Publications by authors named "Augustinus D G Krol"

23 Publications

  • Page 1 of 1

Long-term cause-specific mortality in hodgkin lymphoma patients.

J Natl Cancer Inst 2020 Dec 22. Epub 2020 Dec 22.

Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam.

Background: Few studies examined the impact of treatment-related morbidity on long-term cause-specific mortality in Hodgkin lymphoma (HL) patients.

Methods: This multicenter cohort included 4,919 HL patients, treated before age 51 between 1965-2000, with a median follow-up of 20.2 years. Standardized mortality ratios (SMRs), absolute excess mortality per 10,000 person-years (AEM) and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks were calculated.

Results: HL patients experienced 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 (SMR = 5.2, 95% Confidence Interval (95%CI) = 4.2-6.5; AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL as 71-year old individuals from the general population. While HL mortality statistically significantly decreased over 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 (HR) = 0.65, 95%CI = 0.46-0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (HR = 2.81, 95%CI = 1.55-5.07). For stage I-II, primary treatment with chemotherapy alone was associated with statistically significantly higher HL mortality (p < .001 for CT vs. RT; p = .04 for CT vs. RT+CT), but lower 30-year mortality from causes other than HL (15.8%, 95%CI = 9.7%-23.3%), compared to radiotherapy alone (36.9%, 95%CI = 34.0%-39.8%; p = .001) and radiotherapy and chemotherapy combined (29.8%, 95%CI = 26.8%-32.9%; p = .02).

Conclusion: Compared to 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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December 2020

Therapy-Related Imaging Findings in Patients with Sarcoma.

Semin Musculoskelet Radiol 2020 Dec 11;24(6):676-691. Epub 2020 Dec 11.

Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria.

Knowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in asymptomatic patients or because symptoms, including anxiety, develop. In addition to detection of recurrent disease and assessment of response to therapy, diagnosis of conditions related to therapy that may or may not need treatment has a marked positive impact on quality of life. The purpose of this review is to assist radiologists, nuclear physicians, and others clinicians involved in the diagnosis and treatment of these patients in recognizing imaging findings related to therapy and not to activity of the previously treated sarcoma. Imaging findings are time dependent and often specific in relation to therapy given.
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December 2020

Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcoma: A Nonrandomized Controlled Trial.

JAMA Oncol 2021 Jan 21;7(1):e205865. Epub 2021 Jan 21.

Sarcoma Unit, Department of Radiotherapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands.

Importance: Currently, preoperative radiotherapy for all soft-tissue sarcomas is identical at a 50-Gy dose level, which can be associated with morbidity, particularly wound complications. The observed clinical radiosensitivity of the myxoid liposarcoma subtype might offer the possibility to reduce morbidity.

Objective: To assess whether a dose reduction of preoperative radiotherapy for myxoid liposarcoma would result in comparable oncological outcome with less morbidity.

Design, Setting, And Participants: The Dose Reduction of Preoperative Radiotherapy in Myxoid Liposarcomas (DOREMY) trial is a prospective, single-group, phase 2 nonrandomized controlled trial being conducted in 9 tertiary sarcoma centers in Europe and the US. Participants include adults with nonmetastatic, biopsy-proven and translocation-confirmed myxoid liposarcoma of the extremity or trunk who were enrolled between November 24, 2010, and August 1, 2019. Data analyses, using both per-protocol and intention-to-treat approaches, were conducted from November 24, 2010, to January 31, 2020.

Interventions: The experimental preoperative radiotherapy regimen consisted of 36 Gy in once-daily 2-Gy fractions, with subsequent definitive surgical resection after an interval of 4 or more weeks.

Main Outcomes And Measures: As a short-term evaluable surrogate for local control, the primary end point was centrally reviewed pathologic treatment response. The experimental regimen was regarded as a success when 70% or more of the resection specimens showed extensive treatment response, defined as 50% or greater of the tumor volume containing treatment effects. Morbidity outcomes consisted of wound complications and late toxic effects.

Results: Among the 79 eligible patients, 44 (56%) were men and the median (interquartile range) age was 45 (39-56) years. Two patients did not undergo surgical resection because of intercurrent metastatic disease. Extensive pathological treatment response was observed in 70 of 77 patients (91%; posterior mean, 90.4%; 95% highest probability density interval, 83.8%-96.4%). The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%.

