Publications

The YSRCCYP provides an invaluable and unique source of data that has been used for varied research. Below is a selection from the full list of recent publications from the YSRCCYP.

2020

Purpose: Children and young adults (CYA) are at risk of late morbidity following cancer treatment, with risk varying by disease type and treatment received. Risk-stratified levels of aftercare which stratify morbidity burden to inform the intensity of long-term follow-up care, are well established for survivors of cancer under the age of 18 years, utilizing the National Cancer Survivor Initiative (NCSI) approach. We investigated the applicability of risk-stratified levels of aftercare in predicting long-term morbidity in young adults (YA), aged 18-29 years.
Methods: Long-term CYA survivors followed-up at a regional center in the North of England were risk-stratified by disease and treatments received into one of three levels. These data were linked with local cancer registry and administrative health data (Hospital Episode Statistics), where hospital activity was used as a marker of late morbidity burden.
Results: Poisson modelling with incident rate ratios (IRR) demonstrated similar trends in hospital activity for childhood (CH) and YA cancer survivors across NCSI risk levels. NCSI levels independently predicted long-term hospitalization risk in both CH and YA survivors. Risk of hospitalization was significantly reduced for levels 1 (CH IRR 0.32 (95% CI 0.26-0.41), YA IRR 0.06 (95% CI 0.01-0.43)) and 2; CH IRR 0.46 (95% CI 0.42-0.50), YA IRR 0.49 (95% CI 0.37-0.50)), compared with level 3.
Conclusions: The NCSI pediatric late-effects risk stratification system can be effectively and safely applied to cancer patients aged 18-29, independent of ethnicity or socioeconomic position.
Implications for cancer survivors: To enhance quality of care and resource utilization, long-term aftercare of survivors of YA cancer can and should be risk stratified through adoption of approaches such as the NCSI risk-stratification model.

Clements C, Cromie KJ, Smith L, Feltbower RG, Hughes N, Glaser AW. Risk stratification of young adult survivors of cancer to estimate hospital morbidity burden: applicability of a pediatric therapy-based approach.J Cancer Surviv 2020 (In Press) . doi:10.1007/s11764-020-00939-y.

Aims: Osteonecrosis (ON) can cause considerable morbidity in young people who undergo treatment for acute lymphoblastic leukaemia (ALL). The aims of this study were to determine the operations undertaken for ON in this population in the UK, along with the timing of these operations and any sequential procedures that are used in different joints. We also explored the outcomes of those patients treated by core decompression (CD), and compared this with conservative management, in both the pre- or post-collapse stages of ON.
Methods: UK treatment centres were contacted to obtain details regarding surgical interventions and long-term outcomes for patients who were treated for ALL and who developed ON in UKALL 2003 (the national leukaemia study which recruited patients aged 1 to 24 years at diagnosis of ALL between 2003 and 2011). Imaging of patients with ON affecting the femoral head was requested and was used to score all lesions, with subsequent imaging used to determine the final grade. Kaplan-Meier failure time plots were used to compare the use of CD with non surgical management.
Results: Detailed information was received for 85 patients who had developed ON during the course of their ALL treatment. A total of 206 joints were affected by ON. Of all joints affected by ON, 21% required arthroplasty, and 43% of all hips affected went on to be replaced. CD was performed in 30% of hips affected by ON. The majority of the hips were grade 4 or 5 at initial diagnosis of ON. There was no significant difference in time to joint collapse between those joints in which CD was performed, compared with no joint-preserving surgical intervention.
Conclusion: There is a high incidence of surgery in young people who have received treatment for ALL and who have developed ON. Our results suggest that CD of the femoral head in this group of patients does not delay or improve the rates of femoral head survival.

Amin NL, Kraft J, Fishlock A, White A, Holton C, Kinsey S, James B, Feltbower RG. Surgical management of symptomatic osteonecrosis and utility of core decompression of the femoral head in young people with acute lymphoblastic leukaemia recruited into UKALL 2003. The Bone and Joint Journal 2020 (In press). doi.org/10.1302/0301-620X.103B3.BJJ-2020-0239.R3.

