Guideline for the first-line management of Classical Hodgkin Lymphoma - A British Society for Haematology guideline.

This guideline was compiled according to the British Society for Haematology (BSH) process at BSH Guidelines Process 2016 (b-s-h.org.uk). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline, PubMed/Medline and Cochrane searches beginning from 2013 up to January 2021. The following search terms were used: [Hodgkin lymphoma OR Hodgkin disease] NOT non-Hodgkin; AND [chemotherapy OR radiotherapy]; AND [elderly]; AND [teenage OR adolescent OR young adult]; AND [pregnancy]. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. References pre-2013 were taken from the previous version of this guideline.1 Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haematology Oncology Taskforce, the BSH Guidelines Committee and the Haematology Oncology sounding board of BSH.

Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study.

Survivors of childhood cancer treated with cranial irradiation are at risk of cerebrovascular disease (CVD), but the risks beyond age 50 are unknown. In all, 13457 survivors of childhood cancer included in the population-based British Childhood Cancer Survivor Study cohort were linked to Hospital Episode Statistics data for England. Risk of CVD related hospitalisation was quantified by standardised hospitalisation ratios (SHRs), absolute excess risks and cumulative incidence. Overall, 315 (2.3%) survivors had been hospitalised at least once for CVD with a 4-fold risk compared to that expected (95% confidence interval [CI]: 3.7-4.3). Survivors of a central nervous system (CNS) tumour and leukaemia treated with cranial irradiation were at greatest risk of CVD (SHR = 15.6, 95% CI: 14.0-17.4; SHR = 5.4; 95% CI: 4.5-6.5, respectively). Beyond age 60, on average, 3.1% of CNS tumour survivors treated with cranial irradiation were hospitalised annually for CVD (0.4% general population). Cumulative incidence of CVD increased from 16.0% at age 50 to 26.0% at age 65 (general population: 1.4-4.2%). In conclusion, among CNS tumour survivors treated with cranial irradiation, the risk of CVD continues to increase substantially beyond age 50 up to at least age 65. Such survivors should be: counselled regarding this risk; regularly monitored for hypertension, dyslipidaemia and diabetes; advised on life-style risk behaviours. Future research should include the recall for counselling and brain MRI to identify subgroups that could benefit from pharmacological or surgical intervention and establishment of a case-control study to comprehensively determine risk-factors for CVD.

Limited-stage diffuse large B-cell lymphoma: current management and challenges.

Twenty-five to thirty per cent of diffuse large B-cell lymphoma (DLBCL) presents as limited stage (I-II). Prognosis is generally excellent with four to six cycles of R-CHOP alone (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone) or combined-modality therapy with three or four cycles and involved-site radiotherapy (RT). There is growing interest in optimising algorithms to retain disease control whilst minimising long-term toxicity, with several recent studies focusing on the safety of abbreviating chemotherapy and omitting RT in low-risk patients and the utility of PET-based response-adapted approaches. As these studies are limited to younger patients without risk factors, application of similar approaches in elderly or higher-risk patients is hampered by a lack of evidence. Whilst there has been a move away from using RT in low-risk patients, it remains a useful adjunct in specific situations. Current evidence cannot exclude a clinically meaningful benefit from RT even in low-risk patients and, given the low expected toxicity from modern RT techniques, a risk-benefit assessment should be individualised and considered in a multidisciplinary fashion. The optimal approach for extranodal limited-stage DLBCL (~40% of cases) varies according to site of origin. Herein we discuss the latest clinical trial evidence and how this can be applied in routine practice.

Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines.

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 (Pdifference = .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 (Ptrend < .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 (Pinteraction = .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.

Population-Based Long-Term Cardiac-Specific Mortality Among 34 489 Five-Year Survivors of Childhood Cancer in Great Britain.