Conclusions And Relevance: The findings of the DOREMY nonrandomized clinical trial suggest that deintensification of preoperative radiotherapy dose is effective and oncologically safe and is associated with less morbidity than historical controls, although differences in radiotherapy techniques and follow-up should be considered. A 36-Gy dose delivered in once-daily 2-Gy fractions is proposed as a dose-fractionation approach for myxoid liposarcoma, given that phase 3 trials are logistically impossible to execute in rare cancers.

Trial Registration: Identifier: NCT02106312.
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January 2021

Extrameningeal solitary fibrous tumors-surgery alone or surgery plus perioperative radiotherapy: A retrospective study from the global solitary fibrous tumor initiative in collaboration with the Sarcoma Patients EuroNet.

Cancer 2020 Jul 21;126(13):3002-3012. Epub 2020 Apr 21.

Adult Mesenchymal and Rare Tumor Unit, Medical Oncology, IRCCS Foundation, National Cancer Institute, Milan, Italy.

Background: Solitary fibrous tumor (SFT) is a rare mesenchymal malignancy. Although surgery is potentially curative, the local relapse risk is high after marginal resections. Given the lack of prospective clinical trial data, the objective of the current study was to better define the role of perioperative radiotherapy (RT) in various SFT presentations by location.

Methods: This was retrospective study performed across 7 sarcoma centers. Clinical information was retrieved from all adult patients with extrameningeal, primary, localized SFT who were treated between 1990 and 2018 with surgery alone (S) compared with those who also received perioperative RT (S+RT). Differences in treatment characteristics between subgroups were tested using analysis of variance statistics and propensity score matching. Local control and overall survival rates were calculated from the start of treatment until progression or death from any cause.

Results: Of all 549 patients, 428 (78%) underwent S, and 121 (22%) underwent S+RT. The median follow-up was 52 months. After correction for mitotic count and surgical margins, S+RT was significantly associated with a lower risk of local progression (hazard ratio, 0.19: P = .029), an observation further confirmed by propensity score matching (P = .012); however, this association did not translate into an overall survival benefit.

Conclusions: The results from this retrospective study investigating perioperative RT in patients with primary extrameningeal SFT suggest that combining RT with surgery in the management of this patient population is significantly associated with a reduced risk of local failures, especially in patients who have less favorable resection margins and in those who have tumors with a high mitotic count.
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July 2020

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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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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March 2019

The impact of treatment accuracy on proton therapy patient selection for oropharyngeal cancer patients.

Radiother Oncol 2017 12 23;125(3):520-525. Epub 2017 Oct 23.

Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Background And Purpose: The impact of treatment accuracy on NTCP-based patient selection for proton therapy is currently unknown. This study investigates this impact for oropharyngeal cancer patients.

Materials And Methods: Data of 78 patients was used to automatically generate treatment plans for a simultaneously integrated boost prescribing 70 Gy/54.25 Gy in 35 fractions. IMRT treatment plans were generated with three different margins; intensity modulated proton therapy (IMPT) plans for five different setup and range robustness settings. Four NTCP models were evaluated. Patients were selected for proton therapy if NTCP reduction was ≥10% or ≥5% for grade II or III complications, respectively.

Results: The degree of robustness had little impact on patient selection for tube feeding dependence, while the margin had. For other complications the impact of the robustness setting was noticeably higher. For high-precision IMRT (3 mm margin) and high-precision IMPT (3 mm setup/3% range error), most patients were selected for proton therapy based on problems swallowing solid food (51.3%) followed by tube feeding dependence (37.2%), decreased parotid flow (29.5%), and patient-rated xerostomia (7.7%).

Conclusions: Treatment accuracy has a significant impact on the number of patients selected for proton therapy. Therefore, it cannot be ignored in estimating the number of patients for proton therapy.
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December 2017

Breast Cancer Risk After Radiation Therapy for Hodgkin Lymphoma: Influence of Gonadal Hormone Exposure.

Int J Radiat Oncol Biol Phys 2017 11 18;99(4):843-853. Epub 2017 Jul 18.

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

Background: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk.

Methods: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports.

Results: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause ≥50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for ≥2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve.

Conclusions: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.
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November 2017

Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma.

