Risk of Diabetes Mellitus in Long-Term Survivors of Hodgkin Lymphoma

Purpose Recently, an increased risk of diabetes mellitus (DM) was observed after abdominal irradiation for childhood cancer. Because many Hodgkin lymphoma (HL) survivors have also been treated with infradiaphragmatic radiotherapy, we evaluated the association between HL treatment and DM risk. Patients and Methods Our study cohort comprised 2,264 5-year HL survivors, diagnosed before age 51 years and treated between 1965 and 1995. Treatment and follow-up information was collected from medical records and general practitioners. Radiation dosimetry was performed to estimate radiation dose to the pancreas. Cumulative incidence of DM was estimated, and risk factors for DM were evaluated by using Cox regression. Results After a median follow-up of 21.5 years, 157 patients developed DM. Overall cumulative incidence of DM after 30 years was 8.3% (95% CI, 6.9% to 9.8%). After para-aortic radiation with ≥ 36 Gy, the 30-year cumulative incidence of DM was 14.2% (95% CI, 10.7% to 18.3%). Irradiation with ≥ 36 Gy to the para-aortic lymph nodes and spleen was associated with a 2.30-fold increased risk of DM (95% CI, 1.54- to 3.44-fold) whereas para-aortic radiation alone with ≥ 36 Gy was associated with a 1.82-fold increased risk (95% CI, 1.02- to 3.25-fold). Lower doses (10 to 35 Gy) did not significantly increase risk of DM. The risk of DM significantly increased with higher mean radiation doses to the pancreatic tail (P < .001). Conclusion Radiation to the para-aortic lymph nodes increases the risk of developing DM in 5-year HL survivors. Screening for DM should be considered in follow-up guidelines for HL survivors, and treating physicians should be alert to this increased risk.

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Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

Scientific Reports ◽

10.1038/s41598-021-89216-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Robert Terziev ◽

Dimitri Psimaras ◽

Yannick Marie ◽

Loic Feuvret ◽

Giulia Berzero ◽

...

Keyword(s):

Risk Factors ◽

Cumulative Incidence ◽

High Grade Glioma ◽

High Grade ◽

Nucleotide Polymorphisms ◽

Increased Risk ◽

Radiation Induced ◽

Long Term Survivors

AbstractThe incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

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Abstract P060: Plasma Osteocalcin And Incident Diabetes Mellitus: The Atherosclerosis Risk In Communities (ARIC) Study

Circulation ◽

10.1161/circ.143.suppl_1.p060 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Jeffrey R Misialek ◽

Elizabeth R Stremke ◽

Elizabeth Selvin ◽

Sanaz Sedaghat ◽

James S Pankow ◽

...

Keyword(s):

Diabetes Mellitus ◽

Cox Regression ◽

Self Report ◽

Incident Diabetes ◽

Blood Levels ◽

Total Plasma ◽

Phone Calls ◽

Increased Risk ◽

Primary Model

Introduction: Diabetes is a major risk factor for cardiovascular disease. Osteocalcin is a vitamin K-dependent, bone-derived hormone that functions as an endocrine regulator of energy metabolism, male fertility, and cognition. Early studies of endocrine effects of osteocalcin have shown that genomic deletion of osteocalcin in mice resulted in a diabetic phenotype (i.e. glucose intolerance, and insulin resistance). However, results from clinical studies have shown mixed associations between blood levels of osteocalcin and risk of incident type 2 diabetes mellitus. Hypothesis: Lower values of plasma osteocalcin would be associated with an increased risk of diabetes. Methods: A total of 11,557 ARIC participants without diabetes at baseline were followed from ARIC visit 3 (1993-1995) through 2018. Diabetes cases were identified through self-report on annual and semi-annual follow-up phone calls. Plasma osteocalcin data was measured using an aptamer-based proteomic profiling platform (SomaLogic). We used Cox regression to evaluate the association of quintiles of plasma osteocalcin and incident diabetes. The primary model adjusted for age, sex, and race-center. Results: Participants were age 60 ± 5.6 years at visit 3, 56% identified as female, 21% identified as Black. There were 3,031 incident diabetes cases over a median follow-up of 17.9 years. Mean ± SD was 10.053 ± 0.775. When comparing the highest quintile of plasma osteocalcin (values 10.42 to 14.66) to the lowest quintile (values 9.03 to 9.52), there was no association with incident diabetes (HRs [95% CIs]: 0.92 [0.81, 1.02]). There was also no significant trend across the quintiles (p = 0.19). Results were similar when adjusting for additional potential confounders, and when limiting the follow-up time to 10 years. Conclusions: These data do not support the hypothesis that total plasma osteocalcin, as measured by Somalogic proteomic panel, is a biomarker associated with diabetes risk. It is possible that total plasma or serum osteocalcin and/or other isoforms of osteocalcin protein (i.e. gamma carboxylated or uncarboxylated osteocalcin) measured via other validated methodologies may be linked to diabetes.

