Janine Nuver

Long-Term Risk of Cardiovascular Disease in 5-Year Survivors of Testicular Cancer

PURPOSE To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC). PATIENTS AND METHODS We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis. RESULTS After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. CONCLUSION Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

Acute Chemotherapy-Induced Cardiovascular Changes in Patients With Testicular Cancer

PURPOSE After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. PATIENTS AND METHODS In 65 testicular cancer patients (median age, 27 years; range, 18 to 48 years), we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy: platelet numbers, plasma levels of hemostatic and fibrinolytic factors, 24-hour ambulatory blood pressure, baroreflex sensitivity, intima-media thickness of the common carotid artery, and flow-mediated vasodilation of the brachial artery. RESULTS Compared with prechemotherapy values, the intima-media thickness of the carotid artery and plasma von Willebrand factor levels increased significantly after treatment. Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly. Blood pressure decreased significantly, but flow-mediated vasodilation and baroreflex sensitivity did not change. CONCLUSION In testicular cancer patients treated with cisplatin-based chemotherapy, we found an increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term.

Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

J. Oldenburg1, S. D. Fosså1, J. Nuver2, A. Heidenreich3, H-J Schmoll4, C. Bokemeyer5, A. Horwich6, J. Beyer7 & V. Kataja8, on behalf of the ESMO Guidelines Working Group* Department of Oncology, Oslo University Hospital, Oslo, Norway; Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands; Department of Urology, RWTH University Hospital, Aachen; Department of Oncology/Haematology/Haemostaseology, University Hospital Halle, Halle; Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, University Hospital, Hamburg, Germany; Department of Academic Radiotherapy, Institute of Cancer Research, Royal Marsden Hospital, Sutton Hospital, UK; Department of Haematology and Oncology, Vivantes Klinikum Am Urban, Berlin, Germany; Cancer Centre, Kuopio University Hospital, Kuopio, Finland;

The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures

With increasing numbers of cancer survivors, attention has been drawn to long-term complications of curative cancer treatment, including a range of metabolic disorders. These metabolic disorders often resemble the components of the so-called metabolic syndrome, or syndrome X, which is an important risk factor for the development of cardiovascular disease. The mechanisms behind the development of metabolic disorders in cancer survivors have not been fully elucidated. However, association studies in the general population have demonstrated correlations between the components of the metabolic syndrome on the one hand and hormonal deficiencies, hypomagnesaemia, and endothelial dysfunction on the other. These latter disorders are regularly reported following curative cancer treatment and could, therefore, be important aetiologic factors in the development of the metabolic syndrome in cancer survivors. This review discusses data on the associations between the metabolic syndrome and treatment-related complications in cancer survivors and possibilities for preventive measures.

Variation in Bleomycin Hydrolase Gene Is Associated With Reduced Survival After Chemotherapy for Testicular Germ Cell Cancer

PURPOSE Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival. PATIENTS AND METHODS Data were collected on survival and BLMH genotype of 304 patients with TC treated with bleomycin-containing chemotherapy at the University Medical Center Groningen, the Netherlands, between 1977 and 2003. Survival according to genotype was analyzed using Kaplan-Meier curves with log-rank testing and Cox regression analysis with adjustment for confounders. RESULTS BLMH gene SNP A1450G has a significant effect on TC-related survival (log-rank P = .001). The homozygous variant (G/G) genotype (n = 31) is associated with decreased TC related survival compared with the heterozygous variant (A/G; n = 133) and the wild-type (A/A; n = 140). With Cox regression the G/G genotype proves to be an unfavorable prognostic factor, in addition to the commonly used International Germ Cell Consensus Classification prognosis group, with a hazard ratio of 4.97 (95% CI, 2.17 to 11.39) for TC-related death. Furthermore, the G/G genotype shows a higher prevalence of early relapses. CONCLUSION The homozygous variant G/G of BLMH gene SNP A1450G is associated with reduced survival and higher prevalence of early relapses in TC patients treated with bleomycin-containing chemotherapy. This association is hypothesis generating and may eventually be of value for risk classification and selection for alternative treatment strategies in patients with disseminated TC.

Cardiovascular disease after cancer therapy

Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC). Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results. Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment.

Left ventricular and cardiac autonomic function in survivors of testicular cancer

Background  Following cisplatin‐based chemotherapy, survivors of testicular cancer have a high prevalence of cardiovascular risk factors and an increased risk of cardiovascular disease. Cardiac function has not been extensively studied and no comparisons have been made with men from the general population.

Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer

BACKGROUND Cross-sectional studies showed that treatment with cisplatin chemotherapy for testicular cancer is associated with an increased incidence of cardiac dysfunction. We investigated longitudinal progression of and contributing factors to cardiac dysfunction in testicular cancer survivors. PATIENTS AND METHODS Cardiac assessments were carried out before 10 months (range 7-15 months) and 6.9 years (range 4.9-9.7 years) after start of cisplatin-based chemotherapy, consisting of echocardiography [systolic function (left ventricular ejection fraction, LVEF), diastolic function (myocardial tissue velocities; tissue velocity imaging of early diastole, TVI Et)] and plasma biomarkers (N-Terminal pro brain natriuretic peptide, NT-proBNP; galectin-3). RESULTS In 37 patients [median age 34 years (range 24-51 years)], the incidence of abnormal TVI Et increased from 0% at baseline and 4.5% at 10 months (in 27 patients) to 16.7% at 6.9 years post-chemotherapy (P = 0.03). One patient developed LVEF <50%; no other systolic abnormalities occurred. Hypertension, obesity and age were associated with larger decreases in TVI Et. Changes in NT-proBNP and galectin-3 were not related to echocardiographic abnormalities. CONCLUSIONS In this longitudinal cohort study, we observed a gradual decline in diastolic parameters after cisplatin-based chemotherapy for testicular cancer, whereas the rate of systolic dysfunction remains low. The association of larger declines in diastolic parameters with hypertension and obesity stresses the need to monitor and treat cardiovascular risk factors.

Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients

Objective Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP). Methods From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype. Results BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes. Conclusions The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.