Background: Long-term childhood and young adult cancer survivors are at increased risk of the late effects of multiple chronic conditions. In this study we estimate the cumulative burden of subsequent malignant neoplasms (SMN), cardiovascular and respiratory hospitalisations in long-term survivors of childhood and young adult cancers and associated treatment risks.
Methods: Five-year survivors of cancer diagnosed aged 0-29 years between 1992-2009 in Yorkshire, UK were included. The cumulative count of all hospital admissions (including readmissions) for cardiovascular and respiratory conditions and all SMNs diagnosed up to 2015 was calculated, with death as a competing risk. Associations between treatment exposures and cumulative burden were investigated using multiple-failure time survival models.
Results: A total of 3464 5-year survivors were included with a median follow-up of 8.2 years (IQR 4-13 years). Ten-years post diagnosis, the cumulative incidence for a respiratory admission was 6.0 % (95 %CI 5.2-6.9), a cardiovascular admission was 2.0 % (95 %CI 1.5-2.5), and SMN was 1.0 % (95 % CI 0.7-1.4) with an average of 13 events per 100 survivors observed (95 %CI 11-15). The risk of experiencing multiple events was higher for those treated with chemotherapy drugs with known lung toxicity (HR = 1.35, 95 %CI 1.09-1.68).
Discussion: Survivors of childhood and young adult cancer experience a high burden of morbidity due to respiratory, cardiovascular diseases and SMNs up to 20-years post-diagnosis. Statistical methods that capture multiple morbidities and recurrent events are important when quantifying the burden of late effects in young cancer survivors.

Smith L, Glaser AW, Greenwood DC, Feltbower RG. Cumulative burden of subsequent neoplasms, cardiovascular and respiratory morbidity in young people surviving cancer. Cancer Epidemiol 2020;66:101711. doi.org/10.1016/j.canep.2020.101711.

2019

Introduction: Osteonecrosis is a well-recognised treatment-related morbidity risk in patients diagnosed with acute lymphoblastic leukaemia (ALL) and lymphoblastic lymphoma (LBL), with a high rate of affected patients requiring surgical intervention. Patients may have asymptomatic changes on imaging studies that spontaneously regress, and little is known about the natural history of osteonecrotic changes seen. The main aim of the British OsteoNEcrosis Study (BONES) is to determine the incidence of symptomatic and asymptomatic osteonecrosis in the lower extremities of survivors of ALL or LBL diagnosed aged 10–24 years in the UK at different time points in their treatment. This study also aims to identify risk factors for progression and the development of symptomatic osteonecrosis in this population, as well as specific radiological features that predict for progression or regression in those with asymptomatic osteonecrosis.
Methods and analysis: BONES is a prospective,longitudinal cohort study based at principal treatment centres around the UK. Participants are patients aged 10–24 years diagnosed with ALL or LBL under standard criteria. Assessment for osteonecrosis will be within 4 weeks of diagnosis, at the end of delayed intensification and 1, 2 and 3 years after the start of maintenance therapy. Assessment will consist of MRI scans of the lower limbs and physiotherapy assessment. Clinical and biochemical data will be collected at each of the time points. Bone mineral density data and vertebral fracture assessment using dual-energy X-ray absorptiometry will be collected at diagnosis and annually for 3 years after diagnosis of malignancy.
Ethics and dissemination: Ethical approval has been obtained through the Yorkshire and Humber Sheffield Research Ethics Committee (reference number: 16/YH/0206). Study results will be published on the study website, in peer-reviewed journals and presented at relevant conferences and via social media.

Amin NL, Kinsey S, Feltbower R, Kraft J, Whitehead E, Velangi M, James B. British OsteoNEcrosis Study (BONES) protocol: a prospective cohort study to examine the natural history of osteonecrosis in older children, teenagers and young adults with acute lymphoblastic leukaemia and lymphoblastic lymphoma. BMJ Open 2019;9:e027204. doi:10.1136/bmjopen-2018-027204.

