Gill Levitt

Developing strategies for long term follow up of survivors of childhood cancer

The treatment of childhood cancer has been increasingly successful over the past 30 years. Most paediatric cancers are now curable with multiagent chemotherapy in combination with surgery and radiotherapy. The overall survival five years after diagnosis is now 70% for all paediatric malignancies. The incidence is low (1200-1300 children affected each year in Britain), but with the sustained improvement in survival the number of long term survivors is increasing—about 850 additional survivors of childhood cancer each year. With this improved survival, it is important to increase our knowledge of any long term costs in the form of physical and psychosocial adverse health outcomes. This review looks at the evidence relating to long term clinical follow up after childhood cancer and considers ways to develop such follow up for the future. An awareness of the possible long term complications is important not only for optimising health care for the current survivors but also for modifying future treatment protocols to avoid therapies that are associated with unacceptable morbidity or mortality. We have summarised the evidence on selected long term complications; this evidence is inevitably based on retrospective studies. In the final section we discuss the development of a strategy for the clinical follow up of long term survivors. #### Summary points Long term follow up strategies are needed because of increasing numbers of survivors of childhood cancers Models for follow up need to be developed and formally evaluated Increasing numbers of survivors may have medical problems that will require ongoing specialist follow up The role, training programmes, and career structure of the late effects nurse practitioner needs to be developed The primary care physician may have an important role in long term follow up There is a need for prospective evaluation of new treatments and randomised studies of clinical interventions to resolve substantial uncertainties for …

Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study

The objective of the current study was to examine the risk factors for progression in severity of anthracycline‐induced cardiac dysfunction, thereby providing information that is useful in refining cancer treatment regimes and guiding follow‐up.

Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity.

PURPOSE Late abnormalities of left ventricular (LV) performance occur in most survivors of childhood acute lymphoblastic leukemia (ALL) treated with moderate anthracycline doses. We studied the prevalence of late cardiotoxicity in patients treated with lower anthracycline doses and related this to survival. PATIENTS AND METHODS Echocardiograms were performed in 50 normal children and 120 relapse-free ALL survivors 6.2 +/- 2.0 years after the end of cumulative daunorubicin doses of 90 mg/m2 (n = 40), 180 mg/m2 (n = 40), or 270 mg/m2 (n = 40) on UKALL X pilot (1982 to 1984) or UKALL X (1985 to 1989) protocols. Age at treatment onset was 4.7 +/- 2.8 years. Cardiac abnormalities were reviewed in light of the UKALL X 5-year disease-free survival rates of 57% (95% confidence interval [CI], 51% to 63%), 61% to 62% (95% CI, 56% to 68%), and 71% (95% CI, 66% to 76%) for the groups that received 90, 180, and 270 mg/m2 of daunorubicin, respectively. RESULTS ALL survivors had reduced LV fractional shortening (FS) compared with normal (32.3% +/- 4.4% v 35.9% +/- 4.2%, P < .005), which was accounted for by increased LV end-systolic stress (49.4 +/- 13.5 v 42.2 +/- 9.1 g/cm2, P < .001), whereas LV contractility independent of loading conditions was normal for the group as a whole. Of 27 patients (23%) with cardiac abnormalities, 25 (21%) had increased end-systolic stress, whereas only two (2%) had reduced contractility. The proportion with cardiac abnormality was similar in the three dose groups. Anthracycline dose, age at treatment, sex, follow-up duration, growth hormone, pubertal status, hemoglobin level, and total WBC count at presentation were not predictive of increased LV end-systolic stress. CONCLUSION There was a reduced incidence and severity of cardiac abnormalities with the lower anthracycline dose protocols (90 to 270 mg/m2) studied compared with previous reports in which subjects had received moderate anthracycline doses (approximately 300 to 550 mg/m2). Cumulative anthracycline dose within the range 90 to 270 mg/m2 did not relate to cardiac abnormalities. This suggests that there may be no safe anthracycline dose to avoid late cardiotoxicity, but reinforces the use of the protocol that affords best survival within the dose range studied.

Recommendations for Cardiomyopathy Surveillance for Survivors of Childhood Cancer: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group

Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.

A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence‐based methods, we provide a framework for the harmonization of guidelines for the long‐term follow‐up of childhood and young adult cancer survivors. Pediatr Blood Cancer 2013; 60: 543–549.

