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Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer

Publication: Journal of Clinical Oncology

Abstract

Purpose

To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI).

Methods

Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed.

Results

Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06).

Conclusion

Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.

Introduction

Papillary and follicular thyroid carcinomas are well differentiated thyroid cancers (WDTCs) and comprise > 90% of all thyroid cancer cases in the United States.1 Definitive therapy for WDTC is thyroidectomy with adjuvant radioactive iodine (RAI) to ablate residual or unresectable disease.2 In the last three decades, the incidence of WDTC increased four-fold, with the majority of the increase attributed to improved detection of small, low-risk tumors.1,9 Although adjuvant RAI improves overall and disease-free survival in advanced-stage WDTC, most studies report little or no benefit from RAI in low-risk and intermediate-risk tumors,2 where 5-year recurrence-free survival is already > 97% without RAI.4 Because the widespread use of adjuvant RAI has not improved survival,1 its clinical benefit in the treatment of WDTC is controversial.5 Furthermore, several meta-analyses have reported an increase in the incidence of second primary malignancies in patients with WDTC treated with RAI.6,7
Second hematologic malignancies (SHMs) occurring in patients treated for first cancers are a rare and devastating complication. In addition, the determination of whether acute myeloid leukemia (AML) is treatment related or not has significant prognostic and treatment implications.8,9 Although prior studies have shown an increased risk of SHMs in RAI-treated patients with WDTC, these analyses grouped all types of leukemia under one broad category.3,7,8,10-15 This approach oversimplifies risk estimation, considering the biologic heterogeneity among and within SHM entities, their disparate natural histories, and variable prognosis. Acknowledging the differences in pathogenesis and risk factors of different SHMs, we investigated the risk of developing acute and chronic leukemias of both myeloid and lymphoid lineage, lymphomas, and multiple myeloma in patients with WDTC treated with RAI and assessed outcomes.

Methods

Study Design and Participants

The study cohort was assembled using the April 2017 release of all 18 registries of the SEER program of the National Cancer Institute. SEER provides data from population-based cancer registries, which cover approximately 28% of the US population. Patients were excluded from analysis if their thyroid malignancy was not of follicular or papillary histology (Data Supplement); if they received treatment with chemotherapy or tyrosine kinase inhibitors; if WDTC was not their first cancer; if their hematologic malignancy (HM) was a first, third, or higher order primary cancer; if they received external-beam radiotherapy; and if radiation or survival status was unknown. The primary outcome of interest was the development of SHM, defined as a nonsynchronous HM occurring ≥ 1 year after treatment of WDTC. SHMs included in this study were AML, chronic myeloid leukemia (CML), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma (MM), as defined by International Classification of Diseases for Oncology (3rd edition) histology codes and International Classification of Diseases (9th and 10th revision) codes (Data Supplement). Myelodysplastic syndromes (MDS) and Philadelphia chromosome-negative myeloproliferative neoplasms were excluded because of SEER-related differences between the reporting of MDS and Philadelphia chromosome-negative myeloproliferative neoplasms ALL, AML, CLL, CML, Hodgkin lymphoma, non-Hodgkin lymphoma, and MM (Data Supplement). SHMs occurring < 1 year after WDTC diagnosis were also excluded.16 Low-/intermediate-risk patients with WDTC were defined per the latest American Thyroid Association guidelines as T1-2N0 tumors ≤ 4 cm in size or T1-3N1 tumors in patients older than 45 years of age.2

