Publications by authors named "Berthe M P Aleman"

98 Publications

Clinicopathological features and risk factors for developing colorectal neoplasia in Hodgkin's lymphoma survivors.

Dig Endosc 2021 Apr 30. Epub 2021 Apr 30.

Departments of, Department of, Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1111/den.14004DOI Listing
April 2021

Motion-compensated FDG PET/CT for oesophageal cancer.

Strahlenther Onkol 2021 Sep 7;197(9):791-801. Epub 2021 Apr 7.

Department of Radiation Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Purpose: Respiratory-induced motion of oesophageal tumours and lymph nodes can influence positron-emission tomography/computed tomography (PET/CT). The aim was to compare standard three-dimensional (3D) and motion-compensated PET/CT regarding standardized uptake value (SUV), metabolic tumour volume (MTV) and detection of lymph node metastases.

Methods: This prospective observational study (NCT02424864) included 37 newly diagnosed oesophageal cancer patients. Diagnostic PET/CT was reconstructed in 3D and motion-compensated PET/CT. MTVs of the primary tumour were calculated using an automated region-growing algorithm with SUV thresholds of 2.5 (MTV2.5) and ≥ 50% of SUVmax (MTV50%). Blinded for reconstruction method, a nuclear medicine physician assessed all lymph nodes showing F‑fluorodeoxyglucose uptake for their degree of suspicion.

Results: The mean (95% CI) SUVmax of the primary tumour was 13.1 (10.6-15.5) versus 13.0 (10.4-15.6) for 3D and motion-compensated PET/CT, respectively. MTVs were also similar between the two techniques. Bland-Altman analysis showed mean differences between both measurements (95% limits of agreement) of 0.08 (-3.60-3.75), -0.26 (-2.34-1.82), 4.66 (-29.61-38.92) cm and -0.95 (-19.9-18.0) cm for tumour SUVmax, lymph node SUVmax, MTV2.5 and MTV50%, respectively. Lymph nodes were classified as highly suspicious (30/34 nodes), suspicious (20/22) and dubious (66/59) for metastases on 3D/motion-compensated PET/CT. No additional lymph node metastases were found on motion-compensated PET/CT. SUVmax of the most intense lymph nodes was similar for both scans: mean (95% CI) 6.6 (4.3-8.8) and 6.8 (4.5-9.1) for 3D and motion-compensated, respectively.

Conclusion: SUVmax of the primary oesophageal tumour and lymph nodes was comparable on 3D and motion-compensated PET/CT. The use of motion-compensated PET/CT did not improve lymph node detection.
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http://dx.doi.org/10.1007/s00066-021-01761-wDOI Listing
September 2021

Long-Term Cause-Specific Mortality in Hodgkin Lymphoma Patients.

J Natl Cancer Inst 2021 Jun;113(6):760-769

Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

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.
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http://dx.doi.org/10.1093/jnci/djaa194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168246PMC
June 2021

Gene expression profiles of esophageal squamous cell cancers in Hodgkin lymphoma survivors versus sporadic cases.

PLoS One 2020 21;15(12):e0243178. Epub 2020 Dec 21.

Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243178PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751872PMC
January 2021

Long-term effects of adjuvant treatment for breast cancer on carotid plaques and brain perfusion.

Breast Cancer Res Treat 2021 Feb 5;186(1):167-176. Epub 2020 Nov 5.

Department of Psychosocial Research & Epidemiology, Netherlands Cancer Institute/Antoni Van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Purpose: Breast cancer treatment has been associated with vascular pathology. It is unclear if such treatment is also associated with long-term cerebrovascular changes. We studied the association between radiotherapy and chemotherapy with carotid pathology and brain perfusion in breast cancer survivors.

Methods: We included 173 breast cancer survivors exposed to radiotherapy and chemotherapy, assessed ± 21.2 years after cancer diagnosis, and 346 age-matched cancer-free women (1:2) selected from the population-based Rotterdam Study. Outcome measures were carotid plaque score, intima-media thickness (IMT), total cerebral blood flow (tCBF), and brain perfusion. Additionally, we investigated the association between inclusion of the carotid artery in the radiation field (no/small/large part), tumor location, and these outcome measures within cancer survivors.

Results: Cancer survivors had lower tCBF (- 19.6 ml/min, 95%CI - 37.3;- 1.9) and brain perfusion (- 2.5 ml/min per 100 ml, 95%CI - 4.3;- 0.7) than cancer-free women. No statistically significant group differences were observed regarding plaque score or IMT. Among cancer survivors, a large versus a small part of the carotid artery in the radiation field was associated with a higher IMT (0.05, 95%CI0.01;0.09). Also, survivors with a right-sided tumor had lower left carotid plaque score (- 0.31, 95%CI - 0.60;- 0.02) and higher brain perfusion (3.5 ml/min per 100 ml, 95%CI 0.7;6.2) than those with a left-sided tumor.