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Long term perspective with LBBB: role of stress echocardiography

European Heart Journal ◽

10.1093/ehjci/ehaa946.0020 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Dedic ◽

N Boskovic ◽

V Giga ◽

M Tesic ◽

S Aleksandric ◽

...

Keyword(s):

Diabetes Mellitus ◽

Myocardial Infarction ◽

Left Bundle Branch Block ◽

Stress Echocardiography ◽

Cox Regression ◽

Survival Curve ◽

Bundle Branch Block ◽

Cox Regression Analysis ◽

Increased Risk

Abstract Background Previous studies have shown that left bundle branch block (LBBB), as a relatively common electrocardiographic (ECG) abnormality, represents the condition with often non benign and sometimes adverse outcome. Purpose The Aim of our study was to determine the predictive value of a stress echocardiography test in patients with LBBB. Methods Our study population included 189 patients (88 male, 46.6%, mean age 63.08±9.65) with diagnosed left bundle branch block who performed stress echocardiography (SECHO) according to Bruce protocol. Median follow-up of the patients was 56 months (IQR 48–71 months) for the occurrence of cardiovascular death and non-fatal myocardial infarction, repeat revascularization (coronary artery bypass grafting-CABG or percutaneous coronary intervention-PCI). Results Out of 189 patients, 32 (16.9%) patients had positive, while 157 (83.1%) patients had negative SECHO test. During the follow up period 28 patients had major adverse cardiac event: 1 nonfatal myocardial infarction, 6 heart failure hospitalizations, 5 CABGs, 8 PCIs, while 8 patients had cardiac death. Using the Cox regression analysis, univariate predictors of adverse cardiac events were diabetes mellitus (HR 4.530 [95% CI 1.355–15.141], p=0.014), PCI (HR 4.288 [95% [95% CI 2.010–9.144], p<0.001) and positive SECHO test (HR 2.289 [95% CI 1.006–5207], p=0.048). In the multivariate analysis only previous PCI remained independent predictor of adverse events (HR 3.650 [95% CI 1.665–8.003], p=0.001). p=0.048). Using the Kaplan-Meier survival curve the patients with negative SECHO had better outcome compared to patients with positive SECHO (140/160; 87,5% vs 21/29; 72.4%, p=0.035) and much longer event-free time (77.4±1.6 months vs 67.1±5.4 months, Log Rank 4.136, p=0.042) Conclusion Patients with LBBB and negative SEHO test have good prognosis. Patients with history of CAD and diabetes mellitus and LBBB are at increased risk for future events and need periodical reassessment. Funding Acknowledgement Type of funding source: None

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Treatment-related risk factors for premature menopause following Hodgkin lymphoma

Blood ◽

10.1182/blood-2007-05-090225 ◽

2008 ◽

Vol 111 (1) ◽

pp. 101-108 ◽

Cited By ~ 75

Author(s):

Marie L. De Bruin ◽

Jeannine Huisbrink ◽

Michael Hauptmann ◽

Marianne A. Kuenen ◽

Gabey M. Ouwens ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Cox Regression ◽

Alkylating Agents ◽

Cumulative Risk ◽

Premature Menopause ◽

Related Risk ◽

Increased Risk ◽

Radiotherapy Alone ◽

Actuarial Risk

We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40 years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years after treatment, the actuarial risk of premature menopause was 64% after high cumulative doses (> 8.4 g/m2) and 15% after low doses (≤ 4.2 g/m2) of procarbazine. The cumulative risk of menopause at age 40 years did not differ much according to age, but time to premature menopause was much longer in women treated at early ages. As long as alkylating agents will be used for curing HL, premature menopause will remain a frequent adverse treatment effect, with various clinical implications.

