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Purpose: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages., Methods: We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses., Results: After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m 2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m 2 doxorubicin ( P trend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR] age <21 years , 1.5 [95% CI, 0.9 to 2.6]; HR age ≥21 years , 1.3 [95% CI, 0.9 to 1.9) or chest RT (HR without mantle/axillary field RT , 1.9 [95% CI, 1.06 to 3.3]; HR with mantle/axillary field RT , 1.2 [95% CI, 0.8 to 1.8])., Conclusion: This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.

Background: Breast cancer is the most common treatment-related second malignancy among women with previous chest radiotherapy for Hodgkin lymphoma (HL). Little is known about the effects of this kind of radiotherapy on the outcomes of postmastectomy breast reconstruction (BR). This study compared adverse outcomes of BR after HL-related chest radiotherapy to matched controls., Methods: The authors conducted a retrospective, matched cohort study in two expert cancer centres in the Netherlands. BRs after therapeutic or prophylactic mastectomy in HL survivors who received chest radiotherapy were matched with BRs in nonirradiated patients without HL on age at mastectomy date, date of BR, and type of BR. The primary outcome was complication-related BR failure or conversion and secondary outcomes were complication-related re-operation, capsular contracture, major donor-site complications, and complication-related ICU admission. The authors analyzed all outcomes univariably using Fisher's exact tests and the authors assessed reconstruction failure, complication-related re-operation, and capsular contracture with multivariable Cox regression analysis adjusting for confounding and data clustering., Results: Seventy BRs in 41 patients who received chest radiotherapy for HL were matched to 121 BRs in 110 nonirradiated patients. Reconstruction failure did not differ between HL survivors (12.9%) and controls (12.4%). The comparison groups showed no differences in number of reoperations, major donor-site complications, or capsular contractures. BR in HL survivors more often let to ICU admission due to complications compared with controls ( P =0.048)., Conclusions: We observed no increased risk of adverse outcomes following BR after previous chest radiotherapy for HL. This is important information for counselling these patients and may improve shared decision-making., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Female survivors of Hodgkin lymphoma (HL) treated with chest radiotherapy have a strongly increased risk of breast cancer (BC), but the treatment-specific BC risk in male survivors of HL has not been evaluated. We assessed BC risk in a cohort of 3077 male survivors of 5-year HL treated at age ≤51 years in 20 Dutch hospitals between 1965 and 2013. We estimated standardized incidence ratios (SIRs), absolute excess risks per 10 000 person-years, and cumulative BC incidences. After a 20-year median follow-up, we observed 8 cases of male with BC. Male survivors of HL experienced a 23-fold (95% confidence interval [CI], 10.1-46.0) increased BC risk compared with the general population, representing 1.6 (95% CI, 0.7-3.3) excess BC incidences per 10 000 person-years. The 20- and 40-year cumulative BC incidences after HL treatment were 0.1% (95% CI, 0.02-0.3) and 0.7% (95% CI, 0.3-1.4), respectively. Treatment with chest radiotherapy without alkylating chemotherapy yielded a strongly increased SIR (20.7; 95% CI, 2.5-74.8), which was not significantly different for chest radiotherapy and alkylating chemotherapy (41.1; 95% CI, 13.4-96.0). Males treated with chest radiotherapy and anthracyclines had an SIR of 48.1 (95% CI, 13.1-123.1). Two patients died from BC (median follow-up, 4.7 years). To ensure early diagnosis and treatment, clinicians should be alert to BC symptoms in male survivors of HL., (© 2023 by The American Society of Hematology.)

Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.

Importance: Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear., Objective: To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors., Design, Setting, and Participants: A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022., Exposures: Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets., Main Outcomes and Measures: Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored., Results: The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose., Conclusions and Relevance: This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.