Conclusions: On average two decades post-diagnosis, breast cancer survivors had lower tCBF and brain perfusion than cancer-free women. Also, survivors with a larger area of the carotid artery within the radiation field had a larger IMT. Future studies should confirm if these cerebrovascular changes underlie the frequently observed cognitive problems in cancer survivors.
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http://dx.doi.org/10.1007/s10549-020-05990-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940271PMC
February 2021

Risk of heart failure after systemic treatment for early breast cancer: results of a cohort study.

Breast Cancer Res Treat 2021 Jan 22;185(1):205-214. Epub 2020 Sep 22.

Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Purpose: Anthracyclines and trastuzumab can increase the risk of heart failure (HF), but long-term cardiotoxicity data in breast cancer (BC) patients treated at younger ages are limited. Furthermore, it is unknown whether aromatase inhibitors are associated with HF risk.

Methods: HF risk was studied in a multicenter cohort of BC survivors treated during 2000-2009, at age < 61 years. Information on treatment and cardiovascular disease incidence was collected through medical records, general practitioners and cardiologists. Analyses included multivariable Cox regression and cumulative incidence curves.

Results: In total, 10,209 women with a median age at BC diagnosis of 50.3 years and a median follow-up of 8.9 years were enrolled in the study. Anthracycline-based chemotherapy was associated with HF (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.41-3.39) and risk increased with increasing cumulative anthracycline dose. For trastuzumab, HF risk was highest within the first 2 years after treatment (HR: 13.06, 95% CI 5.70-29.92) and decreased thereafter (HR: 4.84, 95% CI 1.99-11.75 and HR: 0.64, 95% CI 0.23-1.81). The 10-year cumulative incidence of HF was 4.8% (95% CI 3.2-6.8) among patients treated with anthracyclines and trastuzumab. One-third of patients who developed HF after trastuzumab had long-term impaired cardiac function. Patients treated with aromatase inhibitors alone also had higher HF risk (HR 2.18, 95% CI 1.24-3.82) compared to patients not receiving endocrine therapy.

Conclusions: Our results stress the importance of considering anthracycline-free regimens in BC patients who need trastuzumab-containing treatment. The association between aromatase inhibitors and HF needs confirmation.
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http://dx.doi.org/10.1007/s10549-020-05930-wDOI Listing
January 2021

Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction.

Radiother Oncol 2020 12 3;153:155-162. Epub 2020 Sep 3.

Nuffield Department of Population Health, University of Oxford, Oxford, UK; Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Background And Purpose: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses.

Materials/methods: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships.

Results: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses.

Conclusions: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.
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http://dx.doi.org/10.1016/j.radonc.2020.08.022DOI Listing
December 2020

Clinical response assessment on DW-MRI compared with FDG-PET/CT after neoadjuvant chemoradiotherapy in patients with oesophageal cancer.

Eur J Nucl Med Mol Imaging 2021 01 22;48(1):176-185. Epub 2020 Jun 22.

Department of Radiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Purpose: In about 30% of patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection for locally advanced oesophageal cancer no vital tumour is found in the resection specimen. Accurate clinical response assessment is critical if deferral from surgery is considered in complete responders. Our study aimed to compare the performance of MRI and of FDG-PET/CT for the detection of residual disease after nCRT.

Methods: Patients with oesophageal cancer eligible for nCRT and oesophagectomy were prospectively included. All patients underwent FDG-PET/CT and MRI before and between 6 and 8 weeks after nCRT. Two radiologists scored the MRI scans, and two nuclear medicine physicians scored the FDG-PET/CT scans using a 5-point score for residual disease. Histopathology after oesophagectomy represented the reference standard. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated for detection of residual tumour (ypT+), residual nodal disease (ypN+), and any residual disease (ypT+Nx/ypT0N+).

Results: Seven out of 33 (21%) patients had a pathological complete response. The AUCs for individual readers to detect ypT+ were 0.71/0.70 on diffusion-weighted (DW)-MRI and 0.54/0.57 on FDG-PET/CT, and to detect ypN+ were 0.89/0.81 on DW-MRI and 0.75/0.71 on FDG-PET/CT. The AUCs/sensitivities/specificities for the individual readers to detect any residual disease were 0.74/92%/57% and 0.70/96%/43% on MRI; these were 0.49/69%/29% and 0.60/69%/43% on FDG-PET/CT, respectively.