Procedures

A previously validated R program, SEERaBomb,17 was used to assess risks of SHM after WDTC treatment in the SEER cohort and a subset of low-/intermediate-risk WDTCs. SEERaBomb was preferred over SEER*Stat MP-SIR (Multiple Primary-Standardized Incidence Ratio), a statistical companion tool developed by the National Cancer Institute, because SEERaBomb captures more patients with second primary cancer (Data Supplement). SHM risk dynamics after diagnosis of WDTC treated with surgery alone or surgery plus RAI were estimated using methodology previously published.17 SEERaBomb was used to calculate relative risk (RR) time courses for developing SHM after WDTC treatment on the basis of the ratio of the observed and expected patients with SHM for each WDTC treatment group. The expected number of patients with SHM was calculated using the background incidence rates of HMs in the US population and the person-years at risk for an SHM after treatment of WDTC as first cancer. RRs were adjusted for age at diagnosis, sex, and year of diagnosis. Additional potential covariables of interest analyzed are described in the Data Supplement. To assess outcomes of patients with WDTC who developed an SHM, we performed survival analyses using two separate case-control designs, in which each patient with WDTC who developed SHM was compared with either five patients with WDTC who did not develop SHM or with five patients whose HM occurred de novo. Cases and controls were matched by histology, type of treatment received, tumor stage, tumor size, age at diagnosis, sex, year of WDTC/HM diagnosis, and race, in that order of priority.

Statistical Analysis

RRs and RAI-attributable RR ratios with 95% CIs and P values were calculated as described in the Data Supplement and explained previously.18 Because of the low event rate of SHMs, Fine-Gray competing risk regression analyses19 were performed with SHM as a time-dependent end point and death from all causes or development of non-SHM malignancy were treated as competing events to calculate hazard ratios (HRs) with 95% CIs of developing an SHM after WDTC. Censoring occurred at follow-up cutoff defined by the April 2017 SEER release (January 1, 2015), death, development of a second primary cancer other than the HM of interest, or when 20 years of follow-up after WDTC treatment were reached, whichever occurred first. Cox regression and standardized incidence ratio (SIR) calculations were performed to compare our results with previous studies that used these procedures to assess hazards of developing an SHM after WDTC treatment. Variables significant at an alpha level of .05 (two-sided) in univariable analyses were included in multivariable analyses. The final multivariable models were built using a backward selection procedure. For regression analyses and SIR calculations, the follow-up period was limited to 20 years to focus on early-onset SHMs because SHMs occurring in relatively young survivors of WDTC have treatment implications. Survival plots were made using the Kaplan-Meier method, and P values for overall survival (OS) comparisons were calculated using the Gehan-Breslow-Wilcoxon test to provide extra weight to early outcomes. All statistical analyses were performed using R software, and all scripts used to produce the results of this study are provided in the Data Supplement.

Results

Patient Characteristics

Of the 183,894 patients with thyroid cancer identified from the SEER database, 148,215 patients met the inclusion criteria (Fig 1). Baseline demographic and disease characteristics of patients with WDTC by treatment modality are listed in Table 1. A total of 79,033 patients (53%) received surgery alone, and 68,374 patients (47%) received surgery plus RAI. Among the survivors of WDTC, a total of 783 nonsynchronous SHMs were identified, 417 (53%) after surgery alone and 366 (47%) after surgery plus RAI (Data Supplement). Comparisons of characteristics of patients with WDTC on the basis of RAI treatment status who later developed SHM versus those who did not are shown in the Data Supplement.
Fig 1. Population-based assessments of second hematologic malignancy (SHM) risks after well-differentiated thyroid cancers (WDTCs). SEER covers an increasing proportion of the US population, 1.97 billion person-years (PYs) since 1973. Shown is a flowchart of the inclusion of patients with WDTC and SHM and their use in calculations of relative risks (RRs) of SHM occurrence after WDTC. RRs are the number of observed patients with SHM after WDTCs divided by the number of expected patients with SHM after WDTCs. The latter is the background incidence rate of SHM per PY, which is calculated by dividing the number of hematologic malignancy (HM) patients by (B) the number of PYs at risk in the general population (A). Separate calculations were performed for each year of age, sex, and year of diagnosis. This was then multiplied by (C), the PYs at risk among WDTC survivors in these demographic cohorts to obtain the expected number of patients with SHMs after WDTCs. In the boxes entitled, “Expected patients with SHM after WDTC. Background on the basis of PYs divided by patients in panels A though C,” the numbers in the boxes represent the expected numbers of patients with SHM diagnosed <1 year or <1 year after WDTC diagnosis, separated by treatment (surgery or surgery+RAI). In box “PYs at risk for SHM after WDTC,” the total number of patients excludes 808 patients with insufficient follow-up. AML, acute myeloid leukemia; CML. chronic myeloid leukemia; CT, chemotherapy; IR, ionizing radiation; EBRT, external beam radiotherapy; int, intermediate; RAI, radioactive iodine; TKI, tyrosine kinase inhibitor; y, year.
Table 1. Baseline Characteristics of Patients With WDTC by Treatment Type, 1973-2014