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Cardiac Outcomes in a Prospective Cohort of Adult Non-Hodgkin Lymphoma Survivors

Blood ◽

10.1182/blood.v118.21.2656.2656 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2656-2656

Author(s):

Carrie A. Thompson ◽

Hongxiu Luo ◽

Matthew J Maurer ◽

Cristine Allmer ◽

Thomas M. Habermann ◽

...

Keyword(s):

Heart Disease ◽

Hodgkin Lymphoma ◽

Valvular Heart Disease ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Medical Records ◽

P Value ◽

Non Hodgkin Lymphoma ◽

Increased Risk

Abstract Abstract 2656 Background Treatment of non-Hodgkin lymphoma (NHL) can lead to development of cardiovascular disease (CVD). We sought to describe the cumulative incidence of CVD in adult NHL survivors diagnosed in the recent treatment era (since 2002) and identify clinical and treatment predictors for its development. Methods All patients were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). The MER offers enrollment to all consecutive patients with newly diagnosed NHL who are US residents and age >18 years. Clinical data from the time of diagnosis and treatment data are abstracted from medical records using a standard protocol. Patients are prospectively contacted via telephone or in person per protocol every 6 months for the first 3 years from diagnosis and yearly afterwards to assess disease status and development of comorbid conditions. CVD events, including heart failure (HF), myocardial infarction (MI), arrhythmia, pericarditis, and valvular heart disease, occurring after diagnosis were identified during follow-up and validated against medical records. HF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. MI was validated using case definition standards of coronary heart disease, while arrhythmia, pericarditis, and valvular heart disease were validated using clinical definitions. The prevalence of CVD and associations between CVD and clinical characteristics (sex, age) and treatment (radiation, anthracyclines) were performed using Cox models with a competing risk approach. Results 1164 patients with NHL were enrolled into the MER at Mayo Clinic between 9/1/2002–2/28/2008. 646 were male (56%) and median age at diagnosis was 62 years (range 20–93). Median follow-up of all cases was 59 months (range 1–105). 131 patients reported CVD prior to the diagnosis of NHL and were excluded from analyses. An additional 76 patients did not have follow-up and were excluded. Of the 957 remaining patients, 75 (7.8%) self-reported a new diagnosis of CVD. Of these, 71 cases had available medical records. 57 of the 71 reviewed cases (80%) were validated (18 HF, 9 MI, 21 arrhythmia, 2 pericarditis, and 10 valvular heart disease). Cumulative incidence of CVD at 1, 3, 5, and 7 years was 1.3%, 3.7%, 5.2%, and 7.4%, respectively. Median time from NHL diagnosis to CVD was 26.5 months (range 1–84). Older age was associated with increased risk of overall CVD (p-value<0.001). Gender (p=0.59), radiation therapy (p=0.61), and anthracycline treatment (p=0.25) were not associated with the incidence of overall CVD. Among types of CVD, anthracycline use was associated with development of HF (HR=5.30; p-value=0.008) and arrhythmia (HR=2.68; p-value=0.04). Radiation was associated with development of arrhythmia (HR=2.73; p-value=0.03), while older age was associated with development of HF (HR=1.36 per 5 year increment; p-value=0.003) and arrhythmia (HR=1.25 per 5 year increment; p-value=0.02). Conclusions The risk of CVD in patients with NHL is approximately 1% per year after the initial diagnosis of lymphoma. The most commonly occurring CVDs in this cohort of NHL survivors were arrhythmia and HF. Treatment with anthracyclines and radiation are associated with increased risk of developing some types of CVD. 80% of self-reported CVD events in NHL survivors were validated using epidemiologic criteria. Future studies will include building models incorporating comorbid health conditions and lifestyle factors to determine risk of CVD as well as the impact of CVD on quality of life. Disclosures: No relevant conflicts of interest to declare.