Conclusion: MRI reached higher diagnostic accuracies than FDG-PET/CT for the detection of residual tumour in oesophageal cancer patients at 6 to 8 weeks after nCRT.
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http://dx.doi.org/10.1007/s00259-020-04917-5DOI Listing
January 2021

Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lymphoma Radiation Oncology Group Guidelines.

Int J Radiat Oncol Biol Phys 2020 08 7;107(5):909-933. Epub 2020 Apr 7.

Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Denmark.

Involved node radiation therapy for lymphoma was introduced with the aim of using the smallest effective treatment volume, individualized to the patient's disease distribution, to avoid the potentially unnecessary normal tissue exposure and toxicity risks associated with traditional involved field radiation therapy. The successful implementation of involved node radiation therapy requires optimal imaging and precise coregistration of baseline imaging with the radiation therapy planning computed tomography scan. Limitations of baseline imaging, changes in patient position, and anatomic changes after chemotherapy may make this difficult in routine practice. Involved site radiation therapy (ISRT) was introduced by the International Lymphoma Radiation Oncology Group as a slightly larger treated volume, intended to allow for commonly encountered uncertainties. In addition to imaging considerations, the optimal ISRT treatment volume also depends on disease histology, stage, nodal or extranodal location, and the type and efficacy of systemic therapy, which in turn influence the distribution of macroscopic and potential subclinical disease. This article presents a systematic overview of ISRT, updating key evidence and highlighting differences in the application of ISRT across the lymphoma clinical spectrum.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.019DOI Listing
August 2020

Prognosis of acute coronary syndromes after radiotherapy for breast cancer.

Radiother Oncol 2020 05 6;146:110-117. Epub 2020 Mar 6.

Netherlands Cancer Institute, Epidemiology, Amsterdam, The Netherlands. Electronic address:

Background And Purpose: Breast cancer patients treated with radiotherapy are at increased risk of subsequent acute coronary syndromes (ACS). We aimed to study if radiotherapy also influences the prognosis of these ACS.

Materials And Methods: We included all 398 patients diagnosed with ACS following radiotherapy from our hospital-based cohort of early breast cancer patients aged <71 years, treated 1970-2009. Cardiovascular disease incidence and cause of death were acquired through questionnaires to general practitioners and cardiologists. Internal mammary chain (IMC) irradiation delivers the highest heart doses in breast cancer radiotherapy. Hence, we compared ACS prognosis between patients treated with/without IMC-irradiation. ACS prognosis was assessed through cardiac death, death due to ACS and cardiovascular disease incidence, using multivariable Cox proportional hazard models and by estimating cumulative incidence.

Results: In total, 62% of patients with ACS had received IMC-irradiation and 38% did not (median age at ACS diagnosis, 67 years). Median time between breast cancer and ACS was 15 years. After ACS, ten-year cumulative risk of cardiac death was 35% for patients who had IMC-irradiation (95% confidence interval [95%CI] 29-41) compared to 24% (95%CI 17-31) for patients without IMC-irradiation (p = 0.04). After correction for confounders, IMC-irradiation remained associated with a less favourable prognosis of ACS compared to no IMC-irradiation (hazard ratio cardiac death = 1.7, 95%CI 1.1-2.5).

Conclusion: Our results suggest that radiotherapy, in case of substantial heart doses,may worsen ACS prognosis. This is an important, novel finding that may impact upon the risk-based care for breast cancer survivors with ACS.
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http://dx.doi.org/10.1016/j.radonc.2020.02.007DOI Listing
May 2020

Preoperative Prediction of Pathologic Response to Neoadjuvant Chemoradiotherapy in Patients With Esophageal Cancer Using F-FDG PET/CT and DW-MRI: A Prospective Multicenter Study.

Int J Radiat Oncol Biol Phys 2020 04 25;106(5):998-1009. Epub 2020 Jan 25.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht University, the Netherlands. Electronic address:

Purpose: Accurate preoperative prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal cancer could enable omission of esophagectomy in patients with a pathologic complete response (pCR). This study aimed to evaluate the individual and combined value of F-fluorodeoxyglucose positron emission tomography with integrated computed tomography (F-FDG PET/CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) during and after nCRT to predict pathologic response in patients with esophageal cancer.

Methods And Materials: In this multicenter prospective study, patients scheduled to receive nCRT followed by esophagectomy for esophageal cancer underwent F-FDG PET/CT and DW-MRI scanning before the start of nCRT, during nCRT, and before esophagectomy. Response to nCRT was based on histopathologic evaluation of the resection specimen. Relative changes in F-FDG PET/CT and DW-MRI parameters were compared between patients with pCR and non-pCR groups. Multivariable ridge regression analyses with bootstrapped c-indices were performed to evaluate the individual and combined value of F-FDG PET/CT and DW-MRI.