N Engl J Med 2015 Dec;373(26):2499-511

From the Departments of Epidemiology (M.S., A.M.E., I.M., I.M.K., F.E.L.), Radiation Oncology (B.M.P.A.), and Hematology (J.P.B.), Netherlands Cancer Institute, and the Department of Hematology, VU University Medical Center Amsterdam (J.M.Z.), Amsterdam, the Netherlands Comprehensive Cancer Organization (M.S., I.M., O.V., M.W.J.L.) and the Departments of Radiation Oncology (J.R.) and Hematology (E.J.P.), University Medical Center Utrecht, Utrecht, the Departments of Radiation Oncology (C.P.M.J.) and Hematology (P.J.L.), Erasmus Medical Center Cancer Institute, Rotterdam, the Department of Radiation Oncology, Leiden University Medical Center, Leiden (A.D.G.K.), the Department of Radiation Oncology, Radboud University Medical Center (R.W.M.M., P.M.P.P.), and the Department of Education and Science, Canisius-Wilhelmina Hospital (I.M.), Nijmegen, the Department of Hematology, Radboud University Medical Center, Nijmegen-Rijnstate, Arnhem (J.M.M.R.), the Departments of Hematology (G.W.I.) and Radiation Oncology (M.B.), University Medical Center Groningen, Groningen, the Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Tilburg (P.M.P.P.), and the Department of Radiotherapy, Catharina Hospital, Eindhoven (M.L.L.) - all in the Netherlands.

Background: Survivors of Hodgkin's lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown.

Methods: We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkin's lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort.

Results: With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30).

Conclusions: The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkin's lymphoma. (Funded by the Dutch Cancer Society.).
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December 2015

Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma.

J Clin Oncol 2016 Jan 16;34(3):235-43. Epub 2015 Nov 16.

Frederika A. van Nimwegen, Michael Schaapveld, Michael Hauptmann, Karen Kooijman, Berthe M.P. Aleman, and Flora E. van Leeuwen, Netherlands Cancer Institute, Amsterdam; Michael Schaapveld, Netherlands Comprehensive Cancer Organization; Judith Roesink, University Medical Center Utrecht, Utrecht; Cècile P.M. Janus, Erasmus MC Cancer Institute, Rotterdam; Augustinus D.G. Krol, Leiden University Medical Center, Leiden; Richard van der Maazen, Radboud University Medical Center, Nijmegen, Netherlands; David J. Cutter, and Sarah C. Darby, University of Oxford; and David J. Cutter, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

Purpose: Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors.

Patients And Methods: We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive.

Results: The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy(<27.5years), 20.0%; ERR/Gy(27.5-36.4years), 8.8%; ERR/Gy(36.5-50.9years), 4.2%; P(interaction) = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8).

Conclusion: The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors.
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January 2016

Sexual Concerns after (Pelvic) Radiotherapy: Is There Any Role for the Radiation Oncologist?

J Sex Med 2015 Sep;12(9):1927-39

Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.

Introduction: Sexual function is an important aspect of quality of life, and may be impaired after (pelvic) radiation.

Aim: The aim of this study was to identify practice, responsibility attitudes, knowledge, and barriers of Dutch radiation oncologists regarding sexual counseling.

Methods: A cross-sectional survey was performed using a 28-item questionnaire sent to all members of the Dutch Society for Radiotherapy and Oncology.

Main Outcome Measures: Self-reported practice, knowledge, barriers, need for training and responsibility attitudes in regard to demographic characteristics.

Results: Of the surveyed sample, 54.6% of the radiation oncologists completed the instrument (n = 119). Frequency of discussing sexual function was fluctuating, depending on the type of tumor. The majority of the responding radiation oncologists (75%) agreed that discussing sexual function is their responsibility, about one-third (33.6%) pointed at the involved specialist (surgeon, urologist, gynecologist, or oncologist), a fifth also considered the general practitioner responsible (21%). Additional training about discussing sexuality was required according to 44.4%, the majority agreed that sexual counseling should be a regular component of radiation oncology residency (n = 110, 94%). Barriers most mentioned included patient is too ill (36.2%), no angle or reason for asking (32.4%), advanced age of the patient (27%) and culture/religion (26.1%). For prostate cancer patients, phosphodiesterase 5 inhibitor information was supplied regularly (49.2%) and often (40.7%).

Conclusions: Radiation oncologists generally perform sexual counseling in case of pelvic radiation therapy, but not consistently in case of gastrointestinal, breast, and other cancers. The majority of radiation oncologists considered counseling on sexual functioning as a part of their job, some also pointed at the referring specialist or general practitioner. The findings suggest that awareness about sexual dysfunction is present among radiation oncologists, but responsibility for active counseling is uncertain. Results emphasize the need for providing educational and practical training, as well as a list for specialized referral.
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September 2015

Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk.