Risk of SHMs by Treatment Modality

All patient characteristics listed in Table 1 were tested for associations with SHMs as the outcome of interest in univariable (Data Supplement) and multivariable Fine-Gray competing risk regression analysis (Table 2). In multivariable analysis, surgery plus RAI was associated with a significant increase in the risk of developing SHMs (pooled as a group) compared with surgery alone (HR, 1.43; 95% CI, 1.20 to 1.69; P < .001). When analyzed by SHM type, the elevated risk was significant for AML (HR, 1.79; 95% CI, 1.13 to 2.82; P = .01) and CML (HR, 3.44; 95% CI, 1.87 to 6.36; P < .001), but no other SHMs (Table 2). The cumulative risk of any SHM in the first 10 years after WDTC treatment was 0.40% after surgery alone and 0.54% after surgery plus RAI. Cumulative risks of AML and CML during the same time period were 0.08% and 0.01% after surgery alone and 0.12% and 0.06% after surgery plus RAI, respectively. SIR calculations were used to compare the incidence of SHMs among survivors of WDTC with the incidence rates of these HMs in the US population, adjusted for age, sex, and year of WDTC diagnosis. SIRs for the development of all SHMs combined were higher after both surgery alone (SIR, 119; 95% CI, 107 to 132; P = .001) and surgery plus RAI (SIR, 155; 95% CI, 140 to 173; P < .001; Table 3 and Data Supplement). When analyzed by specific SHM, SIRs after surgery plus RAI were significantly higher for ALL, AML, CLL, CML, and non-Hodgkin lymphoma. Excess risk attributable to RAI was observed for all SHMs combined (SIR, 130; 95% CI, 112 to 151; P = .001), and individually for AML (SIR, 211; 95% CI, 142 to 330; P = .001), CLL (SIR, 170; 95% CI, 108 to 269; P = .02), and CML (SIR, 387; 95% CI, 210 to 780; P < .001; Table 3). Conversely, RAI treatment was associated with decreased risk of developing MM (HR, 0.65; 95% CI, 0.44 to 0.97; P = .04; Table 2) and lower SIR (SIR, 68; 95% CI, 45 to 98; P = .05; Table 3).
Table 2. Multivariable Competing Risk Regression Analysis of Risk of Developing Hematologic Malignancies in Patients with WDTC
Table 3. SIRs of SHMs in Patients With WDTC