Results: pCR was found in 26.1% of 69 patients. Relative changes in F-FDG PET/CT parameters after nCRT (Δ standardized uptake value [SUV]P = .016, and Δ total lesion glycolysis P = .024), as well as changes in DW-MRI parameters during nCRT (Δ apparent diffusion coefficient [ADC]P = .008) were significantly different between pCR and non-pCR. A c-statistic of 0.84 was obtained for a model with ΔADC, ΔSUV, and histology in classifying patients as pCR (versus 0.82 for ΔADC and 0.79 for ΔSUV alone).

Conclusions: Changes on F-FDG PET/CT after nCRT and early changes on DW-MRI during nCRT can help identify pCR to nCRT in esophageal cancer. Moreover, F-FDG PET/CT and DW-MRI might be of complementary value in the assessment of pCR.
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http://dx.doi.org/10.1016/j.ijrobp.2019.12.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103753PMC
April 2020

Added value of MRI to endoscopic and endosonographic response assessment after neoadjuvant chemoradiotherapy in oesophageal cancer.

Eur Radiol 2020 May 21;30(5):2425-2434. Epub 2020 Jan 21.

Department of Radiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.

Objectives: In order to select oesophageal cancer patients after neoadjuvant chemoradiotherapy (nCRT) for organ-preserving treatment instead of surgery, a high diagnostic accuracy is required. The aim of this study was to evaluate whether MRI had additional value to gastroscopy with biopsies and endosonographic ultrasound (EUS) with fine needle aspiration (FNA) for the detection of residual tumour after nCRT.

Methods: Twenty-two patients with oesophageal cancer eligible for nCRT followed by oesophagectomy were prospectively included. All patients underwent (T2- and diffusion-weighted) MRI and gastroscopy+EUS before and after nCRT. Histopathology after oesophagectomy was the reference standard with pathological complete response (pCR) defined as ypT0N0. Diagnostic performance regarding the detection of residual tumour was calculated for gastroscopic biopsies and for EUS-FNA without and with MRI.

Results: Nineteen of the 22 patients (86%) did not achieve pCR after nCRT (7 ypT+N+, 11 ypT+N0, 1 ypT0N+). Biopsies detected residual tumour in 6 of 18 ypT+ patients. After adding MRI, 16 of 18 residual tumours were assessed correctly. EUS-FNA detected 3 out of 8 ypN+ patients, while MRI did not improve detection. Overall, adding MRI improved sensitivity for detection of residual tumour to 89% (17 of 19) from 47% (9 of 19) with endoscopic biopsies and EUS-FNA only.

Conclusion: In this small study, the detection of residual tumour after nCRT in oesophageal cancer patients was improved by the addition of MRI to gastroscopy and EUS.

Key Points: • In this small study, the detection of residual tumour after neoadjuvant chemoradiotherapy in oesophageal cancer patients was improved by adding MRI including diffusion-weighted images to gastroscopy and endosonographic ultrasound. • With the addition of MRI assessment to gastroscopy and endosonographic ultrasound, the considerable risk of missing residual tumours decreased from 53 to 11%, while the pitfall was overstaging in one out of three complete responders.
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http://dx.doi.org/10.1007/s00330-019-06605-xDOI Listing
May 2020

Quantification of Esophageal Tumor Motion and Investigation of Different Image-Guided Correction Strategies.

Pract Radiat Oncol 2020 Mar - Apr;10(2):84-92. Epub 2019 Nov 29.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Purpose: To accurately quantify esophageal tumor position variability and to optimize image guided correction strategies.

Material And Methods: Esophageal cancer patients receiving chemoradiotherapy (41.4-50.4 Gy in 23-28 fractions combined with carboplatin plus paclitaxel) were included in a prospective cohort study (NCT02139488). Gold fiducial markers were inserted into the esophageal tumors during diagnostic endoscopic ultrasound. Four-dimensional (4D) planning computed tomography (CT) and daily 4D cone beam (CB) CT scans were acquired. Each CBCT was registered to the planning CT using different regions of interest (bone; 3D), and carina, diaphragm, clinical target volume (CTV), and fiducial markers (4D) for alignment and using the fiducial markers as the true tumor position. Subsequently, a planning target volume (PTV) margin accounting for residual uncertainties, including the average respiratory motion, was calculated for each of these registrations.