JAMA Intern Med 2015 Jun;175(6):1007-17

Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam.

Importance: Hodgkin lymphoma (HL) survivors are at increased risk of cardiovascular diseases. It is unclear, however, how long the increased risk persists and what the risk factors are for various cardiovascular diseases.

Objectives: To examine relative and absolute excess risk up to 40 years since HL treatment compared with cardiovascular disease incidence in the general population and to study treatment-related risk factors for different cardiovascular diseases.

Design, Setting, And Participants: This retrospective cohort study included 2524 Dutch patients diagnosed as having HL at younger than 51 years (median age, 27.3 years) who had been treated from January 1, 1965, through December 31, 1995, and had survived for 5 years since their diagnosis.

Exposures: Treatment for HL, including prescribed mediastinal radiotherapy dose and anthracycline dose.

Main Outcomes And Measures: Data were collected from medical records and general practitioners. Cardiovascular events, including coronary heart disease (CHD), valvular heart disease (VHD), and cardiomyopathy and congestive heart failure (HF), were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Results: After a median follow-up of 20 years, we identified 1713 cardiovascular events in 797 patients. After 35 years or more, patients still had a 4- to 6-fold increased standardized incidence ratio of CHD or HF compared with the general population, corresponding to 857 excess events per 10,000 person-years. Highest relative risks were seen in patients treated before 25 years of age, but substantial absolute excess risks were also observed for patients treated at older ages. Within the cohort, the 40-year cumulative incidence of cardiovascular diseases was 50% (95% CI, 47%-52%). Fifty-one percent of patients with a cardiovascular disease developed multiple events. For patients treated before 25 years of age, cumulative incidences at 60 years or older were 20%, 31%, and 11% for CHD, VHD, and HF as first events, respectively. Mediastinal radiotherapy increased the risks of CHD (hazard ratio [HR], 2.7; 95% CI, 2.0-3.7), VHD (HR, 6.6; 95% CI, 4.0-10.8), and HF (HR, 2.7; 95% CI, 1.6-4.8), and anthracycline-containing chemotherapy increased the risks of VHD (HR, 1.5; 95% CI, 1.1-2.1) and HF (HR, 3.0; 95% CI, 1.9-4.7) as first events compared with patients not treated with mediastinal radiotherapy or anthracyclines, respectively. Joint effects of mediastinal radiotherapy, anthracyclines, and smoking appeared to be additive.

Conclusions And Relevance: Throughout their lives, HL survivors treated at adolescence or adulthood are at high risk for various cardiovascular diseases. Physicians and patients should be aware of this persistently increased risk.
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June 2015

Simple method to estimate mean heart dose from Hodgkin lymphoma radiation therapy according to simulation X-rays.

Int J Radiat Oncol Biol Phys 2015 May;92(1):153-60

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address:

Purpose: To describe a new method to estimate the mean heart dose for Hodgkin lymphoma patients treated several decades ago, using delineation of the heart on radiation therapy simulation X-rays. Mean heart dose is an important predictor for late cardiovascular complications after Hodgkin lymphoma (HL) treatment. For patients treated before the era of computed tomography (CT)-based radiotherapy planning, retrospective estimation of radiation dose to the heart can be labor intensive.

Methods And Materials: Patients for whom cardiac radiation doses had previously been estimated by reconstruction of individual treatments on representative CT data sets were selected at random from a case-control study of 5-year Hodgkin lymphoma survivors (n=289). For 42 patients, cardiac contours were outlined on each patient's simulation X-ray by 4 different raters, and the mean heart dose was estimated as the percentage of the cardiac contour within the radiation field multiplied by the prescribed mediastinal dose and divided by a correction factor obtained by comparison with individual CT-based dosimetry.

Results: According to the simulation X-ray method, the medians of the mean heart doses obtained from the cardiac contours outlined by the 4 raters were 30 Gy, 30 Gy, 31 Gy, and 31 Gy, respectively, following prescribed mediastinal doses of 25-42 Gy. The absolute-agreement intraclass correlation coefficient was 0.93 (95% confidence interval 0.85-0.97), indicating excellent agreement. Mean heart dose was 30.4 Gy with the simulation X-ray method, versus 30.2 Gy with the representative CT-based dosimetry, and the between-method absolute-agreement intraclass correlation coefficient was 0.87 (95% confidence interval 0.80-0.95), indicating good agreement between the two methods.