Risk Dynamics of SHMs After WDTC Treatment

RR time courses and time-to-event courses of developing SHMs after WDTC are shown in Figures 2A, 2B, 2C, and 2D and the Data Supplement. Compared with the background incidence rate of AML, an early increase in the risk of AML was observed in patients with WDTC treated with surgery and RAI that peaked in the second year after treatment (RR, 7.1; 95% CI, 4.3 to 11.2; P < .001; Fig 2A). Beyond 2 years, the risk of AML declined, reaching baseline rates within 6 years after WDTC diagnosis. A similar significant increase in risk of CML was observed in the second year after RAI exposure compared with the background rates; however, this risk remained elevated up to 10 years after WDTC diagnosis (RR for years 2 to 10, 6.3; 95% CI, 4.4 to 8.8; P < .001; Fig 2C). In time-to-event analyses, surgery plus RAI was significantly associated with an increased risk of developing AML compared with surgery alone (HR, 1.6; 95% CI, 1.1 to 2.4; P = .01; Fig 2B) and CML (HR, 2.9; 95% CI, 1.7 to 5.2; P = .001; Fig 2D) but no other SHMs in patients with WDTC treated with adjuvant RAI compared with thyroidectomy alone (Data Supplement). When the RRs of the surgery alone and surgery plus RAI groups were directly compared using radiation-related RR ratios, we observed increased radiation-related RR ratios for AML and CML but no other SHMs (Data Supplement).
Fig 2. Risk time courses for developing second hematologic malignancy (SHM) after well-differentiated thyroid cancer (WDTC) diagnosis. (A to D) Data for all patients with WDTC; (E to H) data for patients with low-/intermediate-risk WDTC (as defined by the American Tumor Association).2 (A, C, E, G) Plotted are mean relative risks (RRs) ± 95% CIs of developing (A, E) acute myeloid leukemia (AML) or (C, G) chronic myeloid leukemia (CML) as second cancer, on the basis of WDTC treatment type compared with the background US population, which is represented by the black line at y = 1. The number of person-years at risk, expected and observed patients, RRs, and 95% CIs for each RR time course graph are shown in the Data Supplement. Risk-time courses for SHMs other than AML or CML are shown in the Data Supplement. (B, D, F. H) Plotted are the percentage of patients with WDTC diagnosed with (B, F) AML or (D, H) CML as function of the years after WDTC diagnosis. Patients were censored at death, when they were alive at January 1, 2015, or when they developed a non-SHM second cancer. Additional hazard curves are shown in the Data Supplement. P values were calculated using the Gehan-Breslow-Wilcoxon test. RAI, radioactive iodine.

Risk of SHMs in Low-/Intermediate-Risk WDTCs

In a subset analysis among patients with low-risk or intermediate-risk WDTCs, where adjuvant RAI carries no or questionable clinical benefit,2 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; 95% CI, 1.46 to 5.63; P = .002) and CML (HR, 3.94; 95% CI, 1.58 to 9.82; P = .003; Data Supplement). RAI treatment was also associated with increased RRs and decreased SHM-free survival for AML and CML in patients with low-risk or intermediate-risk WDTCs (Figs 2E, 2F, 2G, and 2H and Data Supplement).

Outcomes After Development of AML and CML

Regardless of the type of treatment received, patients with WDTC who developed AML had shorter OS compared with matched patients with WDTC who did not (median OS, 8.0 years v 31.0 years; P = .001; Fig 3A and Data Supplement). Between the WDTC treatment groups, there was a trend toward truncated OS in those who developed AML after surgery plus RAI compared with patients who developed AML after surgery alone (median OS, 6.7 years v 9.4 years; P = .12). Consistent with a good prognosis of CML, the OS of patients with WDTC who developed CML after surgery alone or surgery plus RAI was not significantly different from matched controls (Fig 3B). Compared with matched population controls with de novo AML, there was no difference in the OS of patients with WDTC who developed AML after surgery, and there was a trend toward decreased OS in patients with AML after RAI treatment (median OS, 1.2 years v 2.9 years; P = .06; Fig 3C and Data Supplement). We observed no differences in OS on the basis of whether CML occurred after WDTC treatment or de novo (Fig 3D).
Fig 3. Survival curves of patients with well-differentiated thyroid cancer (WDTC) by development of acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) and by treatment type. Shown are Kaplan-Meier plots of case-control studies wherein the following groups were compared: patients with WDTC who developed (A) AML or (B) CML after WDTC treatment (cases) versus those who did not (controls); (C) patients with AML and (D) CML who were diagnosed with these diseases after treatment of WDTC (cases) versus those who developed AML or CML de novo (controls). In all figures, (2) are matched controls for (1), and (4) are matched controls for (2). P values were calculated using the Gehan-Breslow-Wilcoxon test. RAI, radioactive iodine.