Results: Fifty-six patients with tumors located in the proximal (n = 1), mid (n = 7), or distal esophagus (n = 25) or at the gastroesophageal junction (n = 23) were included. The average peak-to-peak respiratory tumor motion was 0.20, 0.92, and 0.34 cm on the planning CT in left-right (LR), cranial-caudal (CC), and anterior-posterior (AP) directions, respectively. The required PTV margin with average motion amplitude, depending on the correction strategy used for image guidance, ranged from 0.8 cm to 1.0 cm, 1.1 cm to 1.6 cm, and 0.7 cm to 0.9 cm in LR, CC, and AP direction, respectively. A registration based on the CTV resulted in the smallest PTV margins (0.8, 1.1, and 0.7 cm in LR, CC, and AP direction, respectively). For bone registration the calculated PTV margins were 1.0, 1.3, and 0.7 cm in LR, CC, and AP directions, respectively. The registration based on the diaphragm increased PTV margins.

Conclusions: Substantial and anisotropic position variability of esophageal tumors was observed during radiation therapy, and nonuniform margins should be considered. Cranial-caudal PTV margins need to be larger than those commonly used. Target positioning during image-guided radiotherapy could be improved with a CTV registration-based correction strategy.
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http://dx.doi.org/10.1016/j.prro.2019.11.012DOI Listing
October 2020

Heart failure after treatment for breast cancer.

Eur J Heart Fail 2020 02 12;22(2):366-374. Epub 2019 Nov 12.

Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: We aimed to develop dose-response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.

Methods And Results: A case-control study was performed within a cohort of breast cancer survivors treated during 1980-2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9-13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) -2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7-21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m (IQR 240-319). A dose-dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m , 95% CI 0.5-4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1-110.1) compared to no chemotherapy.

Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.
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http://dx.doi.org/10.1002/ejhf.1620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137787PMC
February 2020

Myocardial dysfunction in long-term breast cancer survivors treated at ages 40-50 years.

Eur J Heart Fail 2020 02 6;22(2):338-346. Epub 2019 Nov 6.

Department of Epidemiology & Biostatistics, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Aims: Anthracyclines increase heart failure (HF) risk, but the long-term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF.

Methods And Results: Within an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5-7 years (n = 277) or 10-12 years (n = 292) after BC treatment at ages 40-50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured in serum. Associations between patient-related and treatment-related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline-treated patients (n = 313), compared to the no-anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT-proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: -0.40 per cycle of 60 mg/m ; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT-proBNP >125 ng/L was highest for patients who received 241-300 mg/m anthracycline dose compared to the no-anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83-5.96).

Conclusion: Impaired GLS and increased NT-proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment.
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http://dx.doi.org/10.1002/ejhf.1610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077738PMC
February 2020

Gross Tumor Delineation in Esophageal Cancer on MRI Compared With F-FDG-PET/CT.

Adv Radiat Oncol 2019 Oct-Dec;4(4):596-604. Epub 2019 Apr 24.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Purpose: Current delineation of the gross tumor volume (GTV) in esophageal cancer relies on computed tomography (CT) and combination with F-fluorodeoxyglucose (FDG) positron emission tomography (PET). There is increasing interest in integrating magnetic resonance imaging (MRI) in radiation treatment, which can potentially obviate CT- or FDG-PET/CT-based delineation. The aim of this study is to evaluate the feasibility of target delineation on T2-weighted (T2W) MRI and T2W including diffusion-weighted MRI (T2W + DW-MRI) compared with current-practice FDG-PET/CT.

Methods: Ten observers delineated primary esophageal tumor GTVs of 6 patients on FDG-PET/CT, T2W-MRI, and T2W + DW-MRI. GTVs, generalized conformity indices, in-slice delineation variation (root mean square), and standard deviations in the position of the most cranial and caudal delineated slice were calculated.

Results: Delineations on MRI showed smaller GTVs compared with FDG-PET/CT-based delineations. The main variation was seen at the cranial and caudal border. No differences were observed in conformity indices (FDG-PET/CT, 0.68; T2W-MRI, 0.66; T2W + DW-MRI, 0.68) and in-slice variation (root mean square, 0.13 cm on FDG-PET/CT; 0.10 cm on T2W-MRI; 0.14 cm on T2W + DW-MRI). In the 2 tumors involving the gastroesophageal junction, addition of DW-MRI to T2W-MRI significantly decreased caudal border variation.

Conclusions: MRI-based target delineation of the esophageal tumor is feasible with interobserver variability comparable to that with FDG-PET/CT, despite limited experience with delineation on MRI. Most variation was seen at cranial-caudal borders, and addition of DW-MRI to T2W-MRI may reduce caudal delineation variation of gastroesophageal junction tumors.
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http://dx.doi.org/10.1016/j.adro.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817537PMC
April 2019

A Novel Liquid Fiducial Marker in Esophageal Cancer Image Guided Radiation Therapy: Technical Feasibility and Visibility on Imaging.

