst), Genentech (Inst), Gilead Sciences (Inst), Celgene (Inst) Hetty E. Carraway Honoraria: Celgene, Novartis, Baxalta, Jazz Pharmaceuticals, Agios Consulting or Advisory Role: Jazz Pharmaceuticals, Celgene, Agios, Astellas Pharma, H3 Biomedicine, Baxalta Speakers’ Bureau: Celgene, Agios, Baxalta, Novartis Research Funding: Celgene (Inst) Travel, Accommodations, Expenses: Celgene, Agios, Astellas Pharma, Baxalta

Christian Nasr Honoraria: Sanofi, Nevro, Shire, Eisai Speakers’ Bureau: Sanofi, Shire Travel, Accommodations, Expenses: Sanofi, Nevro, Veracyte Jaroslaw P. Maciejewski No relationship to disclose Navneet S. Majhail Consulting or Advisory Role: Anthem Travel, Accommodations, Expenses: Sanofi Mikkael A. Sekeres Consulting or Advisory Role: Celgene, Millennium Pharmaceuticals Sudipto Mukherjee Honoraria: Novartis Consulting or Advisory Role: Novartis, Takeda, Bristol-Myers Squibb Research Funding: Novartis (Inst), Celgene (Inst)

Matt Kalaycio No relationship to disclose

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