This paper provides a summary of the areas of survival from childhood, teenage and young adult cancers and the significant late effects that can arise from treatment; with particular focus on the area of reproductive health and the impact on both fertility and pregnancy. To complete this review, Web of Science and MEDLINE were used. Search terms included: ""survival AND childhood OR teenage OR young adult cancer", "late effects", "childhood cancer", "teenage AND/OR young adult cancer", AND "fertility after cancer" OR "pregnancy AND cancer" OR "fertility preservation". Additionally, the clinical expertise of the authors was drawn upon. Childhood cancer is a thankfully rare occurrence; however, the incidence is increasing. Survival rates remain high and this means that a growing population of childhood and young adult cancer survivors are reaching adulthood. For some of these adults, although cured of their cancer, they are now facing a future with lasting effects on their health from their treatments. These effects, commonly referred to as late effects, are defined as health problems related either directly to the underlying cancer or to its treatment and which occur months or years after treatment has finished. Reproductive health is an important consideration for these patients, and although many will be able to conceive naturally, some will exhibit impaired fertility after their treatments. This can include difficulties at all points along the path from conception to delivery of a live, healthy offspring. High-quality, large-population evidence is sparse in many areas relating to fertility risk from treatment and the maternal and fetal health of childhood cancer survivors. Yet given the potential for complications, the authors advocate consideration of fertility at the time of diagnosis and before potentially gonadotoxic treatment.

Newton, HL, Friend, AJ, Feltbower, R, Hayden, CJ, Picton, HM and Glaser, AW. Survival from cancer in young people: An overview of late effects focusing on reproductive health. Acta Obstetricia et Gynecologica Scandinavica 2019; 98: 573-582. doi:10.1111/aogs.13584.

2018

Respiratory diseases are a major cause of late morbidity and mortality amongst childhood cancer survivors. This population-based study provides comprehensive analysis of hospitalisations for respiratory conditions, the associated risks of admission by earlier cancer treatment and trends in readmissions and subsequent mortality in long-term survivors of cancers diagnosed under 30 years. The risk of hospitalisation was significantly higher in cancer survivors compared to the general population. Treatment with chemotherapy with known lung toxicity was associated with an increased risk of admissions for all respiratory disease especially pneumonia. Subsequent mortality was highest in those admitted for pneumonia compared to other respiratory conditions.

Smith L, Glaser AW, Peckham D, Greenwood DC, Feltbower RG. Respiratory morbidity in young people surviving cancer: population-based study of hospital admissions, treatment-related risk factors and subsequent mortality. Int J Cancer 2018 https://doi.org/10.1002/ijc.32066

Statistical “cure models” provide additional metrics useful to identify and describe trends in survival. Additional measures include the proportion cured which is a summary of the long term survival and the median survival of the uncured which give information on those who are not long-term survivors. In this study we used a statistical cure model to explore trends in long-term survival and relapse for childhood acute lymphoblastic leukaemia (ALL) over time and by clinical characteristics. The proportion of patients cured, defined either by overall survival or relapse free survival, has increased over time while there was slight decrease in the median survival time of the uncured. We also observed a significant reduction in the risk of relapse over time.

Smith L, Glaser AW, Kinsey SE, Greenwood DC, Chilton L, Moorman AV, Feltbower RG. Long-term survival after childhood acute lymphoblastic leukaemia: population-based trends in cure and relapse by clinical characteristics. Br J Haematol 2018; 182: 851-858 doi.org/10.1111/bjh.15424

Background: Studies investigating the population-mixing hypothesis in childhood leukemia principally use two analytical approaches: (1) nonrandom selection of areas according to specific characteristics, followed by comparisons of their incidence of childhood leukemia with that expected based on the national average; and (2) regression analyses of region-wide data to identify characteristics associated with the incidence of childhood leukemia. These approaches have generated contradictory results. We compare these approaches using observed and simulated data.
Methods: We generated 10,000 simulated regions using the correlation structure and distributions from a United Kingdom dataset. We simulated cases using a Poisson distribution with the incidence rate set to the national average assuming the null hypothesis that only population size drives the number of cases. Selection of areas within each simulated region was based on characteristics considered responsible for elevated infection rates (population density and inward migration) and/or elevated leukemia rates. We calculated effect estimates for 10,000 simulations and compared results to corresponding observed data analyses.
Results: When the selection of areas for analysis is based on apparent clusters of childhood leukemia, biased assessments occur; the estimated 5-year incidence of childhood leukemia ranged between zero and eight per 10,000 children in contrast to the simulated two cases per 10,000 children, similar to the observed data. Performing analyses on region-wide data avoids these biases.
Conclusions: Studies using nonrandom selection to investigate the association between childhood leukemia and population mixing are likely to have generated biased findings. Future studies can avoid such bias using a region-wide analytical strategy. See video abstract at http://links.lww.com/EDE/B431.