Pract Radiat Oncol 2019 Nov 4;9(6):e506-e515. Epub 2019 Jul 4.

Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Purpose: To assess the technical feasibility of injection, visibility on imaging modalities, and positional stability of a novel liquid fiducial marker (ie, BioXmark) for radiation therapy in patients with esophageal cancer.

Methods: First, the visibility on imaging of different volumes of the liquid marker was analyzed ex vivo in porcine tissue (ie, on computed tomography [CT], cone beam CT (CBCT), and magnetic resonance imaging [MRI]). Next, for the in vivo part, the liquid fiducial markers were injected under endoscopic (ultrasound) guidance in 10 patients with curable esophageal cancer. The technical feasibility of the injection procedure and the clinical performance (ie, visibility and positional stability on imaging) were evaluated. Planning CT, daily CBCT, and serial MRI images (before, during, and after chemoradiation therapy in a subset of 3 patients) were acquired.

Results: Ex vivo, the optimal volume for good visibility without artifacts was 0.1 mL per injected marker. In vivo, a total of 28 markers were injected in 10 patients (range, 0.025-0.1 mL). No adverse effects were identified. The first 2 cases (4 markers) were considered as learning cases. A total of 19 of 24 of the liquid markers (79%) were visible on CT, 3 of 4 (75%) on MRI, and 19 of 24 (79%) on the first CBCT. All markers with an injected volume of >0.05 mL were visible on the different imaging modalities. Positional stability analysis on CBCT identified no time trend during the radiation therapy course. No artifacts could be detected for liquid marker volumes of 0.05 and 0.025 mL in CT or CBCT.

Conclusions: Injection of a liquid fiducial marker for esophageal cancer radiation therapy is technically feasible with no adverse events identified. Volumes of >0.05 mL have an appropriate visibility on CT, CBCT, and MRI, with an excellent positional stability. Liquid fiducial markers are therefore promising for use in image guided radiation therapy.
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http://dx.doi.org/10.1016/j.prro.2019.06.018DOI Listing
November 2019

Fatigue level changes with time in long-term Hodgkin and non-Hodgkin lymphoma survivors: a joint EORTC-LYSA cross-sectional study.

Health Qual Life Outcomes 2019 Jul 2;17(1):115. Epub 2019 Jul 2.

Centre de Traitement des Données du Cancéropôle Nord-Ouest, Plateforme de Recherche Clinique Ligue Contre le Cancer, Centre François Baclesse, 3 Avenue Général Harris, 14076, Caen, Cedex 5, France.

Background: Long-term lymphoma survivors often complain of persistent fatigue that remains unexplained. While largely reported in Hodgkin lymphoma (HL), long-term fatigue is poorly documented in non-Hodgkin lymphomas (NHL). Data collected in two cohort studies were used to illustrate the fatigue level changes with time in the two populations.

Methods: Two cross-sectional studies were conducted in 2009-2010 (HL) and in 2015 (NHL) in survivors enrolled in European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and Lymphoma Study Association (LYSA) trials. The same protocol and questionnaires were used in both studies including the Multidimensional Fatigue Inventory (MFI) tool to assess fatigue and a checklist of health disorders. Multivariate linear regression models were used in the two populations separately to assess the influence of time since diagnosis and primary treatment, age, gender, education level, cohabitation status, obesity and health disorders on fatigue level changes. Fatigue level changes were compared to general population data.

Results: Overall, data of 2023 HL and 1619 NHL survivors with fatigue assessment available (99 and 97% of cases, respectively) were analyzed. Crude levels of fatigue were similar in the two populations. Individuals who reported health disorders (61% of HL and 64% of NHL) displayed higher levels of fatigue than those who did not (P <  0.001). HL survivors showed increasing fatigue level with age while in NHL survivors mean fatigue level remained constant until age 70 and increased beyond. HL survivors showed fatigue changes with age higher than those of the general population with health disorders while NHL survivors were in between those of the general population with and without health disorders.

Conclusions: Among lymphoma survivors progressive increase of fatigue level with time since treatment completion is a distinctive feature of HL. Our data suggest that changes in fatigue level are unlikely to only depend on treatment complications and health disorders. Investigations should be undertaken to identify which factors including biologic mechanisms could explain why a substantial proportion of survivors develop high level of fatigue.
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http://dx.doi.org/10.1186/s12955-019-1186-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604328PMC
July 2019

Small Cell Carcinoma of the Esophagus: A Nationwide Analysis of Treatment and Outcome at Patient Level in Locoregional Disease.