Studies have shown higher survival rates for patients with Hodgkin lymphoma (HL) treated within clinical trials compared to patients treated outside clinical trials. However, endpoints are often limited to overall survival (OS). In this retrospective cohort study, we investigated the effect of trial participation on OS, the incidence of relapse, second cancer, and cardiovascular disease (CVD). The study population consisted of patients with HL, aged between 14 and 51 years at diagnosis, who started their treatment between 1962 and 2002 at three Dutch cancer centres. Patients were either included in the EORTC Lymphoma Group trials (H1-H9) or treated according to standard guidelines at the time. After adjusting for differences in baseline characteristics, trial participation was associated with longer OS (median OS: 29.4 years [95%CI: 27.0-31.6] for treatment inside trials versus 27.4 years [95%CI: 26.0-28.5] for treatment outside trials, p = .046), a lower incidence of relapse (HR = 0.79, 95%CI: 0.63-0.98, p = .036) and a higher incidence of CVD (HR = 1.49, 95%CI: 1.23-1.79, p < .001). The trial effect for CVD was present only for patients treated before 1983. No evidence of differences in the incidence of second cancer was found. Consequently, essential results from clinical trials should be implemented into standard practice without undue delay., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose: Previous efforts to predict absolute risk of treatment-related cardiovascular diseases (CVDs) have mostly focused on childhood cancer survivors. We aimed to develop prediction models for risk of coronary heart disease (CHD) and heart failure (HF) for survivors of adolescent/adult Hodgkin lymphoma (HL)., Methods: For model development, we used a multicenter cohort including 1,433 5-year HL survivors treated between 1965 and 2000 and age 18-50 years at HL diagnosis, with complete data on administered chemotherapy regimens, radiotherapy volumes and doses, and cardiovascular follow-up. Using cause-specific hazard models, covariate-adjusted cumulative incidences for CHD and HF were estimated in the presence of competing risks of death because of other causes than CHD and HF. Age at HL diagnosis, sex, smoking status, radiotherapy, and anthracycline treatment were included as predictors. External validation for the CHD model was performed using a Canadian cohort of 708 HL survivors treated between 1988 and 2004 and age 18-50 years at HL diagnosis., Results: After a median follow-up of 24 years, 341 survivors had developed CHD and 102 had HF. We were able to predict CHD and HF risk at 20 and 30 years after treatment with moderate to good overall calibration and moderate discrimination (areas under the curve: 0.68-0.74), which was confirmed by external validation for the CHD model (areas under the curve: 0.73-0.74). On the basis of our model including prescribed mediastinal radiation dose, 30-year risks ranged from 4% to 78% for CHD and 3% to 46% for HF, depending on risk factors., Conclusion: We developed and validated prediction models for CHD and HF with good overall calibration and moderate discrimination. These models can be used to identify HL survivors who might benefit from targeted screening for CVD and early treatment for CVD risk factors.

Background: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes., Methods: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC-HL) with 5988 age- and calendar year-matched patients with first primary BC (BC-1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment., Results: Compared to BC-1 patients, BC-HL patients received anthracycline-containing chemotherapy (23.7% vs. 43.8%, p < .001) and breast-conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p < .001) less often. BC treatment considerations were reported for 71% of BC-HL patients. BC-HL patients had a significantly higher risk of 15-year overall mortality than BC-1 patients (61% vs. 23%). Furthermore, risks of BC-specific mortality and nonfatal BC events were significantly increased among BC-HL patients, also when accounting for tumor and treatment characteristics (2.2- to 4.5-fold). BC-HL patients with a screen-detected BC had a significantly reduced (61%) BC-specific mortality. One-third of BC-HL patients had CVD at BC-diagnosis, compared to <0.1% of BC-1 patients. Fifteen-year CVD-specific mortality and CVD incidence were significantly higher in BC-HL patients than in BC-1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment., Conclusions: BC-HL patients experience a higher burden of CVD and worse BC outcomes than BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors., Lay Summary: Patients with breast cancer after Hodgkin lymphoma (BC-HL) may have limited options for BC treatment, due to earlier HL treatment and an associated increased risk of cardiovascular disease (CVD). BC treatment considerations were reported for 71% of BC-HL patients. We examined whether BC-HL patients have a higher risk of CVD or BC events (recurrences/metastases) compared to patients with breast cancer that had no earlier tumors (BC-1). We observed a higher burden of CVD and worse BC outcomes in HL patients compared to BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors., (© 2022 American Cancer Society.)

Background: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups., Methods: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG)., Results: Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG)., Conclusions: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy., Impact: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients., Methods: We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined., Results: Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed., Conclusion: Mean breast dose predicts subsequent BC risk in long-term HL survivors., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: The risk of developing gastric cancer is increased in patients treated with radiotherapy for Hodgkin lymphoma (HL) or testicular cancer (TC). This study aims to assess if gastric adenocarcinoma after treatment for HL/TC (t-GC) is molecularly different from gastric adenocarcinoma in the general population., Methods: Patients were diagnosed with t-GC ≥5 years after treatment for HL/TC. Four molecular subtypes were identified using immunohistochemical and molecular analyses: Epstein-Barr virus (EBV), mismatch repair (MMR) deficiency or microsatellite instability (MSI), aberrant p53 staining as surrogate for chromosomal instability (sCIN), and a surrogate for genomic stability (sGS) without these aberrations. Results were compared with gastric cancer in the general population (p-GC) described in literature., Results: Molecular subtyping of 90 t-GCs resulted in 3% EBV, 8% MSI, 36% sCIN and 53% sGS. 3/6 of MSI t-GCs had MLH1 promoter methylation and 2/6 were explained by double somatic mutations in MMR genes. T-GCs were more frequently sGS than p-GCs (53% vs. 38%, p = 0.04). T-GC was more frequently sGS in HL/TC patients diagnosed before 1990, than after 1990 (63% vs. 38%, p = 0.03). T-GCs located in the antrum, an area that receives high irradiation doses, were more frequently sGS (61% vs. 28% in p-GCs, p = 0.02)., Conclusion: Our results demonstrate that t-GCs are more frequently of the sGS subtype than p-GCs. An association of t-GC of the sGS subtype with prior anticancer treatment is suggested by the high frequency in HL/TC patients who were treated before 1990, a time period in which HL/TC treatments were more extensive., Competing Interests: The authors have declared no conflict of interest.