Berrie L, Ellison GT, Norman PD, Baxter PD, Feltbower RG, Tennant PW, Gilthorpe MS. The association between childhood leukemia and population mixing: an artifact of focusing on clusters? Epidemiology 2018;30:75-82. doi: 10.1097/EDE.0000000000000921 .

Purpose: The diagnosis of cancer is often prolonged in teenagers and young adults (TYA). There may be lessons in improving this from international comparisons. However, international studies are complex and so we conducted a pilot study to examine the key barriers to large-scale research in this field.
Methods: We provided translated questionnaires covering key aspects of presentation and clinical management within 60 days of a confirmed cancer diagnosis, to patients 13-29 years of age inclusive, to their primary care physicians and to the cancer specialists managing their cancer. We conducted descriptive analyses of the data and also the process of study implementation.
Results: For our pilot, collecting triangulated data was feasible, but varying regulatory requirements and professional willingness to contribute data were key barriers. The time of data collection and the method for collecting symptom reports were important for timely and accurate data synthesis. Patients reported more symptoms than professionals recorded. We observed substantial variation in pathways to cancer diagnosis to explore definitively in future studies.
Conclusion: Focused research upon the mechanisms underpinning complex cancer pathways, and focusing that research upon specific cancer types within TYA may be the next key areas of study.

Smith L, Pini S, Ferrari A, Yeomanson D, Hough R, Riis Olsen P, Gofti-Laroche L, Fleming T, Elliott M, Feltbower R, Kertesz G, Stark D. Pathways to diagnosis for Teenagers and Young Adults with cancer in European nations – a pilot study. Journal of Adolescent and Young Adult Oncology 2018; 7:604-611. doi:10.1089/jayao.2018.0045.

Childhood cancer is increasing in prevalence whilst survival rates are improving. The prevalence of adult survivors of childhood cancer is consequently increasing. Many survivors suffer long‐term consequences of their cancer treatment. Whilst many of these are well documented, relatively little is known about the mental health of survivors of childhood cancer. This article aimed to describe the prevalence and spectrum of mental health problems found in adult survivors of childhood cancer using a systematic review methodology. Our review included 67 articles, describing a number of problems, including depression, anxiety, behavioural problems and drug misuse. Factors increasing the likelihood of mental health problems included treatment with high‐dose anthracyclines, cranial irradiation, diagnoses of sarcoma or central nervous system tumours and ongoing physical ill health. There were numerous limitations to the studies we found, including use of siblings of survivors as a control group, self‐report methodology and lack of indications for prescriptions when prescribing data were used. This review has identified many mental health problems experienced by survivors of childhood cancer; however, the exact incidence, prevalence and risk‐factors for their development remain unclear. Further work to identify childhood cancer patients who are at risk of developing late mental health morbidity is essential.

Friend AJ, Feltbower RG, Hughes EJ, Dye KP and Glaser AW, Mental Health of Long Term Survivors of Childhood and Young Adult Cancer: A Systematic Review. International Journal of Cancer 2018;143:1279-1286. doi:10.1002/ijc.31337.

2017

In this study we compared cancer incidence trends using different methods for assigning ethnic groups to individuals: 1 – using ethnic group recorded in hospital medical records, 2 – using a naming software program to assign an ethnic group based on the ethnic origins of the individuals and 3 – using a combination of both processes. We found that using different methods of assigning ethnicity can result in different estimates of ethnic variation in cancer incidence. Combining ethnicity from multiple sources results in a more complete estimate of ethnicity than the use of one single source.

Smith L, Norman P, Kapetanstrataki M, et al. Comparison of ethnic group classification using naming analysis and routinely collected data: application to cancer incidence trends in children and young people. BMJ Open 2017;7:e016332. doi: 10.1136/bmjopen-2017-016332

This study described access to Principal Treatment Centres (PTC) for children (0-14 years) and teenagers and young adults (15-24 years) and the associated trends in survival. Between 1998 and 2009, 72% of all patients aged 0-24 years received all their treatment at PTC whilst 13% had no treatment at PTC. Leukaemia patients who received no treatment at PTC had an increased risk of death which was partially explained by differences in patient case-mix (Adjusted hazard ratio = 1.73 (95% Confidence interval 0.98-3.04). For leukaemia, survival outcomes for low risk patients receiving no treatment at PTC were similar to high risk patients who received all treatment at PTC, implying a benefit of care at the PTC. Soft tissue sarcoma patients who had some or no treatment at PTC had better survival outcomes, which remained after adjustment for patient case-mix (adjusted HR = 0.48 (95%CI 0.23–0.99)), however we were unable to account for differences in stage at presentation, which may confound this finding. There were no significant differences in outcomes for other diagnostic groups (lymphoma, CNS tumours, bone tumours and germ cell tumours).