Conclusion: Estimating mean heart dose from radiation therapy simulation X-rays is reproducible and fast, takes individual anatomy into account, and yields results comparable to the labor-intensive representative CT-based method. This simpler method may produce a meaningful measure of mean heart dose for use in studies of late cardiac complications.
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May 2015

Risk of valvular heart disease after treatment for Hodgkin lymphoma.

J Natl Cancer Inst 2015 Apr 23;107(4). Epub 2015 Feb 23.

Clinical Trial Service Unit, University of Oxford, Oxford, UK (DJC, SCD); Department of Psychosocial Research, Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands (MS, MH, FAvN, FEvL); Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands (ADGK); Department of Radiation Oncology, Erasmus Medical Center/Daniel den Hoed Clinic, Rotterdam, the Netherlands (CPMJ); Department of Radiation Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands (BMPA).

Background: Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response.

Methods: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided.

Results: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02).

Conclusions: Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up.
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April 2015

Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma.

J Clin Oncol 2014 Oct 25;32(29):3257-63. Epub 2014 Aug 25.

Frederika A. van Nimwegen, Michael Schaapveld, Berthe M.P. Aleman, and Flora E. van Leeuwen, The Netherlands Cancer Institute; Michael Schaapveld, Comprehensive Cancer Centre the Netherlands; Leontien C.M. Kremer, Emma Children's Hospital/Academic Medical Center, Amsterdam; Cecile P.M. Janus, Erasmus Medical Center Cancer Institute, Rotterdam; Augustinus D.G. Krol, Leiden University Medical Center, Leiden; John M.M. Raemaekers, Radboud University Medical Center, Nijmegen, and Rijnstate Hospital, Arnhem, the Netherlands; and Marilyn Stovall, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Recently, an increased risk of diabetes mellitus (DM) was observed after abdominal irradiation for childhood cancer. Because many Hodgkin lymphoma (HL) survivors have also been treated with infradiaphragmatic radiotherapy, we evaluated the association between HL treatment and DM risk.

Patients And Methods: Our study cohort comprised 2,264 5-year HL survivors, diagnosed before age 51 years and treated between 1965 and 1995. Treatment and follow-up information was collected from medical records and general practitioners. Radiation dosimetry was performed to estimate radiation dose to the pancreas. Cumulative incidence of DM was estimated, and risk factors for DM were evaluated by using Cox regression.

Results: After a median follow-up of 21.5 years, 157 patients developed DM. Overall cumulative incidence of DM after 30 years was 8.3% (95% CI, 6.9% to 9.8%). After para-aortic radiation with ≥ 36 Gy, the 30-year cumulative incidence of DM was 14.2% (95% CI, 10.7% to 18.3%). Irradiation with ≥ 36 Gy to the para-aortic lymph nodes and spleen was associated with a 2.30-fold increased risk of DM (95% CI, 1.54- to 3.44-fold) whereas para-aortic radiation alone with ≥ 36 Gy was associated with a 1.82-fold increased risk (95% CI, 1.02- to 3.25-fold). Lower doses (10 to 35 Gy) did not significantly increase risk of DM. The risk of DM significantly increased with higher mean radiation doses to the pancreatic tail (P < .001).

Conclusion: Radiation to the para-aortic lymph nodes increases the risk of developing DM in 5-year HL survivors. Screening for DM should be considered in follow-up guidelines for HL survivors, and treating physicians should be alert to this increased risk.
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October 2014

Risk of multiple primary malignancies following treatment of Hodgkin lymphoma.

Blood 2014 Jul 16;124(3):319-27; quiz 466. Epub 2014 Apr 16.

Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;

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

Long-term risk of secondary skin cancers after radiation therapy for Hodgkin's lymphoma.

Radiother Oncol 2013 Oct 7;109(1):140-5. Epub 2013 Aug 7.

Department of Clinical Oncology, Leiden University Medical Center, The Netherlands. Electronic address:

Purpose: Survivors of Hodgkin's lymphoma (HL) are at risk of secondary tumors. We investigated the risk of secondary skin cancers after radiotherapy compared to treatment without radiation and to an age-matched population.