Models of care for survivors of childhood cancer

With improvements in therapy for childhood cancer, the expectation that most childhood cancer patients will survive and enter adulthood is a reality. There is clear evidence that survivors are at risk for adverse health‐related long‐term sequelae associated with their cancer and its treatment, requiring appropriate health care resources. What is less clear is how this health care should optimally be delivered. We review the functional and operational needs for long‐term follow‐up for childhood cancer survivors and present alternatives for models of care. Programs for childhood cancer survivors should provide mechanisms for monitoring and management of late effects, as well as support and advocacy for addressing psychosocial issues, health education, and assistance with financial concerns. Access to research is an important component as clinical care and research are integrally related. A multidisciplinary model that provides continuity of care throughout the disease course is optimal, providing transitions from acute anti‐neoplastic therapy to follow‐up and primary care, as well as from pediatric care to adult‐oriented care. There is no single best model of care for all childhood cancer survivors. In evaluating different models, considerations include available resources as well as the particular cancer population being served. Not all survivors require the same level of services and the service level requirement for individual patients may change with time. As outcome research progresses for childhood cancer survivors, methodological issues of optimal health care delivery for this population deserve to be the subject of such research. Pediatr Blood Cancer 2006;46:159–168.

Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.

Do doctors discuss fertility issues before they treat young patients with cancer

BACKGROUND Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys.

Prospective longitudinal assessment of late anthracycline cardiotoxicity after childhood cancer: the role of diastolic function

Anthracyclines are highly effective in the treatment of childhood malignancies, but are potentially cardiotoxic at all dose ranges. Early studies suggested that as many as 65% of acute lymphoblastic leukaemia (ALL) survivors have subclinical abnormalities of left ventricular (LV) systolic function at medium term follow up. More recent reports have shown that the prevalence of cardiac abnormalities is much lower with cumulative anthracycline doses of less than 250–300 mg/m2.1–4 It has been suggested that diastolic changes precede systolic dysfunction in various conditions and predict later deterioration. Similarly, LV restriction has been suggested to be a late functional event after anthracycline exposure. Most reports of anthracycline cardiotoxicity are cross-sectional studies of heterogeneous diagnostic groups receiving various anthracycline schedules.5 We obtained prospective longitudinal diastolic data in two well defined cohorts of long term survivors of ALL and Wilms’ tumor (WT) and compared this to systolic function. Both cohorts underwent echocardiographic evaluation in 1991–92 and again in 1995–96. The original cohort consisted of 120 ALL survivors, comprising a convenience sample of 40 survivors from each of three treatment groups receiving a total dose of 90, 180 or 270 mg/m2 of daunorubicin. Initially, 106 of these subjects underwent investigation of diastolic filling on average 6.2 years after anthracyline treatment, and 94 patients underwent follow up leaving comparative diastolic data available in 88 patients. From 110 WT patients treated between 1970 and 1990, 90 underwent investigation of diastolic filling in 1991–92, and 78 were reinvestigated in 1995–96, on average 6.7 years and 11.1 years after treatment, respectively. Of these, 66 subjects had complete comparative diastolic data sets. Mean cumulative doxorubicin dose at first study was 303 (79) mg/m2. One hundred healthy children and adolescents were studied on a single occasion using identical echocardiographic methods. LV diastolic …

Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice

Background: Most Wilms tumours occur in otherwise healthy children, but a small proportion occur in children with genetic syndromes associated with increased risks of Wilms tumour. Surveillance for Wilms tumour has become widespread, despite a lack of clarity about which children are at increased risk of these tumours and limited evidence of the efficacy of screening or guidance as to how screening should be implemented. Methods: The available literature was reviewed. Results: The potential risks and benefits of Wilms tumour surveillance are finely balanced and there is no clear evidence that screening reduces mortality or morbidity. Prospective evidence-based data on the efficacy of Wilms tumour screening would be difficult and costly to generate and are unlikely to become available in the foreseeable future. Conclusions: The following pragmatic recommendations have been formulated for Wilms tumour surveillance in children at risk, based on our review: (1) Surveillance should be offered to children at >5% risk of Wilms tumour. (2) Surveillance should only be offered after review by a clinical geneticist. (3) Surveillance should be carried out by renal ultrasonography every 3–4 months. (4) Surveillance should continue until 5 years of age in all conditions except Beckwith–Wiedemann syndrome, Simpson–Golabi–Behmel syndrome and some familial Wilms tumour pedigrees where it should continue until 7 years. (5) Surveillance can be undertaken at a local centre, but should be carried out by someone with experience in paediatric ultrasonography. (6) Screen-detected lesions should be managed at a specialist centre.