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia., Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors., Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right-sided, were detected, as published previously. An average-risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy., Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high-grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4-9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient., Conclusions: Colorectal neoplasia in HL survivors differ from average-risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow-up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors., (© 2021 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients., Methods: This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated., Results: HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02)., Conclusions: Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity., (© The Author(s) 2020. Published by Oxford University Press.)

Hodgkin lymphoma (HL) survivors are at increased risk of developing second primary esophageal squamous cell cancer (ESCC). We aimed to gain insight in the driving events of ESCC in HL survivors (hESCC) by using RNA sequencing and NanoString profiling. Objectives were to investigate differences in RNA signaling between hESCC and sporadic ESCC (sESCC), and to look for early malignant changes in non-neoplastic esophageal tissue of HL survivors (hNN-tissue). We analyzed material of 26 hESCC cases, identified via the Dutch pathology registry (PALGA) and 17 sESCC cases from one academic institute and RNA sequencing data of 44 sESCC cases from TCGA. Gene expression profiles for the NanoString panel PanCancer IO 360 were obtained from 16/26 hESCC and four hNN-tissue, while non-neoplastic squamous tissue of four sporadic cases (sNN-tissue) served as reference profile. Hierarchical clustering, differential expression and pathway analyses were performed. Overall, the molecular profiles of hESCC and sESCC were similar. There was increased immune, HMGB1 and ILK signaling compared to sNN-tissue. The profiles of hNN-tissue were distinct from sNN-tissue, indicating early field effects in the esophagus of HL survivors. The BRCA1 pathway was upregulated in hESCC tissue, compared to hNN tissue. Analysis of expression profiles reveals overlap between hESCC and sESCC, and differences between hESCC and its surrounding hNN-tissue. Further research is required to validate our results and to investigate whether the changes observed in hNN-tissue are already detectable before development of hESCC. In the future, our findings could be used to improve hESCC patient management., Competing Interests: The authors have declared that no competing interests exist.

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors., Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis., Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P < .001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P < .001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P = .08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P < .001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P < .001)., Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered., (© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients., (© 2019 by The American Society of Hematology.)

