Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

BACKGROUND: Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking. AIM: To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers. METHODS: A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations. RESULTS: 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations. CONCLUSION: These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.

Prevalence of cardiovascular late sequelae in long-term survivors of childhood cancer: A systematic review and meta-analysis.

BACKGROUND: Cardiovascular diseases are well-known late effects of childhood cancer and research on these late effects is a highly important emerging field. We conducted a systematic review with a meta-analysis to give an overview of the current evidence and the prevalence of late cardiovascular events. PROCEDURE: We included publications in which the study populations were children and adolescents who survived cancer. Outcome was defined as all cardiovascular clinical and subclinical endpoints or diagnoses appearing at least one year after cancer diagnosis. A systematic overview is presented for all included studies. A quantitative meta-analysis was conducted for hypertension and stroke. RESULTS: Sixty-four papers were included in the review. The age range at cancer diagnosis was 0-24 years; age at the end of follow-up ranged from 7 to 71 years. Prevalence of cardiovascular late effects varied from 0% for stroke up to 70% for subclinical hypertension. Large heterogeneity was found regarding study size, study design, definition of endpoints, and investigation/examination method. The weighted average prevalence was 19.7% for hypertension and 2.3% for stroke. As no specific results for gender, cancer therapy, or age at cancer diagnosis were present in most papers, a detailed comparison and pooled analysis was difficult. CONCLUSION: This review showed the vast range of cardiovascular late effects after childhood or adolescent cancer therapy. The differences between the papers prevented drawing a conclusive picture of the prevalence of cardiovascular late effects. Large cohort studies and better reporting are needed to improve the knowledge on this topic.

Radiotherapy and subsequent thyroid cancer in German childhood cancer survivors: a nested case-control study.

BACKGROUND: Radiotherapy is associated with a risk of subsequent neoplasms (SN) in childhood cancer survivors. It has been shown that children's thyroid glands are especially susceptible. The aim is to quantify the risk of a second neck neoplasm after primary cancer radiotherapy with emphasis on thyroid cancer. METHODS: We performed a nested case-control study: 29 individuals, diagnosed with a solid SN in the neck region, including 17 with thyroid cancer, in 1980-2002 and 57 matched controls with single neoplasms were selected from the database of the German Childhood Cancer Registry. We investigated the risk associated with radiotherapy exposure given per body region, adjusted for chemotherapy. RESULTS: 16/17 (94.1 %) thyroid SN cases, 9/12 (75 %) other neck SN cases and 34/57 (59.6 %) controls received radiotherapy, with median doses of 27.8, 25 and 24 Gy, respectively. Radiotherapy exposure to the neck region increased the risk of the other neck SNs by 4.2 % (OR = 1.042/Gy (95 %-CI 0.980-1.109)) and of thyroid SN by 5.1 % (OR = 1.051/Gy (95 %-CI 0.984-1.123)), and radiotherapy to the neck or spine region increased the thyroid risk by 6.6 % (OR = 1.066/Gy (95 %-CI 1.010-1.125)). Chemotherapy was not a confounder. Exposure to other body regions was not associated with increased risk. CONCLUSIONS: Radiotherapy in the neck or spine region increases the risk of thyroid cancer, while neck exposure increases the risk of any other solid SN to a similar extent. Other studies showed a decreasing risk of subsequent thyroid cancer for very high doses; we cannot confirm this.

Local radiation dose and solid second malignant neoplasms after childhood cancer in Germany: a nested case-control study.

Radiotherapy (RT) has been associated with the development of solid second malignant neoplasms (SMNs) in childhood cancer survivors. The aim of this study was to analyse the effect of cumulative doses of previous RT received at the SMN body region, at all other body regions and at body regions adjacent to the SMN, on the risk of developing a solid SMN. A total of 190 cases diagnosed with a solid second malignant neoplasm in 1980-2002 were matched with 368 controls with single neoplasm from the database of the German Childhood Cancer Registry (GCCR) (33,809 patients at cut-off date). The GCCR registers approximately 97 % of all childhood malignancies which occur at an age of less than 15 years in Germany since 1980. It was found that 147 (77.4 %) cases had received RT compared to 208 (56.6 %) controls with cumulative focus doses from 8 to 110 Gy. Fifty per cent of the SMNs and 60 % of RT affected the head region. RT was shown to increase the risk of a solid second tumour within the body region of radiation by 5.3 % per Gy (odds ratio 1.053; 95 % confidence interval 1.036-1.071). With increasing age at diagnosis and with more recent treatment eras, this effect decreased. Cumulative RT doses received at all other body regions or only at body regions adjacent to the SMN did not show an additional effect on the risk of developing an SMN. It is thus concluded that RT is the main risk factor for the development of SMNs within the irradiated body region. Late effects surveillance of former patients should give special attention to the originally irradiated parts of the body.

Congenital central hypoventilation syndrome with hyperinsulinism in a preterm infant.

Congenital central hypoventilation syndrome (CCHS), a rare disorder typically presenting in the newborn period, results in over 90% of cases from PHOX2B polyalanine repeat mutations. It is characterized by alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung's disease and, later, tumors of neural crest origin. We describe a preterm infant with severe phenotype of CCHS and hyperinsulinism. A novel de novo heterozygote missence mutation (Gly68Cys) in the PHOX2B gene could be identified. Based on the observation of three patients presenting with the combination of congenital hyperinsulinism and CCHS, hyperinsulinism might represent an additional clinical feature of CCHS.