Discussion

With rising incidence rates of WDTC20 and a growing population of long-term survivors of WDTC who received prior RAI, there is a clinical concern regarding the risks of adverse effects from this treatment.3,5 This concern is particularly heightened because population-level data show that a majority of patients with WDTC treated with RAI have low-risk tumors, a scenario where patients likely do not derive therapeutic benefit from adjuvant RAI but are exposed to its carcinogenic effects.11 In this population-based study, we performed a comprehensive evaluation of the risk dynamics for development of SHMs in patients with WDTC and the clinical outcome of WDTC patients who developed SHM. The main findings include that (1) patients with WDTC exposed to RAI have a significantly increased risk of AML and CML compared with background incidence rates in the US population; (2) increased risk for AML and CML is seen even in low-/intermediate-risk patients with WDTC treated with RAI; (3) the latency period for AML and CML after RAI therapy is short; (4) although the risk of AML declines quickly to baseline rates by 3 years, the risk of CML remains elevated for up to 10 years after RAI treatment; and (5) development of AML in patients with WDTC predicted for truncated survival compared with de novo AML.
Comparison of SHM risk attributable to RAI across different studies is challenging for several reasons, because of varying definitions of WDTC and SHM nomenclature, including grouping of disparate SHM histologies under broad leukemia and lymphoma categories, differences in methodologic and statistical considerations, and length of follow-up duration—all affecting the interpretation of results.3,6,7,10-15 On one hand, our RR time plots show that the median follow-up of 6.5 years after WDTC diagnosis is adequate for SHM risk assessments; on the other hand, a proportion of SHMs developing in atomic bomb survivors occurred at even later time points21 and these late occurrences may not have been captured by our analysis. We chose to use Fine-Gray competing risk regressions because this approach adequately corrects the risk of developing SHM against the competing risks of occurrence of a nonhematologic second primary malignancy or death, either WDTC-related or WDTC-unrelated. This is a critical consideration because most patients with WDTC are long-term survivors who continue to be at risk for developing solid tumor malignancies and have increased treatment-related cardiovascular mortality.22 Although the occurrence of AML23-26 and CML27 after RAI treatment of WDTC has been previously reported, to our knowledge, this is the first comprehensive report of risk dynamics of individual SHM entities over time after RAI treatment of WDTC. Furthermore, our analyses did not show increased hazards for the development of other SHMs among WDTC survivors previously treated with RAI. Although SIRs yield interesting data on the frequency of SHMs in RAI-treated WDTC survivors compared with the background population (2.5 times higher for AML and 5.3 times higher for CML), SIRs were only corrected for age, sex, and year of diagnosis, but not for other possible confounders. Whereas the Cox regression is inferior for situations where competing risks are at play, they were the preferred approach in previous studies that described second primary cancer risk after RAI treatment of WDTC.10 Therefore, we also performed Cox regression analysis to compare our results with those of previous studies and arrived at the same conclusions resulting from our competing risk regressions (Data Supplement). In conclusion, our findings clearly demonstrate increased hazards of developing myeloid leukemias but no other type of SHMs with adjuvant RAI use. An interesting finding in our study was lower risks of MM after RAI treatment compared with thyroidectomy, the possible mechanism of which needs further investigation.
This study has certain limitations. The decision to use RAI is contingent on several covariables of interest that are not captured in the SEER cohort, such as completeness of resection, tumor multicentricity, and findings from postoperative radiologic scans.2 The SEER database does not record the RAI doses administered to patients; hence, it is not possible to determine the leukemogenic dose-response effect of RAI that some non-SEER studies have shown.10,12 Another drawback is that SEER only captures radiation data during initial treatment and not if patients received delayed radiation or radiation for recurrent disease. Although this can potentially lead to misclassification of patients with RAI-positive disease into the RAI-negative cohort, this is unlikely to affect our conclusions and if at all present, might reflect an underestimation of the elevated risk attributable to RAI. Another limitation of a retrospective study such as ours is that it may be vulnerable to overascertainment bias, a possible explanation of more recorded occurrences of myeloid leukemias after RAI treatment. However, such assumptions are incompatible with the quick rise and fall in AML risk dynamics that we observed. To further address the issue of latency impacting risk estimates, we re-ran the SHM risk analysis using a 2-year cut-off that excluded all SHMs occurring within 24 months from the diagnosis of WDTC. Our repeat analysis showed that the risk of AML and CML following RAI exposure in WDTC patients continued to be significantly elevated even with 2-year cut-off (Data Supplement 2 [http://ascopubs.org/doi/suppl/10.1200/JCO.2017.75.0232/suppl_file/ds_2017.75.0232.pdf]). The strengths of this study include a large population with relatively homogenous treatment exposure; a novel methodology to maximize capture of patients with SHM across all 18 SEER registries, adjusting for competing risk in statistical analysis; and information on post-SHM outcomes.
Development of therapy-related AML is a devastating complication because of its dismal prognosis.8,9 Although patients with WDTC who developed an RAI-related AML had a worse prognosis than matched patients with de novo AML, outcomes for AML that arose after thyroidectomy were comparable to matched de novo controls. This suggests that AML that occurs after RAI treatment of WDTC resembles a treatment-related AML (t-AML) phenotype, which is characterized by inherent refractoriness to conventional chemotherapies.8,9 Our findings corroborate a previous comparison of patients with AML after RAI administration for thyroid cancer or hyperthyroidism and patients with de novo AML.25 A higher proportion of patients with AML with an antecedent history of RAI therapy harbored high-risk cytogenetic abnormalities similar to t-AML/treatment-related MDS arising after other cytotoxic anticancer treatments.25 Unfortunately, SEER does not carry genomic information to facilitate interrogation of molecular and cytogenetic features of SHM arising after RAI treatment.
Our 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.2 Furthermore, our results support using the least effective dose to treat patients who have high-risk features to avoid excess bone marrow exposure, because the risk of SHM is dose dependent.10,12 These results should also be incorporated in the surveillance strategies for patients who receive high doses of RAI to appropriately monitor blood counts to detect development of myeloid malignancies. It is encouraging to see that after the 2009 release of guidelines from American Thyroid Association, there has been a modest decrease in the use of RAI.28 Strict adherence to these guidelines is essential to decrease the catastrophic consequence of inducing t-AML with RAI in a group of cancers with high cure rates affecting a relatively young patient population.