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Increased risk of cardiac ischaemia in a pan-European cohort of 36 205 childhood cancer survivors: a PanCareSurFup study

Heart ◽

10.1136/heartjnl-2020-316655 ◽

2020 ◽

Vol 107 (1) ◽

pp. 33-40 ◽

Cited By ~ 2

Author(s):

Elizabeth Arnoldina Maria Feijen ◽

Elvira C van Dalen ◽

Heleen J H van der Pal ◽

Raoul C Reulen ◽

David L Winter ◽

...

Keyword(s):

Risk Factors ◽

Cancer Survivors ◽

Childhood Cancer ◽

Cumulative Incidence ◽

Cox Regression ◽

Childhood Cancer Survivors ◽

Cardiac Ischaemia ◽

Number Of Patients ◽

Increased Risk

ObjectiveIn this report, we determine the cumulative incidence of symptomatic cardiac ischaemia and its risk factors among European 5-year childhood cancer survivors (CCS) participating in the PanCareSurFup study.MethodsEight data providers (France, Hungary, Italy (two cohorts), the Netherlands, Slovenia, Switzerland and the UK) participating in PanCareSurFup ascertained and validated symptomatic cardiac events among their 36 205 eligible CCS. Data on symptomatic cardiac ischaemia were graded according to the Criteria for Adverse Events V.3.0 (grade 3–5). We calculated cumulative incidences, both overall and for different subgroups based on treatment and malignancy, and used multivariable Cox regression to analyse risk factors.ResultsOverall, 302 out of the 36 205 CCS developed symptomatic cardiac ischaemia during follow-up (median follow-up time after primary cancer diagnosis: 23.0 years). The cumulative incidence by age 60 was 5.4% (95% CI 4.6% to 6.2%). Men (7.1% (95% CI 5.8 to 8.4)) had higher rates than women (3.4% (95% CI 2.4 to 4.4)) (p<0.0001). Of importance is that a significant number of patients (41/302) were affected as teens or young adults (14–30 years). Treatment with radiotherapy/chemotherapy conferred twofold risk (95% CI 1.5 to 3.0) and cases in these patients appeared earlier than in CCS without treatment/surgery only (15% vs 3% prior to age 30 years, respectively (p=0.04)).ConclusionsIn this very large European childhood cancer cohort, we found that by age 60 years, 1 in 18 CCS will develop a severe, life-threatening or fatal cardiac ischaemia, especially in lymphoma survivors and CCS treated with radiotherapy and chemotherapy increases the risk significantly.

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Abstract P85: Are Myocardial Bridges Associated With Increased Risk of Death or Myocardial Infarction?

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.4.suppl_1.ap85 ◽

2011 ◽

Vol 4 (suppl_1) ◽

Author(s):

Mouaz H Al-Mallah ◽

Kamal Kassem ◽

Owais Khawaja ◽

Thomas Song ◽

Chad Poopat ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Prognostic Value ◽

Cox Regression ◽

Study Cohort ◽

Risk Of Death ◽

Increased Risk ◽

Artery Disease

Background: Myocardial bridging (MB) is frequently seen on coronary CT angiography (CCTA). However, there has been conflicting data on the prognostic value of MB. The aim of this analysis is to determine the prognostic value of MB in patients without obstructive coronary artery disease (CAD) (<50 diameter stenosis). Methods: We included patients with no known prior coronary artery disease (CAD) who underwent CCTA for various clincial reasons. Patients with obstructive CAD on CCTA were excluded. The study cohort was followed for all cause mortality or myocardial infarction (MI) (median follow-up 1.7 years). Group comparisons were made between patients with patients with or without MB. Results: A total of 715 patients were included in this analysis of which 68 patients had MB (10%). 73% of the bridges were in the mid LAD and 22% had bridging in the distal LAD. 48% of the study cohort had normal coronaries, while 52% had evidence of non obstructive CAD. There were no differences in the baseline characteristics, symptomatic status or prevalence of non obstructive CAD between the two groups (all p>0.5). After a median follow-up duration of 1.7 years, 23 patients died and 10 patients experienced myocardial infarction. There were no statistically significant differences in the rate of death/MI between the two groups (figure). Using multivariable Cox regression, the presence of MB was not associated with increased risk for death/MI (Adjusted HR 0.4, 95% confidence interval 0.1 -2.8, p=0.34) Conclusions: In patients with non-obstructive CAD, MB is not associated with increased risk for all cause death or MI.