Am J Clin Oncol 2019 06;42(6):534-538

Department of Radiation Oncology, Academic Medical Center Amsterdam.

Background And Purpose: Small cell carcinoma of the esophagus (SCEC) is a rare subtype of esophageal cancer for which optimal treatment is unknown. We analyzed the impact of treatment factors on outcome in patients with nonmetastasized SCEC.

Methods: Patients with a histologically confirmed SCEC without distant metastases were analyzed in a nationwide multicenter retrospective cohort. All patients received radiotherapy as part of curative treatment between January 2000 and December 2014. Details on treatment and outcome were retrieved from individual charts. Cox regression analysis was used to determine prognostic factors for survival.

Results: Fifty-eight patients were analyzed. Median survival was 16 months (95% confidence interval, 11-21 mo). Infield recurrences occurred in 25%, distant metastases in 45%, and brain metastases in 12%. In total, 63% of patients developed a recurrence. Most recurrences (67%) occurred within 1 year. In univariable analyses an increased number of chemotherapy cycles (>3) and lower radiotherapy doses (<45 Gy) were associated with improved survival. T-stage, N-stage, treatment period, type of chemotherapy, prophylactic cranial irradiation, and age were not associated with survival. In multivariable analyses, only the number of chemotherapy cycles was associated with better survival (hazard ratio, 0.78; P=0.006).

Conclusions: SCEC recurs frequently at distant sites after definitive chemoradiotherapy and usually within 1 year after curative treatment. With a dose of 45 to 50 Gy, infield recurrence rate was low. We found a relationship between number of received chemotherapy cycles and survival with best results obtained after at least 4 cycles of chemotherapy.
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http://dx.doi.org/10.1097/COC.0000000000000546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554014PMC
June 2019

Salvage Treatment and Survival for Relapsed Follicular Lymphoma Following Primary Radiation Therapy: A Collaborative Study on Behalf of ILROG.

Int J Radiat Oncol Biol Phys 2019 07 8;104(3):522-529. Epub 2019 Mar 8.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: We previously reported that ∼30% of patients with localized follicular lymphoma (FL) staged by F-fluorodeoxyglucose positron emission tomography-computed tomography receiving primary radiation therapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed.

Methods And Materials: We conducted a multicenter, retrospective study of patients aged ≥18 years who received RT ≥ 24 Gy for stage I to II, grade 1 to 3A FL, staged with F-fluorodeoxyglucose (F-FDG) positron emission tomography-computed tomography. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier analysis and univariable and multivariable analyses with Cox regression.

Results: Of 512 patients with median follow-up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median of 23 months (range, 1-143) after primary RT. Median follow-up was 33 months after relapse. Three-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others-88.7% versus 97.6%, respectively (P = .01)-and remained significantly worse on multivariable analyses (follicular lymphoma international prognostic index-adjusted hazard ratio, 3.61; P = .009). Histology at relapse included 93 indolent (grade 1-3A), 3 FL grade 3B/not otherwise specified, and 18 diffuse large B-cell lymphoma; 35 patients did not undergo biopsy. Of those with follow-up ≥3 months who underwent biopsy (n = 74) or had presumed (n = 23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) had RT, and 4 (4.1%) had systemic therapy + RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n = 59, including 20 initially observed) 3-year FFP was 73.9%.

Conclusions: Prognosis for patients with relapsed FL after primary radiation therapy is excellent, supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival compared with those with longer disease-free interval.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162056PMC
July 2019

Elevated Pretreatment CEA and CA19-9 Levels are Related to Early Treatment Failure in Esophageal Adenocarcinoma.

Am J Clin Oncol 2019 04;42(4):345-350

Departments of Surgical Oncology.

Introduction: Chemoradiotherapy and surgery are the basis of the potentially curative treatment for esophageal cancer. Approximately 1 in 5 patients, however, do not benefit from this intensive treatment due to early treatment failure. The aim of this study was to evaluate levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 at diagnosis, in relation to survival and early treatment failure (disease recurrence or death within 1 year after surgery).

Methods: Patients with esophageal adenocarcinoma scheduled for chemoradiotherapy followed by surgery between 1998 and 2014 were selected from a retrospectively collected database if both CEA and CA19-9 levels were measured before the start of treatment.