Publisher's Note

The article by Molenaar et al entitled "Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer" (J Clin Oncol 10.1200/JCO.2017.75.0232) was published online December 18, 2017, with errors.

In Figure 1, the bar indicating thyroid cancers included read as:

Thyroid cancers included (n= 150,250)

This should have read as:

Thyroid cancers included (n= 148,215).

In box "Observed patients with SHM," the 1 y column should be the 1 y column.

Also, the numbers 410 and 360 in the column should have read as:

417 and 366, respectively.

In box "Expected number of patients with SHM after WDTC," the 1 y column should be the 1 y column.

Also, the numbers 364,3 and 241,4 in the column should have read as:

370.5 and 245.4, respectively.

In the legend of Figure 1, the following last sentence should be added:

In box "PYs at risk for SHM after WDTC," the total number of patients excludes 808 patients with insufficient follow-up.

In the legend of Table 1, the following last sentence should be added:

The total number of patients excludes 808 patients with unknown follow-up, all in the "Surgery Alone" column.

In Table 2, there is a typo in line 2 of the abbreviation list. The abbreviation for SHM reads as:

SHM, well-differentiated thyroid cancer

The abbreviation should read as:

SHM, second hematologic malignancy

In the third paragraph of the Discussion, the 7th and 8th sentences read:

However, such assumptions are incompatible with the quick rise and fall in AML risk dynamics that we observed. The strengths of this study include a large population with relatively homogenous treatment exposure; a novel methodology to maximize capture of patients with SHM across all 18 SEER registries, adjusting for competing risk in statistical analysis; and information on post-SHM outcomes.

To include reference to new additional materials, this section of the paragraph should read as:

However, such assumptions are incompatible with the quick rise and fall in AML risk dynamics that we observed. To further address the issue of latency impacting risk estimates, we re-ran the SHM risk analysis using a 2-year cut-off that excluded all SHMs occurring within 24 months from the diagnosis of WDTC. Our repeat analysis showed that the risk of AML and CML following RAI exposure in WDTC patients continued to be significantly elevated even with 2-year cut-off (Data Supplement 2 [http://ascopubs.org/doi/suppl/10.1200/JCO.2017.75.0232/suppl_file/ds_2017.75.0232.pdf]). The strengths of this study include a large population with relatively homogenous treatment exposure; a novel methodology to maximize capture of patients with SHM across all 18 SEER registries, adjusting for competing risk in statistical analysis; and information on post-SHM outcomes.