Background: Hodgkin lymphoma (HL) survivors have an increased risk of gastrointestinal (GI) cancer. This study aims to evaluate whether survival of patients who survived HL and developed GI cancer differs from survival of first primary GI cancer patients., Methods: Overall and cause-specific survival of GI cancer patients in a HL survivor cohort (GI-HL, N = 104, including esophageal, gastric, small intestinal, and colorectal cancer) was compared with survival of a first primary GI cancer patient cohort (GI-1, N = 1025, generated by case matching based on tumor site, gender, age, and year of diagnosis). Cox proportional hazards regression was used for survival analyses. Multivariable analyses were adjusted for GI cancer stage, grade of differentiation, surgery, radiotherapy, and chemotherapy., Results: GI-HL cancers were diagnosed at a median age of 54 years (interquartile range 45-60). No differences in tumor stage or frequency of surgery were found. GI-HL patients less often received radiotherapy (8% vs 23% in GI-1 patients, P < 0.001) and chemotherapy (28% vs 41%, P = 0.01) for their GI tumor. Compared with GI-1 patients, overall and disease-specific survival of GI-HL patients was worse (univariable hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.03-1.65, P = 0.03; and HR 1.29, 95% CI 1.00-1.67, P = 0.049, respectively; multivariable HR 1.33, 95% CI 1.05-1.68, P = 0.02; and HR 1.33, 95% CI 1.03-1.72, P = 0.03, respectively)., Conclusions: Long-term overall and disease-specific survival of GI cancer in HL survivors is worse compared with first primary GI cancer patients. Differences in tumor stage, grade of differentiation, or treatment could not explain this worse survival., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Hodgkin's lymphoma (HL) has become the prototype of a curable disease. However, many young survivors suffer from late adverse effects of treatment. Both chemotherapy (CT) and radiotherapy (RT) may induce primary ovarian insufficiency (POI), which has been associated with reduced bone mineral density (BMD), neurocognitive dysfunction and possibly cardiovascular disease (CVD). While the general assumption is that POI increases CVD risk, other hypotheses postulate reverse causality, suggesting that cardiovascular risk factors determine menopausal age or that biological ageing underlies both POI and CVD risk. None of these hypotheses are supported by convincing evidence. Furthermore, most studies on POI-associated conditions have been conducted in women with early natural or surgery-induced menopause with short follow-up times. In this study, we will examine the long-term effects of CT-induced and/or RT-induced POI on BMD, cardiovascular status, neurocognitive function and quality of life in female HL survivors., Methods and Analysis: This study will be performed within an existing Dutch cohort of HL survivors. Eligible women were treated for HL at ages 15-39 years in three large hospitals since 1965 and survived for ≥8 years after their diagnosis. Women visiting a survivorship care outpatient clinic will be invited for a neurocognitive, cardiovascular and BMD assessment, and asked to complete several questionnaires and to provide a blood sample. Using multivariable regression analyses, we will compare the outcomes of HL survivors who developed POI with those who did not. Cardiovascular status will also be compared with women with natural POI., Ethics and Dissemination: This study has been approved by the Institutional Review Board of the Netherlands Cancer Institute and has been registered at 'Toetsingonline' from the Dutch Central Committee on Research involving Human Subjects (file no. NL44714.031.13). Results will be disseminated through peer-reviewed publications and will be incorporated in follow-up guidelines for HL survivors., Competing Interests: Competing interests: JMZ declares she has conducted a research project funded by Roche in the past 2 years (unrelated to the current study). CBL’s Department of Reproductive Medicine has received educational and research grants from Merck Serono, Ferring and Auxogyn, and he received speakers’ fees from MSD, Merck Serono, Ferring and Auxogyn. He is also a consultant for Ferring. PL provided advice to Friesland Campina. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cancer related fatigue (CRF) is one of the most prevalent and distressing long-term complaints reported by (non-) Hodgkin survivors. To date there has been no standard treatment for CRF in this population. A novel and promising approach to treat CRF is exposure to bright white light therapy. Yet, large scale randomized controlled trials testing its efficacy in these patients and research on potential mechanisms is lacking. The objective of the current study is to investigate the efficacy of light therapy as a treatment for CRF and to explore potential mechanisms., Methods/design: In a multicenter, randomized controlled trial we are evaluating the efficacy of two intensities of light therapy in reducing CRF complaints and restrictions caused by CRF in survivors of Hodgkin lymphoma or diffuse large B-cell lymphoma. Secondary outcomes include sleep quality, depression, anxiety, quality of life, cognitive complaints, cancer worries, fatigue catastrophizing, self-efficacy to handle fatigue, biological circadian rhythms of melatonin, cortisol and activity, and biomarkers of inflammation. We will recruit 128 survivors, with fatigue complaints, from academic and general hospitals. Survivors are randomized to either an intervention (exposure to bright white light) or a comparison group (exposure to dim white light). The longitudinal design includes four measurement points at baseline (T0), post-intervention at 3.5 weeks (T1), 3 months post-intervention (T2) and 9 months post-intervention (T3). Each measurement point includes self-reported questionnaires and actigraphy (10 days). T0 and T1 measurements also include collection of blood and saliva samples., Discussion: Light therapy has the potential to be an effective treatment for CRF in cancer survivors. This study will provide insights on its efficacy and potential mechanisms. If proven to be effective, light therapy will provide an easy to deliver, low-cost and low-burden intervention, introducing a new era in the treatment of CRF., Trial Registration: The study is registered at ClinicalTrials.gov on August 8th 2017( NCT03242902 ).

This corrects the article DOI: 10.1038/bjc.2017.85.