Results: Pretreatment CEA and CA19-9 levels were known in 102 patients. Median overall survival differed (P<0.001) between patients with normal levels of both CEA and CA19-9 (n=59; 51 mo), patients with elevated CEA only (n=13; 43 mo), patients with elevated CA19-9 only (n=19; 24 mo), and those with elevated levels of both CEA and CA19-9 (n=11; 11 mo). Elevation of both CEA and CA19-9 was associated with early treatment failure (odds ratio: 10.4; 95% confidence interval: 2.4-45.5, P=0.002). Median time to tumor recurrence was 34 months in patients with normal CEA and CA19-9 levels, and 7 months in those with elevated levels of both (P=0.003).

Conclusions: Pretreatment elevated CEA and CA19-9 levels were significantly associated with early treatment failure and decreased overall survival in this esophageal adenocarcinoma patient cohort treated with curative intent. Until prospective validation, CEA and CA19-9 might play a role in identifying high-risk patients before the start of intensive locoregional therapy.
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http://dx.doi.org/10.1097/COC.0000000000000525DOI Listing
April 2019

Overall and disease-specific survival of Hodgkin lymphoma survivors who subsequently developed gastrointestinal cancer.

Cancer Med 2019 01 27;8(1):190-199. Epub 2018 Dec 27.

Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1002/cam4.1922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346242PMC
January 2019

Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma.

Blood 2019 03 20;133(10):1130-1139. Epub 2018 Dec 20.

Department of Epidemiology and Biostatistics.

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 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.
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http://dx.doi.org/10.1182/blood-2018-07-862607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405334PMC
March 2019

High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors.

Cancer 2019 03 18;125(6):990-999. Epub 2018 Dec 18.

Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

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.
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http://dx.doi.org/10.1002/cncr.31903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590398PMC
March 2019

Definitive radiotherapy for localized follicular lymphoma staged by F-FDG PET-CT: a collaborative study by ILROG.

Blood 2019 01 16;133(3):237-245. Epub 2018 Nov 16.

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As F-fluorodeoxyglucose (F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II ( < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.
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http://dx.doi.org/10.1182/blood-2018-04-843540DOI Listing
January 2019

Radiation Dose-Response for Risk of Myocardial Infarction in Breast Cancer Survivors.

Int J Radiat Oncol Biol Phys 2019 03 29;103(3):595-604. Epub 2018 Oct 29.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Purpose: Previous reports suggest that radiation therapy for breast cancer (BC) can cause ischemic heart disease, with the radiation-related risk increasing linearly with mean whole heart dose (MWHD). This study aimed to validate these findings in younger BC patients and to investigate additional risk factors for radiation-related myocardial infarction (MI).

Methods And Materials: A nested case-control study was conducted within a cohort of BC survivors treated during 1970 to 2009. Cases were 183 patients with MI as their first heart disease after BC. One control per case was selected and matched on age and BC diagnosis date. Information on treatment and cardiovascular risk factors was abstracted from medical and radiation charts. Cardiac doses were estimated for each woman by reconstructing her regimen using modern 3-dimensional computed tomography planning on a typical patient computed tomography scan.

Results: Median age at BC of cases and controls was 50.2 years (interquartile range, 45.7-54.7). Median time to MI was 13.6 years (interquartile range, 9.9-18.1). Median MWHD was 8.9 Gy (range, 0.3-35.2 Gy). MI rate increased linearly with increasing MWHD (excess rate ratio [ERR] per Gy, 6.4%; 95% confidence interval, 1.3%-16.0%). Patients receiving ≥20 Gy MWHD had a 3.4-fold (95% confidence interval, 1.5-7.6) higher MI rate than unirradiated patients. ERRs were higher for younger women, with borderline significance (ERR, 24.2%/Gy; ERR, 2.5%/Gy; P = .054). Whole heart dose-volume parameters did not modify the dose-response relationship significantly.

Conclusions: MI rate after radiation for BC increases linearly with MWHD. Reductions in MWHD are expected to contribute to better cardiovascular health of BC survivors.
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http://dx.doi.org/10.1016/j.ijrobp.2018.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361769PMC
March 2019

Risk of diabetes after para-aortic radiation for testicular cancer.

Br J Cancer 2018 10 9;119(7):901-907. Epub 2018 Oct 9.

Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated.

Methods: Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case-cohort design.

Results: With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7-1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11-0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: -0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose.

Conclusion: Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.
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http://dx.doi.org/10.1038/s41416-018-0248-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189211PMC
October 2018

Rationale and design of a cohort study on primary ovarian insufficiency in female survivors of Hodgkin's lymphoma: influence on long-term adverse effects (SOPHIA).

BMJ Open 2018 09 11;8(9):e018120. Epub 2018 Sep 11.

Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1136/bmjopen-2017-018120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144325PMC
September 2018
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