Material And Methods: We conducted a retrospective cohort study of 889 HL patients treated between 1965 and 2005. Data on secondary skin cancers and treatment fields were retrieved. Incidence rates were compared to observed rates in the Dutch population.

Results: 318 skin cancers were diagnosed in 86 patients, showing significantly higher risks of skin cancers, the majority being BCC. The standardized incidence ratio (SIR) of BCC in HL survivors was significantly increased (SIR 5.2, 95% CI 4.0-6.6), especially in those aged <35 years at diagnosis (SIR 8.0, 95% CI 5.8-10.7). SIR increased with longer follow-up to 15.9 (95% CI 9.1-25.9) after 35 years, with 626 excess cases per 10,000 patients per year. Most (57%) skin cancers developed within the radiation fields, with significantly increased risk in patients treated with radiotherapy compared to chemotherapy alone (p=0·047, HR 2·75, 95% CI 1·01-7.45).

Conclusion: Radiotherapy for HL is associated with a strongly increased long-term risk of secondary skin cancers, both compared to the general population and to treatment with chemotherapy alone.
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October 2013

Persisting fatigue in Hodgkin lymphoma survivors: a systematic review.

Ann Hematol 2013 Aug 1;92(8):1023-32. Epub 2013 Jun 1.

Departments of Clinical Oncology, K1-P, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands.

Hodgkin Lymphoma (HL) survivors are at risk for adverse psychosocial events as a result from cancer diagnosis and treatment. Fatigue is one of the most frequently reported long-term symptoms and is often reported to interfere with daily life. We conducted a systematic review to determine prevalence, severity and predisposing factors of fatigue in HL survivors. A literature search was conducted up to August 2012. Twenty-two articles comparing HL survivors with norm population data met all predefined selection criteria. Prevalence rates, levels of fatigue and clinical relevance of the results were determined. Prevalence of fatigue ranged from 11-76 % in HL survivors compared to 10 % in the general population. Mean fatigue scores were 5-13 % higher compared to the normative population; these findings were clinically relevant in 7 out of 11 studies. Increasing age was associated with higher levels of fatigue in HL survivors. Treatment modality and stage of initial disease were not associated with higher fatigue levels, while comorbidities or other treatment sequelae seemed to impact on the levels of fatigue. HL survivors are at serious risk for developing clinically relevant, long-term fatigue. The impact of patient and treatment characteristics on risk of fatigue is limited. Focus for future research should shift to the role of late-treatment sequelae and psychological distress symptoms.
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August 2013

Clinical and pathological features of testicular diffuse large B-cell lymphoma: a heterogeneous disease.

Leuk Lymphoma 2012 Feb 19;53(2):242-6. Epub 2011 Sep 19.

Department of Oncology, Waikato DHB, Hamilton, New Zealand.

Most testicular lymphomas are of diffuse large B-cell (DLBCL) type with an outcome inferior to nodal DLBCL. Within an apparently homogeneous group of testicular DLBCLs, small cell components, plasmacytoid differentiation and lymphoepithelial lesions (LELs), features of extranodal marginal zone lymphoma (eMZL), can be identified. The aim of this study was to define the histological features of testicular DLBCL and correlate this with their clinical behavior and outcome. Thirty-six patients with testicular DLBCL (Ann Arbor stage I/II) were identified through the databases of two Dutch regional cancer registries, diagnosed between 1981 and 1999. Follow-up for patients alive was more than 10 years. Medical records and pathology specimens were reviewed. eMZL features were found in 53% of the cases of localized stage testicular DLBCL. Compared to patients with "pure" DLBCL, patients with DLBCL with eMZL features presented more often with stage I disease, normal lactate dehydrogenase, smaller tumors and absence of B-symptoms, and they responded more favorably to initial treatment. Their median survival was 48 months versus 12 months for "pure" DLBCL (p = 0.87). Features of eMZL were commonly identified in testicular DLBCL and they correlated with a more favorable clinical presentation and better response to initial therapy. However, these differences did not reach statistical significance due to small numbers.
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February 2012

Long-term results: adjuvant radiotherapy in en bloc resection of sacrococcygeal chordoma is advisable.

Spine (Phila Pa 1976) 2011 May;36(10):E656-61

Department of Neurosurgery, Leiden University Medical Centre, Leiden, The Netherlands.

Study Design: A cross-sectional study.

Objective: The purpose of this report is to define the role of postoperative radiotherapy in the prevention of local recurrence (LR).