Objective: Hodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics., Design: 54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS / BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111)., Results: KRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome., Conclusions: We have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment., Competing Interests: Competing interests: MEvL obtained funding from the Dutch Society of Gastroenterology and Hepatology (Maag Lever Darm Stichting (MLDS) funding project FP14-04)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk., Methods: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports., Results: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause ≥50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for ≥2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve., Conclusions: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Hodgkin lymphoma (HL) survivors are at increased risk of second malignancies, but few studies have assessed colorectal cancer (CRC) risk after HL treatment. We assessed long-term, subsite-specific CRC risk associated with specific radiation fields and chemotherapy regimens., Methods: In a Dutch cohort of 3121 5-year HL survivors treated between 1965 and 1995, subsite-specific CRC incidence was compared with general population rates. Treatment effects were quantified by Cox regression analyses., Results: After a median follow-up of 22.9 years, 55 patients developed CRC. The standardized incidence ratios (SIR) was 2.4-fold increased (95% confidence interval (95%CI) 1.8-3.2), leading to 5.7 excess cases per 10 000 patient-years. Risk was still increased 30 years after HL treatment (SIR: 2.8; 95%CI: 1.6-4.6). The highest (SIR: 6.5, 95%CI: 3.3-11.3) was seen for transverse colon cancer (15.0 (95%CI: 4.3-40.8) after inverted-Y irradiation). A prescribed cumulative procarbazine dose >4.2 g m -2 was associated with a 3.3-fold higher CRC risk (95%CI: 1.8-6.1) compared to treatment without procarbazine. Patients receiving >4.2 g m -2 procarbazine and infradiaphragmatic radiotherapy had a hazard ratio of 6.8 (95%CI: 3.0-15.6) compared with patients receiving neither treatment, which is significantly higher than an additive joint effect (P additivity =0.004)., Conclusions: Colorectal cancer surveillance should be considered for HL survivors who received Infradiaphragmatic radiotherapy and a high cumulative procarbazine dose.

Hodgkin lymphoma (HL) survivors treated with radiotherapy and/or chemotherapy are known to have increased risks of heart failure (HF), but a radiation dose-response relationship has not previously been derived. A case-control study, nested in a cohort of 2617 five-year survivors of HL diagnosed before age 51 years during 1965 to 1995, was conducted. Cases (n = 91) had moderate or severe HF as their first cardiovascular diagnosis. Controls (n = 278) were matched to cases on age, sex, and HL diagnosis date. Treatment and follow-up information were abstracted from medical records. Mean heart doses and mean left ventricular doses (MLVD) were estimated by reconstruction of individual treatments on representative computed tomography datasets. Average MLVD was 16.7 Gy for cases and 13.8 Gy for controls ( P difference = .003). HF rate increased with MLVD: relative to 0 Gy, HF rates following MVLD of 1-15, 16-20, 21-25, and ≥26 Gy were 1.27, 1.65, 3.84, and 4.39, respectively ( P trend < .001). Anthracycline-containing chemotherapy increased HF rate by a factor of 2.83 (95% CI: 1.43-5.59), and there was no significant interaction with MLVD ( P interaction = .09). Twenty-five-year cumulative risks of HF following MLVDs of 0-15 Gy, 16-20 Gy, and ≥21 Gy were 4.4%, 6.2%, and 13.3%, respectively, in patients treated without anthracycline-containing chemotherapy, and 11.2%, 15.9%, and 32.9%, respectively, in patients treated with anthracyclines. We have derived quantitative estimates of HF risk in patients treated for HL following radiotherapy with or without anthracycline-containing chemotherapy. Our results enable estimation of HF risk for patients before treatment, during radiotherapy planning, and during follow-up., (© 2017 by The American Society of Hematology.)

Background: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires., Methods/design: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived ≥8 years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses., Discussion: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors., Trial Registration: Registered at the Dutch Trial Registry (NTR): NTR4961 .

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Long-term survivors of Hodgkin lymphoma (HL) experience several late adverse effects of treatment, with second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) being the leading causes of death in these patients. Other late effects have also been identified, such as pulmonary dysfunction, endocrinopathies (thyroid dysfunction, infertility), neck muscle atrophy, and persistent fatigue. HL survivors have two- to fourfold increased risks to develop SMNs and CVD compared with the general population. With respect to SMNs, radiotherapy is associated with 1.5- to 15-fold increased risk of solid malignancies. The relative risk (RR) of solid tumors increases steadily with increasing follow-up time from 5 to 15 years since radiotherapy, and remains elevated for at least 40 years. The RR of solid SMNs increases strongly with younger age at first treatment. Risks of lung, breast, and gastrointestinal (GI) cancers increase with higher radiation dose. Alkylating agent chemotherapy, especially procarbazine, does not only increase risk of leukemia but also of solid malignancies, in particular, cancers of the lung and GI tract. In contrast, gonadotoxic chemotherapy decreases the risk of radiation-associated breast cancer, through induction of premature menopause. Smoking appears to multiply the radiation- and chemotherapy-associated risks of lung cancer. Both radiotherapy and chemotherapy for HL may cause cardiovascular toxicity. Radiotherapy increases the risk of coronary heart disease, valvular heart disease, congestive heart failure (HF), and pericarditis, whereas anthracycline-containing chemotherapy increases the risks of HF and valvular heart disease. Cardiovascular toxicity following radiotherapy is usually observed from 5 to at least 35 years after therapy, whereas anthracycline-related toxicity is already observed during treatment, up to at least 25 years. The joint effects of anthracyclines, radiotherapy, and conventional cardiovascular risk factors (eg, hypertension, smoking, and physical inactivity) appear to be additive rather than multiplicative. HL survivors need lifelong risk-based screening for selected SMNs and CVDs. Furthermore, preventive strategies should include lifestyle and drug-based interventions to minimize exposure to conventional risk factors for cancer and CVD., (© 2016 by The American Society of Hematology. All rights reserved.)