This has been corrected as of April 5, 2018. The authors apologize for the errors.

Data Supplement

Authors retain all rights in any data supplements associated with their articles

The ideas and opinions expressed in this Data Supplement do not necessarily reflect those of the American Society of Clinical Oncology (ASCO). The mention of any product, service, or therapy in this Data Supplement should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify approved uses, the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in this publication or to any errors or omissions. Readers should contact the corresponding author with any comments related to Data Supplement materials.

Authors' Disclosures of Potential Conflicts of Interest

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 = Immediate Family Member, Inst = 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

Surbhi Sidana

Honoraria: Janssen

Tomas Radivoyevitch

No relationship to disclose

Anjali S. Advani

Honoraria: Sigma-Tau, EUSA Pharma
Consulting or Advisory Role: Seattle Genetics
Research Funding: Pfizer (Inst), Millennium (Inst), KaloBios (Inst), Seattle Genetics (Inst)

Aaron T. Gerds

Consulting or Advisory Role: Incyte, AstraZeneca/MedImmune, CTI
Research Funding: Pfizer, CTI, Incyte, Roche/Genentech, Gilead Sciences, Celgene

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
Research Funding: Celgene
Travel, Accommodations, Expenses: Celgene, Agios, Astellas Pharma, Baxalta

Dana Angelini

No relationship to disclose

Matt Kalaycio

No relationship to disclose

Aziz Nazha

No relationship to disclose

David J. Adelstein

No relationship to disclose

Christian Nasr

Honoraria: Sanofi, Nevro, Shire
Speakers' Bureau: Sanofi, Shire
Travel, Accommodations, Expenses: Sanofi, Nevro

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

Sudipto Mukherjee

Honoraria: Novartis
Consulting or Advisory Role: Novartis, Takeda Pharmaceuticals, Bristol Myers Squibb
Research Funding: Novartis, Celgene

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Published In

Journal of Clinical Oncology
Pages: 1831 - 1839
PubMed: 29252123

History

Published online: December 18, 2017
Published in print: June 20, 2018

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Remco J. Molenaar
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Surbhi Sidana
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Tomas Radivoyevitch
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Anjali S. Advani
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Aaron T. Gerds
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Hetty E. Carraway
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Dana Angelini
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Matt Kalaycio
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Aziz Nazha
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
David J. Adelstein
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Christian Nasr
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Jaroslaw P. Maciejewski
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Navneet S. Majhail
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Mikkael A. Sekeres
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.
Sudipto Mukherjee [email protected]
Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, and Sudipto Mukherjee, Cleveland Clinic, Cleveland, OH; Remco J. Molenaar, University of Amsterdam, Amsterdam, the Netherlands; and Surbhi Sidana, Mayo Clinic, Rochester, MN.

Notes

R.J.M. and S.S. contributed equally to this study.
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].

Author Contributions

Conception and design: Remco J. Molenaar, Surbhi Sidana, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Sudipto Mukherjee
Financial support: Remco J. Molenaar, Sudipto Mukherjee
Administrative support: Matt Kalaycio, Mikkael A. Sekeres
Collection and assembly of data: Remco J. Molenaar, Surbhi Sidana, Sudipto Mukherjee
Data analysis and interpretation: Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, Sudipto Mukherjee
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

Funding Information

Supported by American Cancer Society, Institutional research Grant No. IRG-91-022-18 to S.M. and an AMC PhD Scholarship (2013-2017) to R.J.M.

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Remco J. Molenaar, Surbhi Sidana, Tomas Radivoyevitch, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Dana Angelini, Matt Kalaycio, Aziz Nazha, David J. Adelstein, Christian Nasr, Jaroslaw P. Maciejewski, Navneet S. Majhail, Mikkael A. Sekeres, Sudipto Mukherjee
Journal of Clinical Oncology 2018 36:18, 1831-1839

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