BACKGROUND: Increased risks of cardiac morbidity and mortality among childhood cancer survivors have been described previously. However, little is known about the very long-term risks of cardiac mortality and whether the risk has decreased among those more recently diagnosed. We investigated the risk of long-term cardiac mortality among survivors within the recently extended British Childhood Cancer Survivor Study. METHODS: The British Childhood Cancer Survivor Study is a population-based cohort of 34 489 five-year survivors of childhood cancer diagnosed from 1940 to 2006 and followed up until February 28, 2014, and is the largest cohort to date to assess late cardiac mortality. Standardized mortality ratios and absolute excess risks were used to quantify cardiac mortality excess risk. Multivariable Poisson regression models were used to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity and trends. RESULTS: Overall, 181 cardiac deaths were observed, which was 3.4 times that expected. Survivors were 2.5 times and 5.9 times more at risk of ischemic heart disease and cardiomyopathy/heart failure death, respectively, than expected. Among those >60 years of age, subsequent primary neoplasms, cardiac disease, and other circulatory conditions accounted for 31%, 22%, and 15% of all excess deaths, respectively, providing clear focus for preventive interventions. The risk of both overall cardiac and cardiomyopathy/heart failure mortality was greatest among those diagnosed from 1980 to 1989. Specifically, for cardiomyopathy/heart failure deaths, survivors diagnosed from 1980 to 1989 had 28.9 times the excess number of deaths observed for survivors diagnosed either before 1970 or from 1990 on. CONCLUSIONS: Excess cardiac mortality among 5-year survivors of childhood cancer remains increased beyond 50 years of age and has clear messages in terms of prevention strategies. However, the fact that the risk was greatest in those diagnosed from 1980 to 1989 suggests that initiatives to reduce cardiotoxicity among those treated more recently may be having a measurable impact.

Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study).

BACKGROUND: Survivors of teenage and young adult cancer are at risk of cerebrovascular events, but the magnitude of and extent to which this risk varies by cancer type, decade of diagnosis, age at diagnosis, and attained age remains uncertain. This is the largest-ever cohort study to evaluate the risks of hospitalization for a cerebrovascular event among long-term survivors of teenage and young adult cancer. METHODS: The population-based TYACSS (Teenage and Young Adult Cancer Survivor Study) (N=178,962) was linked to Hospital Episode Statistics data for England to investigate the risks of hospitalization for a cerebrovascular event among 5-year survivors of cancer diagnosed when 15 to 39 years of age. Observed numbers of first hospitalizations for cerebrovascular events were compared with that expected from the general population using standardized hospitalization ratios (SHRs) and absolute excess risks per 10 000 person-years. Cumulative incidence was calculated with death considered a competing risk. RESULTS: Overall, 2782 cancer survivors were hospitalized for a cerebrovascular event-40% higher than expected (SHR=1.4, 95% confidence interval, 1.3-1.4). Survivors of central nervous system (CNS) tumors (SHR=4.6, 95% confidence interval, 4.3-5.0), head and neck tumors (SHR=2.6, 95% confidence interval, 2.2-3.1), and leukemia (SHR=2.5, 95% confidence interval, 1.9-3.1) were at greatest risk. Males had significantly higher absolute excess risks than females (absolute excess risks =7 versus 3), especially among head and neck tumor survivors (absolute excess risks =30 versus 11). By 60 years of age, 9%, 6%, and 5% of CNS tumor, head and neck tumor, and leukemia survivors, respectively, had been hospitalized for a cerebrovascular event. Beyond 60 years of age, every year, 0.4% of CNS tumor survivors were hospitalized for a cerebral infarction (versus 0.1% expected), whereas at any age, every year, 0.2% of head and neck tumor survivors were hospitalized for a cerebral infarction (versus 0.06% expected). CONCLUSIONS: Survivors of a CNS tumor, head and neck tumor, and leukemia are particularly at risk of hospitalization for a cerebrovascular event. The excess risk of cerebral infarction among CNS tumor survivors increases with attained age. For head and neck tumor survivors, this excess risk remains high across all ages. These groups of survivors, particularly males, should be considered for surveillance of cerebrovascular risk factors and potential pharmacological interventions for cerebral infarction prevention.

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study.

BACKGROUND: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. METHODS: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. RESULTS: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. CONCLUSIONS: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines.

Long-term hospitalisation rates among 5-year survivors of Hodgkin lymphoma in adolescence or young adulthood: A nationwide cohort study.