Long-term survivors of Hodgkin lymphoma (HL) are at risk for a range of late effects, with second malignant neoplasm and cardiovascular diseases being the leading causes of death in these patients. The excess risks remain significantly elevated decades after treatment, and are clearly associated with extent of treatment exposures. Other late effects have also been identified, such as pulmonary dysfunction, endocrinopathies, muscle atrophy, and persistent fatigue. Systemic documentation of late effects and recognition of treatment- and patient-related risk factors are important, as they inform optimal surveillance and risk-reduction strategies, as well as guide therapeutic modifications in newly diagnosed patients to minimize treatment-related complications. As HL therapy evolves over time, with adoption of novel agents and contemporary treatment techniques, late effect risks and follow-up recommendations need to be continuously updated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors., Patients and Methods: We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive., Results: The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy(<27.5years), 20.0%; ERR/Gy(27.5-36.4years), 8.8%; ERR/Gy(36.5-50.9years), 4.2%; P(interaction) = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8)., Conclusion: The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors., (© 2015 by American Society of Clinical Oncology.)

Background: Survivors of Hodgkin's lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown., Methods: We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkin's lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort., Results: With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30)., Conclusions: The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkin's lymphoma. (Funded by the Dutch Cancer Society.).

Importance: Hodgkin lymphoma (HL) survivors are at increased risk of cardiovascular diseases. It is unclear, however, how long the increased risk persists and what the risk factors are for various cardiovascular diseases., Objectives: To examine relative and absolute excess risk up to 40 years since HL treatment compared with cardiovascular disease incidence in the general population and to study treatment-related risk factors for different cardiovascular diseases., Design, Setting, and Participants: This retrospective cohort study included 2524 Dutch patients diagnosed as having HL at younger than 51 years (median age, 27.3 years) who had been treated from January 1, 1965, through December 31, 1995, and had survived for 5 years since their diagnosis., Exposures: Treatment for HL, including prescribed mediastinal radiotherapy dose and anthracycline dose., Main Outcomes and Measures: Data were collected from medical records and general practitioners. Cardiovascular events, including coronary heart disease (CHD), valvular heart disease (VHD), and cardiomyopathy and congestive heart failure (HF), were graded according to the Common Terminology Criteria for Adverse Events, version 4.0., Results: After a median follow-up of 20 years, we identified 1713 cardiovascular events in 797 patients. After 35 years or more, patients still had a 4- to 6-fold increased standardized incidence ratio of CHD or HF compared with the general population, corresponding to 857 excess events per 10,000 person-years. Highest relative risks were seen in patients treated before 25 years of age, but substantial absolute excess risks were also observed for patients treated at older ages. Within the cohort, the 40-year cumulative incidence of cardiovascular diseases was 50% (95% CI, 47%-52%). Fifty-one percent of patients with a cardiovascular disease developed multiple events. For patients treated before 25 years of age, cumulative incidences at 60 years or older were 20%, 31%, and 11% for CHD, VHD, and HF as first events, respectively. Mediastinal radiotherapy increased the risks of CHD (hazard ratio [HR], 2.7; 95% CI, 2.0-3.7), VHD (HR, 6.6; 95% CI, 4.0-10.8), and HF (HR, 2.7; 95% CI, 1.6-4.8), and anthracycline-containing chemotherapy increased the risks of VHD (HR, 1.5; 95% CI, 1.1-2.1) and HF (HR, 3.0; 95% CI, 1.9-4.7) as first events compared with patients not treated with mediastinal radiotherapy or anthracyclines, respectively. Joint effects of mediastinal radiotherapy, anthracyclines, and smoking appeared to be additive., Conclusions and Relevance: Throughout their lives, HL survivors treated at adolescence or adulthood are at high risk for various cardiovascular diseases. Physicians and patients should be aware of this persistently increased risk.