Level of treatment at PTC by diagnostic group and age group, Yorkshire 1998–2009

Fairley, L., Stark, D.P., Yeomanson, D. et al. Access to principal treatment centres and survival rates for children and young people with cancer in Yorkshire, UK. BMC Cancer 17, 168 (2017). doi.org/10.1186/s12885-017-3160-5

Objectives: To establish prevalence, management and long-term outcomes of osteonecrosis (ON) in young people diagnosed with acute lymphoblastic leukaemia (ALL) between 2003 and 2011.
Design, setting, participants: This study assessed ON in 3113 patients aged 1–24 years who participated in the UK national leukaemia study UKALL 2003. UKALL 2003 recruited patients in 40 UK hospitals between 2003 and 2011 and included patients between ages 1 and 25 diagnosed with ALL.
Results: 170 patients were diagnosed with ON, giving a prevalence of 5.5%. The multivariable analysis showed that the risk of ON was highest for children aged between 10 and 20 years (ages 10–15 years, OR 23.7, 95% CI 14.8 to 38.0; ages 16–20 years, OR 22.5, 95% CI 12.7 to 39.8, compared with age <10 years). Among ethnic groups, Asian patients had the highest risk of ON (OR 1.92, 95% CI 1.1 to 3.6, compared with White patients). Eighty-five per cent of patients with ON had multifocal ON. Thirty-eight per cent of patients with ON required surgery and 19% of patients with ON required a hip replacement. Fifteen per cent of patients who had surgery still describe significant disability or use of a wheelchair.
Conclusions: ON has considerable morbidity for patients being treated for ALL, with a high burden of surgery. Age and ethnicity were found to be the most significant risk factors for development of ON, with Asian patients and patients aged 10–20 years at diagnosis of ALL at greatest risk. These results will help risk stratify patients at diagnosis of ALL, and help tailor future prospective studies in this area.

Amin NL, Feltbower RG, Kinsey S, et al. Osteonecrosis in patients with acute lymphoblastic leukaemia: a national questionnaire study. BMJ Paediatrics Open 2017;1:e000122. doi:10.1136/ bmjpo-2017-000122.

2016

This study investigated the associations between infection transmission using the population mixing proxy and incidence of cancers in 15-24 year olds in Yorkshire. No significant associations between population mixing and cancer incidence were found for leukaemias, lymphomas, central nervous system tumours or germ cell tumours. This effect did not differ between urban and rural areas.

Imam A, Fairley L, Parslow RC, Feltbower RG. Population mixing and incidence of cancers in adolescents and young adults between 1990 and 2013 in Yorkshire, UK. Cancer Causes Control. 2016;27(10):1287-1292. doi:10.1007/s10552-016-0797-3

This study described the incidence and survival from CNS embryonal tumours, specifically medulloblastoma and primitive neuroectodermal tumours (CNS PNET), for children (0-14 years) and teenagers and young adults (15-24 years) in the North of England. Between 1990 and 2013 the incidence of medulloblastoma decreased over time, most likely due to improvements in molecular testing and classification of tumours over time. The risk of death was 2.4 times higher for patients with CNS PNET compared to medulloblastoma (Hazard ratio = 2.4 (95% Confidence Interval 1.6-3.7) and the risk of death decreased by 39% for patients diagnosed since 2000 compared to those diagnosed in the 1990s (HR=0.61 (95%CI 0.43, 0.87). Although the initial prognosis was worse for CNS PNET compared to medulloblastoma, for those who survived 3 years from diagnosis, survival probabilities for the next five years were similar in both groups (85% for medulloblastoma and CNS PNET)

Fairley L, Picton SV, McNally RJQ, Bailey S, McCabe MG, Feltbower RG. 2016. Incidence and survival of children and young people with central nervous system embryonal tumours in the North of England, 1990-2013. European Journal of Cancer. 61, pp. 36-43 doi:10.1016/j.ejca.2016.03.083