Summary Of Background Data: Sacrococcygeal chordoma is a slow growing, malignant tumor with a clinical poor outcome due to a high LR rate. Several studies emphasize that margin-free tumor resection is the most important predictor of LR. However, even after extralesional resection a high LR up to 80% remains.

Methods: A retrospective series of 15 patients who underwent surgical treatment for sacrococcygeal chordoma in one center between 1981 and 2003 was reviewed. Overall survival and continuous disease-free survival rates were compared between patients with intralesional resection with standard radiotherapy and patients with extralesional resection and no standard radiotherapy.

Results: The median age at surgery was 53 years. The mean follow-up was 7 years or until death. Mean duration of preoperative complaints was 3 years. In 10 patients, an en bloc resection was (histologic resection margins were free) performed and in 5 patients, an intralesional resection was achieved. All but one patients with intralesional resection received radiotherapy (>50 Gy) and patients with extralesional resection only received radiotherapy in case of LR (6 of 10 patients). After extralesional resection (no initial radiotherapy), all 10 patients had LR of the tumor with a mean time to recurrence of 2 years. Six of these ten patients received radiotherapy after LR and had mean survival duration of 7 years. Only one (of five patients) in the group with intralesional resection and postoperative radiotherapy had LR after 11 years. The time to recurrence was significantly longer and we found a trend toward a longer overall survival in the group that received immediate radiotherapy after surgery.

Conclusion: The results support the strategy to add radiotherapy as standard adjuvant therapy to sacrococcygeal chordoma tumor resection.
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May 2011

Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma.

J Natl Cancer Inst 2009 Jul 17;101(13):928-37. Epub 2009 Jun 17.

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

Background: Information on clinically verified stroke and transient ischemic attack (TIA) following Hodgkin lymphoma is scarce. We quantified the long-term risk of cerebrovascular disease associated with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma and explored potential pathogenic mechanisms.

Methods: We performed a retrospective cohort study among 2201 five-year survivors of Hodgkin lymphoma treated before age 51 between 1965 and 1995. We compared incidence rates of clinically verified stroke and TIA with those in the general population. We used multivariable Cox regression techniques to study treatment-related factors and other risk factors. All statistical tests were two-sided.

Results: After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both TIA and stroke; median age = 52 years). Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio for stroke was 2.2 (95% confidence interval [CI] = 1.7 to 2.8), and for TIA, it was 3.1 (95% CI = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% CI = 5% to 8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% CI = 1.1 to 5.6 vs without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not.

Conclusions: Patients treated for Hodgkin lymphoma experience a substantially increased risk of stroke and TIA, associated with radiation to the neck and mediastinum. Physicians should consider appropriate risk-reducing strategies.
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July 2009

Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials.

J Clin Oncol 2006 Jul 5;24(19):3128-35. Epub 2006 Jun 5.

Department of Radiotherapy, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.

Purpose: In early-stage Hodgkin's lymphoma (HL), subtotal nodal irradiation (STNI) and combined chemotherapy/radiotherapy produce high disease control rates but also considerable late toxicity. The aim of this study was to reduce this toxicity using a combination of low-intensity chemotherapy and involved-field radiotherapy (IF-RT) without jeopardizing disease control.

Patients And Methods: Patients with stage I or II HL were stratified into two groups, favorable and unfavorable, based on the following four prognostic factors: age, symptoms, number of involved areas, and mediastinal-thoracic ratio. The experimental therapy consisted of six cycles of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) followed by IF-RT. It was randomly compared, in favorable patients, to STNI and, in unfavorable patients, to six cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV hybrid) and IF-RT.

Results: Median follow-up time of the 722 patients included was 9 years. In 333 favorable patients, the 10-year event-free survival rates (EFS) were 88% in the EBVP arm and 78% in the STNI arm (P = .0113), with similar 10-year overall survival (OS) rates (92% v 92%, respectively; P = .79). In 389 unfavorable patients, the 10-year EFS rate was 88% in the MOPP/ABV arm compared with 68% in the EBVP arm (P < .001), leading to 10-year OS rates of 87% and 79%, respectively (P = .0175).

Conclusion: A treatment strategy for early-stage HL based on prognostic factors leads to high OS rates in both favorable and unfavorable patients. In favorable patients, the combination of EBVP and IF-RT can replace STNI as standard treatment. In unfavorable patients, EBVP is significantly less efficient than MOPP/ABV.
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July 2006