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Risk of New Cancers After Radiotherapy in Long-Term Survivors of Retinoblastoma: An Extended Follow-Up

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.054 ◽

2005 ◽

Vol 23 (10) ◽

pp. 2272-2279 ◽

Cited By ~ 308

Author(s):

Ruth A. Kleinerman ◽

Margaret A. Tucker ◽

Robert E. Tarone ◽

David H. Abramson ◽

Johanna M. Seddon ◽

...

Keyword(s):

Cumulative Incidence ◽

Tumor Registry ◽

Risk Of Death ◽

Medical Centers ◽

New Information ◽

Increased Risk ◽

Long Term Survivors ◽

The Brain

Purpose Many children diagnosed with retinoblastoma (Rb) survive into adulthood and are prone to subsequent cancers, particularly hereditary patients, who have germline Rb-1 mutations. We have extended the follow-up of a large cohort of Rb patients for 7 more years to provide new information on the risk of additional cancers after radiotherapy in long-term survivors. Patients and Methods We analyzed the risk of new cancers through 2000 in 1,601 Rb survivors, diagnosed from 1914 to 1984, at two US medical centers. The standardized incidence ratio (SIR) was calculated as the ratio of the observed number of cancers after hereditary and nonhereditary Rb to the expected number from the Connecticut Tumor Registry. The cumulative incidence of a new cancer after hereditary and nonhereditary Rb and radiotherapy was calculated with adjustment for competing risk of death. Results Subsequent cancer risk in 963 hereditary patients (SIR, 19; 95% CI, 16 to 21) exceeded the risk in 638 nonhereditary Rb patients (SIR, 1.2; 95% CI, 0.7 to 2.0). Radiation further increased the risk of another cancer in hereditary patients by 3.1-fold (95% CI, 2.0 to 5.3). Hereditary patients continued to be at significantly increased risk for sarcomas, melanoma, and cancers of the brain and nasal cavities. The cumulative incidence for developing a new cancer at 50 years after diagnosis of Rb was 36% (95% CI, 31% to 41%) for hereditary and 5.7% (95% CI, 2.4% to 11%) for nonhereditary patients. Conclusion Hereditary Rb predisposes to a variety of new cancers over time, with radiotherapy further enhancing the risk of tumors arising in the radiation field.

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Incidence of hypothyroidism after treatment for breast cancer—a Danish matched cohort study

Breast Cancer Research ◽

10.1186/s13058-020-01337-z ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Anne Mette Falstie-Jensen ◽

Buket Ö. Esen ◽

Anders Kjærsgaard ◽

Ebbe L. Lorenzen ◽

Jeanette D. Jensen ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Cancer Treatment ◽

Cumulative Incidence ◽

Breast Cancer Survivors ◽

Cox Regression ◽

Metastatic Breast ◽

Incidence Rates ◽

Diagnostic Codes ◽

Increased Risk

Abstract Background Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment. Methods Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996–2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities. Results We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7–1.9) and 1.6% (95%CI = 1.5–1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25–4.67) and 3.81 (95%CI = 3.73–3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11–1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50–2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14–1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45–2.01 and HR = 1.36, 95%CI = 1.17–1.58, respectively]. Conclusions BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

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Subsequent malignant neoplasms among children with Hodgkin lymphoma: A report from the Children's Oncology Group

Blood ◽

10.1182/blood.2020007225 ◽

2020 ◽

Author(s):

Lisa Giulino-Roth ◽

Qinglin Pei ◽

Allen Buxton ◽

Rizvan Bush ◽

Yue Wu ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Solid Tumors ◽

Cumulative Incidence ◽

Absolute Risk ◽

Combined Modality Therapy ◽

Early Response ◽

Malignant Neoplasms ◽

Oncology Group ◽

Increased Risk

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group Study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1,711 patients enrolled on AHOD0031. Patients were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to two additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% CI: 0.6%-2.0%). SMNs included 3 patients with AML, 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI 4.5-15.2) with an excess absolute risk of 1.2 per 1,000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (p=0.037). In multivariate analysis, RT, B-symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia. Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. ClinicalTrials.gov Identifier: NCT00025259.

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