In the present study, we report on the full range of physical diseases acquired by survivors of Hodgkin lymphoma diagnosed in adolescence or young adulthood. In a Danish nationwide population-based cohort study, 1,768 five-year survivors of Hodgkin lymphoma diagnosed at ages 15-39 years during 1943-2004 and 228,447 comparison subjects matched to survivors on age and year of birth were included. Hospital discharge diagnoses and bed-days during 1977-2010 were obtained from the Danish Patient Register for 145 specific disease categories gathered in 14 main diagnostic groups. The analysis was conducted separately on three subcohorts of survivors, that is, survivors diagnosed 1943-1976 for whom we had no information on rehospitalisation for Hodgkin lymphoma and survivors diagnosed 1977-2004, split into a subcohort with no expected relapses and a subcohort for whom a rehospitalisation for Hodgkin lymphoma indicated a relapse. The overall standardised hospitalisation rate ratios (RRs) were 2.0 [95% confidence interval (CI), 1.9-2.1], 1.5 (1.4-1.6) and 2.9 (2.6-3.1) respectively, and the corresponding RRs for bed-days were 3.5 (3.4-3.5), 1.8 (1.8-1.9) and 10.4 (10.3-10.6). Highest RRs were seen for nonmalignant haematological conditions (RR: 2.6; 3.1 and 9.7), malignant neoplasms (RR: 3.2; 2.5 and 4.7) and all infections combined (RR: 2.5; 2.2 and 5.3). Survivors of Hodgkin lymphoma in adolescence or young adulthood are at increased risk for a wide range of diseases that require hospitalisation. The risk depends on calendar period of treatment and on whether the survivors were rehospitalised for Hodgkin lymphoma, and thus likely had a relapse.

Risk stratification of childhood cancer survivors necessary for evidence-based clinical long-term follow-up.

BACKGROUND: Reorganisation of clinical follow-up care in England was proposed by the National Cancer Survivorship Initiative (NCSI), based on cancer type and treatment, ranging from Level 1 (supported self-management) to Level 3 (consultant-led care). The objective of this study was to provide an investigation of the risks of serious adverse health-outcomes associated with NCSI Levels of clinical care using a large population-based cohort of childhood cancer survivors. METHODS: The British Childhood Cancer Survivor Study (BCCSS) was used to investigate risks of specific causes of death, subsequent primary neoplasms (SPNs) and non-fatal non-neoplastic outcomes by NCSI Level. RESULTS: Cumulative (excess) risks of specified adverse outcomes by 45 years from diagnosis among non-leukaemic survivors assigned to NCSI Levels 1, 2 and 3 were for: SPNs-5% (two-fold expected), 14% (four-fold expected) and 21% (eight-fold expected); non-neoplastic death-2% (two-fold expected), 4% (three-fold expected) and 8% (seven-fold expected); non-fatal non-neoplastic condition-14%, 27% and 40%, respectively. Consequently overall cumulative risks of any adverse health outcome were 21%, 45% and 69%, respectively. CONCLUSIONS: Despite its simplicity the risk stratification tool provides clear and strong discrimination between survivors assigned to different NCSI Levels in terms of long-term cumulative and excess risks of serious adverse outcomes.

Risk of ischemic heart disease in women after radiotherapy for breast cancer.

BACKGROUND: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. METHODS: We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. RESULTS: The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy. CONCLUSIONS: Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

Cardiovascular disease incidence rates: a study using routinely collected health data.

BACKGROUND: There is substantial evidence that systemic anticancer therapies and radiotherapy can increase the long-term risk of cardiovascular disease (CVD). Optimal management decisions for cancer patients therefore need to take into account the likely risks from a proposed treatment option, as well as its likely benefits. For CVD, the magnitude of the risk depends on the incidence of the disease in the general population to which the patient belongs, including variation with age and sex, as well as on the treatment option under consideration. The aim of this paper is to provide estimates of CVD incidence rates in the general population of England for use in cardio-oncology and in other relevant clinical, research and health policy contexts. METHODS: We studied a population-based representative cohort, consisting of 2,633,472 individuals, derived by electronic linkage of records from primary care with those of admitted-patient care in England during April 1, 2010, to April 1, 2015. From 38 individual CVDs available via the linked dataset we identified five relevant categories of CVD whose risk may be increased by cancer treatments: four of heart disease and one of stroke. RESULTS: We calculated incidence rates by age-group and sex for all relevant CVD categories combined, for the four relevant categories of heart disease combined, and for the five relevant CVD categories separately. We present separate incidence rates for all 38 individual CVDs available via the linked dataset. We also illustrate how our data can be used to estimate absolute CVD risks in a range of people with Hodgkin lymphoma treated with chemotherapy and radiotherapy. CONCLUSIONS: Our results provide population-based CVD incidence rates for a variety of uses, including the estimation of absolute risks of CVD from cancer treatments, thus helping patients and clinicians to make appropriate individualized cancer treatment decisions. Graphical Abstract: Cardiovascular incidence rates for use in cardio-oncology and elsewhere: A presentation of age- and sex-specific cardiovascular disease (CVD) incidence rates for use in calculation of absolute cardiovascular risks of cancer treatments, and in other clinical, research and health policy contexts. Abbreviations - CVD: cardiovascular disease; y: years.

