A. Postma

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.

Academic career after treatment for acute lymphoblastic leukaemia

AIM To evaluate academic career in long term survivors of childhood acute lymphoblastic leukaemia (ALL), in comparison to their healthy siblings. PATIENTS Ninety four children treated for ALL with cranial irradiation 18 or 25 Gy and intrathecal methotrexate as CNS prophylaxis. Median age at evaluation was 20 years; median follow up since diagnosis was 15 years at the time of the study. METHODS Patients and their 134 siblings completed a questionnaire on school career. The percentage of referrals to special primary schools for learning disabled, and the final level of secondary education in patients and siblings were compared, using a six point classification. Within the patient group, the effect of possible risk factors (age at diagnosis, irradiation dose, and gender) was investigated. RESULTS Significantly more patients than siblings were placed in special educational programmes. A significant difference was found for level of secondary education. No effect of gender or irradiation dose was found, but younger age at diagnosis was significantly related to both referrals and school levels. CONCLUSION Treatment for childhood ALL with cranial irradiation and chemotherapy at a young age is clearly associated with poorer academic career.

Late cardiotoxicity after treatment for a malignant bone tumor

Cardiac function was assessed in long-term survivors of malignant bone tumors who were treated according to Rosens T5 or T10 protocol, both including doxorubicin. Thirty-one patients, age 10-45 years (median age 17.8 years) were evaluated 2.3-14.1 years (median 8.9 years) following completion of treatment. Cumulative doses of doxorubicin were 225-550 mg/m2 (median dose 360). The evaluation consisted of a history, physical examination, electrocardiogram (ECG), signal averaged ECG, 24-hour ambulatory ECG, echocardiography and radionuclide angiography. Eighteen of 31 (58%) patients showed cardiac toxicity, defined as having one or more of the following abnormalities: late potentials, complex ventricular arrhythmias, left ventricular dilation, decreased shortening fraction, or decreased ejection fraction. The incidence of cardiac abnormalities increased with length of follow-up (P< or = .05). No correlation could be demonstrated between cumulative dose of doxorubicin and cardiac status, except for heart rate variability. When adjusted to body surface area, the left ventricular posterior wall thickness (LVPW index) was decreased in all patients. The incidence of doxorubicin-induced cardiotoxicity is high and increases with follow-up, irrespective of cumulative dose. Life-long cardiac follow-up in these patients is warranted. The results of our study suggest that heart rate variability and LVPW index could be sensitive indicators for cardiotoxicity.

Systolic and diastolic dysfunction in long-term adult survivors of childhood cancer.

AIM To assess systolic and diastolic function in adult childhood-cancer survivors (CCS) after treatment entailing potential cardiovascular toxicity. METHODS The study cohort consisted of 277 adult CCS (median age 28 [range 18-48]years), who had been treated with anthracyclines, platinum, and/or radiotherapy between 1976 and 1999, along with 130 healthy sibling controls. The assessments included echocardiography, baroreflex sensitivity measurement, and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP). Echocardiography measurements were shortening fraction (SF) (abnormal<29%) for systolic function and tissue velocity imaging of early diastole (TVI Et) (abnormal<8.00)cm/sec for diastolic function; systolic function was also assessed by the wall motion score index (WMSI). RESULTS At 18 (5-31)years post-treatment, the prevalence of both impaired SF and abnormal WMSI was increased in CCS compared to controls (p=0.003 and p<0.001, respectively). CCS also had an increased prevalence of diastolic dysfunction compared to the controls (12% versus 1%, p<0.001). Abnormal SF and/or abnormal diastolic function were found in 43% of CCS. NT-proBNP was higher in CCS and was associated to increased WMSI. Baroreflex sensitivity was lower in CCS and was associated with diastolic dysfunction. Systolic as well as diastolic dysfunction was associated with cumulative dose of anthracyclines and mediastinal irradiation. CONCLUSION After treatment with potential cardiovascular toxic therapies, the risk of systolic and diastolic dysfunction in CCS is considerable. Since these abnormalities, in particular diastolic dysfunction, are age related, the observed effects might be considered a sign of precocious cardiac ageing.

The willingness of general practitioners to be involved in the follow-up of adult survivors of childhood cancer.

BackgroundLong-term follow-up of childhood cancer survivors is mainly organised by paediatric oncologists and until now general practitioners (GPs) are rarely involved. To ensure appropriate follow-up for all survivors into adulthood, a combined effort of paediatric oncologists and general practitioners might be the solution. We investigated the willingness of GPs, who had followed a postgraduate course on late effects of cancer treatment, to participate in a shared care model for follow-up of adult childhood cancer survivors as well as what their requirements would be in case of participation.MethodsFrom the Northern Netherlands, 358 GPs participated in a postgraduate course on late effects in paediatric cancer survivors. After the course, they were asked to complete a 10-item questionnaire on motivation to participate in the regular follow-up of adult childhood cancer survivors as well as their conditions to participate.ResultsThe response rate was 65%. Of the responders, 97% were willing to participate in a shared care model for follow-up and 64% felt that it was their responsibility to be in charge of childhood cancer survivors. The main requirements for participation were the availability of guidelines (64%), sufficient information about the patient’s medical history (37%), and short communication lines (45%). The main barriers to participate were workload (16%), lack of knowledge (15%), and lack of communication (13%).ConclusionA significant number of GPs are ready to participate in the long-term follow-up of adult childhood cancer survivors if adequate guidelines and medical information is provided and communication lines are clear.

Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation

Impaired linear growth is a well‐recognized complication in long‐term childhood ALL survivors who received cranial irradiation. However, as many patients achieve a final height between the 5th and the 95th centile, the true incidence of linear growth impairment might be underestimated.

An extendable modular endoprosthetic system for bone tumour management in the leg

A modular endoprosthetic system has been developed at the Groningen University Hospital and the University of Twente. The system can bridge a defect resulting from the resection of a malignant bone tumour which has developed around the knee joint of a child. Since the other healthy leg continues to grow, the system includes an element whose length can be adjusted non-invasively by using an external magnetic field. In addition to this lengthening element, there are one hip and two knee components, connectors of various lengths, and fixation elements. The paper describes the elements of the modular endoprosthetic system. Tables are created by means of which the elemental composition of such an endoprosthesis can be determined for each individual patient.

The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors

BACKGROUND The Late Effects of Childhood Cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) developed a guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors (CCS). In this paper, we present the methods, available evidence and final recommendations of our guideline. MATERIALS AND METHODS A multidisciplinary working group specified clinical questions that should be answered to get to recommendations for the guideline. We carried out short or extensive evidence summaries and determined methodological quality of studies and levels of evidence in order to answer all clinical questions. When evidence was lacking for CCS, we carefully extrapolated evidence from other populations. Final recommendations were based on evidence and consensus. RESULTS There was high-level evidence for the increased risk of cardiac dysfunction in CCS and its main risk factors. Evidence was lacking regarding the prognosis, diagnosis and treatment of cardiac dysfunction in CCS. We recommended echocardiographic screening for asymptomatic cardiac dysfunction in CCS treated with cardiotoxic treatments and counseling about potential advantages and disadvantages of our screening recommendations. CONCLUSION The DCOG LATER guideline recommends risk-based screening for asymptomatic cardiac dysfunction in CCS, but it should be noted that recommendations are not completely supported by evidence in CCS.

Endothelial Damage in Long-Term Survivors of Childhood Cancer

PURPOSE To evaluate the presence of vascular damage in long-term childhood cancer survivors (CCS) and sibling controls, and to evaluate the association between vascular damage parameters and cancer treatment and influence of cardiovascular risk factors. PATIENTS AND METHODS Vascular assessment was performed in 277 adult CCSs (median age at diagnosis, 9 years; range, 0 to 20 years; median current age, 28 years; range, 18 to 48 years) treated with potentially cardiovascular toxic anticancer treatment (ie, anthracyclines, platinum, and/or radiotherapy [RT]). Measurements included carotid- and femoral-wall intima-media thickness (IMT), flow-mediated vasodilatation of the brachial artery by ultrasound, assessment of endothelial and inflammatory marker proteins (including tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor type 1 [PAI-I]), and cardiovascular risk factors. CCS assessments were compared with those of 130 sibling controls (median age, 26 years; range, 18 to 51 years). RESULTS At a median of 18 years (range, 5 to 31 years) after treatment, carotid and femoral IMTs in CCSs were not different from those of controls. However, CCSs who received RT as part of their treatment regimen had increased carotid and femoral IMTs and higher t-PA and PAI-I levels, indicating vascular damage and persistent endothelial activation. Patients treated with RT to the neck or chest also had greater femoral IMT. Greater IMT was associated with presence of cardiovascular risk factors (eg, hypertension and overweight). CONCLUSION After potentially cardiovascular toxic anticancer treatment, CCSs who received RT showed signs of endothelial damage and an unfavorable cardiovascular risk profile compared with controls. CCSs treated with localized RT had increased IMT outside the primary irradiation field. These abnormalities are probably involved in the pathogenesis of cardiovascular morbidity in CCSs.

Evaluation of sub-acute changes in cardiac function after cisplatin-based combination chemotherapy for testicular cancer

Long-term cardiovascular morbidity is increasingly observed in chemotherapy-treated testicular cancer survivors, but little is known of early sub-clinical changes in cardiac function. We prospectively evaluated cardiac function in testicular cancer patients by echocardiography. Systolic (Wall Motion Score Index) and diastolic (E/A-ratio and Tissue Velocity Imaging (TVI)) parameters, and serum levels of N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) were assessed before the start of chemotherapy and 1 year later. Echocardiography data were compared with an age-matched group of healthy controls. Forty-two patients treated with bleomycin, etoposide and cisplatin were evaluated (median age 27 years, range 18–50). Systolic function and E/A-ratio did not change, whereas the median TVI decreased (12.0 vs 10.0 cms−1; P=0.002). Median levels of NT-proBNP increased (5 vs 18 pmoll−1, P=0.034). Compared with controls, TVI before the start of chemotherapy was not significantly different. In conclusion, we found that at a median of 10 months after cisplatin-based treatment for testicular cancer, TVI decreased significantly, indicating a deterioration of diastolic cardiac function. Serum levels of NT-proBNP increased. The prognostic significance of these changes for future cardiovascular morbidity is not clear.