Purpose: To describe a new method to estimate the mean heart dose for Hodgkin lymphoma patients treated several decades ago, using delineation of the heart on radiation therapy simulation X-rays. Mean heart dose is an important predictor for late cardiovascular complications after Hodgkin lymphoma (HL) treatment. For patients treated before the era of computed tomography (CT)-based radiotherapy planning, retrospective estimation of radiation dose to the heart can be labor intensive., Methods and Materials: Patients for whom cardiac radiation doses had previously been estimated by reconstruction of individual treatments on representative CT data sets were selected at random from a case-control study of 5-year Hodgkin lymphoma survivors (n=289). For 42 patients, cardiac contours were outlined on each patient's simulation X-ray by 4 different raters, and the mean heart dose was estimated as the percentage of the cardiac contour within the radiation field multiplied by the prescribed mediastinal dose and divided by a correction factor obtained by comparison with individual CT-based dosimetry., Results: According to the simulation X-ray method, the medians of the mean heart doses obtained from the cardiac contours outlined by the 4 raters were 30 Gy, 30 Gy, 31 Gy, and 31 Gy, respectively, following prescribed mediastinal doses of 25-42 Gy. The absolute-agreement intraclass correlation coefficient was 0.93 (95% confidence interval 0.85-0.97), indicating excellent agreement. Mean heart dose was 30.4 Gy with the simulation X-ray method, versus 30.2 Gy with the representative CT-based dosimetry, and the between-method absolute-agreement intraclass correlation coefficient was 0.87 (95% confidence interval 0.80-0.95), indicating good agreement between the two methods., Conclusion: Estimating mean heart dose from radiation therapy simulation X-rays is reproducible and fast, takes individual anatomy into account, and yields results comparable to the labor-intensive representative CT-based method. This simpler method may produce a meaningful measure of mean heart dose for use in studies of late cardiac complications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response., Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided., Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02)., Conclusions: Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up., (© The Author 2015. Published by Oxford University Press.)

The Dutch BETER consortium has established a national care infrastructure for Hodgkin lymphoma survivors. 'BETER' [the Dutch word for 'better'] stands for Better care after Hodgkin lymphoma (HL): Evaluation of long-term Treatment Effects and screening Recommendations. The survivorship care focuses on long-term effects of HL treatment. Over 10,000 HL survivors who were treated in the period spanning 1965-2008 have been identified. As part of the survivorship care initiative, specific BETER out-patient clinics have been set up. A dedicated website, www.beternahodgkin.nl, provides HL survivors with relevant information. The stakeholders of the BETER survivorship care programme aim to achieve an improved healthy life expectancy for patients treated for HL.

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., (© 2014 by American Society of Clinical Oncology.)

We assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2, 1.6, and 1.1 for patients aged <25, 25 to 34, and 35 to 50 years at HL treatment, respectively. In HL survivors who had a second malignancy, treating physicians should be aware of the increased risk of subsequent malignancies., (© 2014 by The American Society of Hematology.)

Purpose: Survivors of Hodgkin's lymphoma (HL) are at risk of secondary tumors. We investigated the risk of secondary skin cancers after radiotherapy compared to treatment without radiation and to an age-matched population., Material and Methods: We conducted a retrospective cohort study of 889 HL patients treated between 1965 and 2005. Data on secondary skin cancers and treatment fields were retrieved. Incidence rates were compared to observed rates in the Dutch population., Results: 318 skin cancers were diagnosed in 86 patients, showing significantly higher risks of skin cancers, the majority being BCC. The standardized incidence ratio (SIR) of BCC in HL survivors was significantly increased (SIR 5.2, 95% CI 4.0-6.6), especially in those aged <35 years at diagnosis (SIR 8.0, 95% CI 5.8-10.7). SIR increased with longer follow-up to 15.9 (95% CI 9.1-25.9) after 35 years, with 626 excess cases per 10,000 patients per year. Most (57%) skin cancers developed within the radiation fields, with significantly increased risk in patients treated with radiotherapy compared to chemotherapy alone (p=0·047, HR 2·75, 95% CI 1·01-7.45)., Conclusion: Radiotherapy for HL is associated with a strongly increased long-term risk of secondary skin cancers, both compared to the general population and to treatment with chemotherapy alone., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear., Patients and Methods: We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location., Results: Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m(2)) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m(2) (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m(2); however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses., Conclusion: Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.

Women treated at young ages with supradiaphragmatic radiotherapy for Hodgkin lymphoma (HL) have a highly increased risk of breast cancer. For personalized advice and follow-up regimens for patients, information is needed on how the radiotherapy-related risk is affected by other breast cancer risk factors. Genome-wide association studies have identified 14 independently replicated common single nucleotide polymorphisms that influence breast cancer risk. To examine whether these variants contribute to risk of radiation-associated breast cancer in HL, we analyzed 2 independent case-control series, from the United Kingdom and The Netherlands, totaling 693 HL patients, 232 with breast cancer and 461 without. rs1219648, which annotates the FGFR2 gene, was associated with risk in both series (combined per-allele odds ratio = 1.59, 95% confidence interval: 1.26-2.02; P = .000111). These data provide evidence that genetic variation in FGFR2 influences radiation-induced breast cancer risk.