Predicted cardiac and second cancer risks for patients undergoing VMAT for mediastinal Hodgkin lymphoma.

BACKGROUND AND PURPOSE: To predict treatment-related cardiovascular disease (CVD) and second cancer 30-year absolute mortality risks (AMR30) for patients with mediastinal Hodgkin lymphoma in a large multicentre radiation oncology network in Ireland. MATERIAL AND METHODS: This study includes consecutive patients treated for mediastinal lymphoma using chemotherapy and involved site radiotherapy (RT) 2016-2019. Radiation doses to heart, left ventricle, cardiac valves, lungs, oesophagus, carotid arteries and female breasts were calculated. Individual CVD and second cancer AMR30 were predicted using Irish background population rates and dose-response relationships. RESULTS: Forty-four patients with Hodgkin lymphoma were identified, 23 females, median age 28 years. Ninety-eight percent received anthracycline, 80% received 4-6 cycles ABVD. Volumetric modulated arc therapy (VMAT) ± deep inspiration breath hold (DIBH) was delivered, median total prescribed dose 30 Gy. Average mean heart dose 9.8 Gy (range 0.2-23.8 Gy). Excess treatment-related mean AMR30 from CVD was 2.18% (0.79, 0.90, 0.01, 0.13 and 0.35% for coronary disease, heart failure, valvular disease, stroke and other cardiac diseases), 1.07% due to chemotherapy and a further 1.11% from RT. Excess mean AMR30 for second cancers following RT were: lung cancer 2.20%, breast cancer in females 0.34%, and oesophageal cancer 0.28%. CONCLUSION: For patients with mediastinal lymphoma excess mortality risks from CVD and second cancers remain clinically significant despite contemporary chemotherapy and photon-RT. Efforts to reduce the toxicity of combined modality treatment, for example, using DIBH, reduced margins and advanced RT, e.g. proton beam therapy, should be continued to further reduce potentially fatal treatment effects.

Breast cancer mortality in 500 000 women with early invasive breast cancer diagnosed in England, 1993-2015: population based observational cohort study.

OBJECTIVES: To describe long term breast cancer mortality among women with a diagnosis of breast cancer in the past and estimate absolute breast cancer mortality risks for groups of patients with a recent diagnosis. DESIGN: Population based observational cohort study. SETTING: Routinely collected data from the National Cancer Registration and Analysis Service. PARTICIPANTS: All 512 447 women registered with early invasive breast cancer (involving only breast and possibly axillary nodes) in England during January 1993 to December 2015, with follow-up to December 2020. MAIN OUTCOME MEASURES: Annual breast cancer mortality rates and cumulative risks by time since diagnosis, calendar period of diagnosis, and nine characteristics of patients and tumours. RESULTS: For women with a diagnosis made within each of the calendar periods 1993-99, 2000-04, 2005-09, and 2010-15, the crude annual breast cancer mortality rate was highest during the five years after diagnosis and then declined. For any given time since diagnosis, crude annual breast cancer mortality rates and risks decreased with increasing calendar period. Crude five year breast cancer mortality risk was 14.4% (95% confidence interval 14.2% to 14.6%) for women with a diagnosis made during 1993-99 and 4.9% (4.8% to 5.0%) for women with a diagnosis made during 2010-15. Adjusted annual breast cancer mortality rates also decreased with increasing calendar period in nearly every patient group, by a factor of about three in oestrogen receptor positive disease and about two in oestrogen receptor negative disease. Considering just the women with a diagnosis made during 2010-15, cumulative five year breast cancer mortality risk varied substantially between women with different characteristics: it was <3% for 62.8% (96 085/153 006) of women but ≥20% for 4.6% (6962/153 006) of women. CONCLUSIONS: These five year breast cancer mortality risks for patients with a recent diagnosis may be used to estimate breast cancer mortality risks for patients today. The prognosis for women with early invasive breast cancer has improved substantially since the 1990s. Most can expect to become long term cancer survivors, although for a few the risk remains appreciable.