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10(-8)), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10(-13)) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10(-8)). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10(-50)). These data provide new insight into the pathogenesis of cHL.

Purpose: Women who received irradiation for Hodgkin's lymphoma have a strong increased risk for developing breast cancer. Approximately 90% of the breast cancers in these patients can be attributed to their radiation treatment, rendering such series extremely useful to determine whether a common radiation-associated cause underlies the carcinogenic process., Methods and Materials: In this study we used gene expression profiling technology to assess gene expression changes in radiation-associated breast tumors compared with a set of control breast tumors of women unexposed to radiation, diagnosed at the same age. RNA was obtained from fresh frozen tissue samples from 22 patients who developed breast cancer after Hodgkin's lymphoma (BfHL) and from 20 control breast tumors., Results: Unsupervised hierarchical clustering of the profile data resulted in a clustering of the radiation-associated tumors separate from the control tumors (p < 0.001). Using a supervised class prediction tool, a nearest centroid classifier of 198 probes was identified. The BfHL tumors were often of the intrinsic basal breast tumor subtype, and they showed a chromosomal instability profile and a higher expression of the proliferation marker Ki-67., Conclusion: These results indicate that radiation-associated tumors are different from other breast tumors on the basis of their expression profile and that they are mainly of one specific cause that is characterized by high proliferation and a more aggressive tumor type., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the roles of radiation dose, chemotherapy, and other factors in the etiology of stomach cancer in long-term survivors of testicular cancer or Hodgkin lymphoma., Methods and Materials: We conducted a cohort study in 5,142 survivors of testicular cancer or Hodgkin lymphoma treated in the Netherlands between 1965 and 1995. In a nested case-control study, detailed information on treatment, smoking, gastrointestinal diseases, and family history was collected for 42 patients with stomach cancer and 126 matched controls. For each subject, the mean radiation dose to the stomach was estimated. Relative risks (RRs) of stomach cancer and the radiation-related excess relative risk (ERR) per gray were calculated by conditional logistic regression analysis., Results: The risk of stomach cancer was 3.4-fold increased compared with the general population. The risk increased with increasing mean stomach dose (p for trend, <0.001), at an ERR of 0.84 per Gy (95% confidence interval [CI], 0.12-15.6). Mean stomach doses of more than 20 Gy were associated with a RR of 9.9 (95% CI, 3.2-31.2) compared with doses below 11 Gy. The risk was 1.8-fold (95% CI, 0.8-4.4) increased after chemotherapy and 5.4-fold (95% CI, 1.2-23.9) increased after high doses of procarbazine (>or=13,000 mg) vs. <10,000 mg. The RR of smoking more than 10 cigarettes per day vs. no smoking was 1.6 (95% CI, 0.6-4.2)., Conclusions: Stomach cancer risk is strongly radiation dose dependent. The role of chemotherapy, particularly of procarbazine and related agents, needs further study, because of the relatively small numbers of chemotherapy-treated subjects.

Purpose: We assessed the long-term risk of breast cancer (BC) after treatment for Hodgkin's lymphoma (HL). We focused on the volume of breast tissue exposed to radiation and the influence of gonadotoxic chemotherapy (CT)., Patients and Methods: We performed a cohort study among 1,122 female 5-year survivors treated for HL before the age of 51 years between 1965 and 1995. We compared the incidence of BC with that in the general population. To assess the risk according to radiation volume and hormone factors, we performed multivariate Cox regression analyses., Results: After a median follow-up of 17.8 years, 120 women developed BC (standardized incidence ratio [SIR], 5.6; 95% CI, 4.6 to 6.8), absolute excess risk 57 per 10,000 patients per year. The overall cumulative incidence 30 years after treatment was 19% (95% CI, 16% to 23%); for those treated before age 21 years, it was 26% (95% CI, 19% to 33%). The relative risk remained high after prolonged follow-up (> 30 years after treatment: SIR, 9.5; 95% CI, 4.9 to 16.6). Mantle field irradiation (involving the axillary, mediastinal, and neck nodes) was associated with a 2.7-fold increased risk (95% CI, 1.1 to 6.9) compared with similarly dosed (36 to 44 Gy) mediastinal irradiation alone. Women with >or= 20 years of intact ovarian function after radiotherapy at young ages (< 31 years) experienced significantly higher risks for BC than those with fewer than 10 years of intact ovarian function., Conclusion: Reduction of radiation volume appears to decrease the risk for BC after HL. In addition, shorter duration of intact ovarian function after irradiation is associated with a significant reduction of the risk for BC.