Cardiac Disease in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Radiation therapy (RT) is an essential component in the treatment of many pediatric malignancies. Thoracic RT may expose the heart to radiation dose and thereby increase the risk of late cardiac disease. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on late cardiac disease in survivors of childhood cancer treated with RT. METHODS AND MATERIALS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We identified 1496 articles; 4 were included for dose-response modeling between mean cardiac radiation dose and risk of late coronary artery disease, heart failure (HF), valvular disease, and any cardiac disease. RESULTS: For each 10-Gy increase in corrected mean cardiac radiation dose in 1.8- to 2.0-Gy fractions, we estimated a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25) for coronary artery disease, of 1.87 (95% CI, 1.70-2.06) for HF, of 1.87 (95% CI, 1.78-1.96) for valvular disease, and of 1.88 (95% CI, 1.75-2.03) for any cardiac disease. From the same model, for each 100-mg/m2 increase in cumulative anthracycline dose, the hazard ratio for the development of HF was 1.93 (95% CI, 1.58-2.36), equivalent to an increase in mean heart dose of approximately 10.5 Gy. Other nontreatment factors were inconsistently reported in the analyzed articles. CONCLUSIONS: Radiation dose to the heart increases the risk of late cardiac disease, but survivors of childhood cancer who receive a mean dose <10 Gy at standard fractionation are at low absolute risk (<∼2% approximately 30 years after exposure) of late cardiac disease in the absence of anthracycline exposure. Minimizing cardiac radiation dose is especially relevant in children receiving anthracyclines. When cardiac sparing is not possible, we recommend prioritizing target coverage. It is likely that individual cardiac substructure doses will be a better predictor of specific cardiac diseases than mean dose, and we urge the pediatric oncology community to further study these relationships.

Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma.

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.

Pericardial Effusion during Proton Therapy in a Patient with Chemorefractory Hodgkin Lymphoma.

We present a case of recurrent pericardial effusion presenting during proton therapy in a 24-year-old female receiving mediastinal treatment for classical Hodgkin lymphoma. Pericardial effusion is typically considered an event accompanying lymphoma diagnosis or as a subacute or late effect of radiotherapy. Rarely has it been described as occurring during radiation treatment with photon-based radiotherapy, let alone proton therapy. It is unclear what underlying cause triggered recurrent effusion in this patient. Identifying and managing pericardial effusion during treatment delivery is important to consider as it may affect radiation dosimetry, particularly with proton therapy. Doing so will help ensure patients receive optimal treatment and minimize the risks of morbidity and mortality.

Informing radiotherapy decisions in stage I/IIa Hodgkin lymphoma: modeling life expectancy using radiation dosimetry.

In recent randomized trials, omitting consolidative radiotherapy (RT) in early-stage Hodgkin lymphoma (ESHL) increased relapses. However, decades of follow-up are required to observe whether lower initial disease control is compensated by reduced risk of late effects. Extrapolation beyond trial follow-up is therefore necessary to inform current treatment decisions. To this end, we developed a microsimulation model to estimate lifetime quality-adjusted life years (QALYs) after combined modality treatment (CMT) or chemotherapy-alone for stage I/IIa ESHL. For CMT, the model included risks of breast and lung cancer, coronary heart disease, and ischemic stroke. Comparative outcomes were assessed for a clinically relevant range of example patients differing by age, sex, smoking status, and representative organs at risk (OAR) radiation doses informed by the RAPID trial. Analysis was performed with and without a 3.5% discount rate on future health. Smoking status had a large effect on optimal treatment choice. CMT was superior for nearly all never smoker example patients regardless of age, sex, and OAR doses. At a maximum, CMT produced a 1.095 (95% CI: 1.054-1.137) gain in undiscounted QALYs for a 20-year-old male never smoker with unilateral neck disease. In contrast, current smokers could substantially gain from chemotherapy-alone treatment. Again at a maximum, a 20-year-old male current smoker with bilateral neck and whole mediastinum involvement gained 3.500 (95% CI: 3.400 to 3.600) undiscounted QALYs with chemotherapy-alone treatment. Overall, CMT was more favorable the younger the patient, when future health discounting was included, and in never smokers.