key: cord-0289235-jli9iheq
authors: Kane, E.; Kinsey, S.; Bonaventure, A.; Johnston, T.; Simpson, J.; Howell, D.; Smith, A. G.; Roman, E.
title: Excess morbidity and mortality among survivors of childhood acute lymphoblastic leukaemia: 25 years of follow-up from the United Kingdom Childhood Cancer Study (UKCCS)
date: 2021-07-29
journal: nan
DOI: 10.1101/2021.07.27.21261102
sha: 658015e241e1d6000d9482d9314fa5a278095c46
doc_id: 289235
cord_uid: jli9iheq

Objectives To examine morbidity and mortality in survivors of childhood acute lymphoblastic leukaemia (ALL) across their teenage and young adult (TYA) years; comparing the patterns observed with individually matched general population controls. Design Case-control study with follow-up linkage to administrative healthcare databases for up to 25 years. Setting The study population comprises all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996. Participants 1082 five-year survivors of ALL diagnosed <15 years of age, and 2018 age- and sex-matched population-based controls; followed to 15 March 2020. Main outcome measures Associations with hospital activity, cancer, and mortality were assessed using incidence rate ratios and absolute risk difference. Results Mortality 5-25 years after diagnosis was 20 times higher in cases than controls (Rate Ratio 21.3, 95% Confidence Interval 11.2-45.6), and cancer incidence 10 time higher (IRR 9.9 95% CI 4.1-29.1). Hospital activity was increased for many clinical specialties, the strongest effects being for endocrinology; outpatient IRR 36.7, 95% CI 17.3-93.4 and inpatient 19.7, 95% CI 1.9-25.5 for males, and 11.0, 95% CI 6.2-21.1 and 6.2 95% CI 3.1-13.5 respectively for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology, ENT (ear, nose and throat), urology, and dermatology; while females were more likely to be seen in plastic surgery and less likely in midwifery. Conclusions Adding to a large excess risk of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years. Involving most clinical specialties, the observed effects are striking, showing no signs of diminishing over the first 25 years of follow-up. These findings underscore the need to take prior ALL drug and/or radiation treatment into account when interpreting seemingly unrelated symptoms in later life.

Comprising around 40% of all cancers diagnosed in children before 15 years of age, acute lymphoblastic leukaemia (ALL) is the commonest paediatric malignancy in high income countries. Epitomizing one of the major therapeutic success stories of the last 50 years, five-year overall survival for childhood ALL is now around 90% in high-income settings. (1) As a result, the global prevalence of survivors is increasing year-on-year; and will continue to do so as treatments improve, populations age, costs fall, and new clinical collaborations between high-and low-income countries are forged. (2) In contrast to many other childhood cancers, ALL treatment is prolonged, with current protocols typically administering chemotherapy in phases extending over a 2-to 3-year period. (3) That children who survive ALL tend to have higher mortality and morbidity in later life, including subsequent cancers and a wide range of other therapy-related conditions (Table 1) , is established. (4) (5) (6) With respect to the latter, however, much of the information on late effects among survivors has come either from analyses of hospitalizations or from questionnaires completed by consenting individuals. (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) As is evident from the studies summarized in Table 1 (which includes those that examined all leukaemias combined and those that also included young adults), less attention has been paid to chronic conditions that do not require hospital admission, (17, 18) and to morbidity patterns that change over time. (11, 19) The longitudinal data examined in this report contain information on hospital outpatient attendances, as well as inpatient episodes, cancer registrations, and deaths. Adding significantly to the existing knowledge base, a large cohort of children (<15 years) diagnosed with ALL in England during 1992-6 and their individually sex-and age-matched population controls have been tracked for up to 25 years through their teenage and young adult (TYA) years. Increasing the power to detect effects should they exist, this diagnostic time period (1992-6) coincides with the UKALL XI randomised controlled trial (RCT) (20) ; the last very intensive UK RCT prior to the era of clinical investigations enabling reduction in therapy for patients with rapid early response to treatment. (21) Methods Data are from the United Kingdom Childhood Cancer Study (UKCCS), a national population-based case-control study established in the 1990s to investigate potential causes of childhood cancer. Full details of the UKCCS's original methods and ethical permissions have been published. (22) (23) (24) Briefly, the study population comprised all children (0-14 years) registered for primary care with the National Health Service (NHS). All children newly diagnosed with cancer (cases) were ascertained via proactive notification systems established in all treatment centres across England, Scotland and Wales; and each child whose parents agreed to be interviewed (87%; all cancers combined) was individually matched on sex, date of birth and region of residence to up to 10 randomly selected controls. The general practitioners (GPs) of the first two controls identified ("first-choice controls") were approached and, with their permission, the parents of the children were contacted and asked to participate in the study. Overall, 72% of first-choice control families participated; but if the GP refused permission to contact the parents, or the parents themselves declined, the next control on the list was selected, and so on until two control families agreed. (22) (23) (24) For methodological purposes (23, 24) , details of all non-participating cases and controls were retained in the UKCCS registration database.

With a view to examining childhood cancer sequelae, the UKCCS in England now operates on a legal basis that permits information to be obtained from NHS administrative healthcare records without . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.27.21261102 doi: medRxiv preprint explicit consent; and all registered cases and first-choice controls, along with participating replacement controls, are now being prospectively tracked by NHS Digital (https://digital.nhs.uk/) via linkage to nationwide (England) information on deaths, cancer registrations, and Hospital Episode Statistics (HES; inpatient admissions and outpatient attendances).

The present report focuses on the health of children who survived for 5-years or more following a diagnosis of ALL. The number of ALL cases diagnosed in England in the original UKCCS study and their corresponding first-choice controls, as well as deaths and losses to follow-up occurring within 5-years of diagnosis, or pseudo-diagnosis (matched controls), are shown in Figure 1 . In total, 1372 children were diagnosed with ALL in England during the study period (1992 to 1996) , and the parents of 92% (1262/1372) agreed to participate, each of whom had two sex-and age-matched first-choice controls selected (n=2524). Of the 1104 ALL cases (80.5%) who survived for five years or more, 1004 (90.9%) had B-ALL and 70 (6.3%) T-ALL. The cell lineage of the remaining eight ALL survivors is unknown; they were not entered into a clinical trial and the parents did not participate in the original study (hence no controls). Finally, because Down syndrome is a well-established risk factor for ALL, and is also associated with a range of other morbidities, the 22 surviving case children with Down syndrome (no first-choice control had Down syndrome) and their matched controls were excluded from the analysis.

For the 1082 cases and 2018 controls included in this report, linked healthcare data were available on all cancer registrations and deaths up to March 2020, inpatient HES from April 1997 to March 2019, and outpatient HES from April 2003 to March 2019. Data were analysed using non-parametric time-to-event analyses and exact methods to estimate hospital visit hazard rates and risks associated with specific clinical specialties (two or more outpatient visits, or at least one hospital admission). Follow-up began five years post-diagnosis and ended either at the date of death, 25 years post-diagnosis, or end date for hospital data. For controls follow-up could also end when their matched case died. Migrations out of England, any subsequent returns, as well as time spent in hospital were also accounted for. All analyses were conducted using Stata 16.1.

The original case-control study was established over 30 years ago, and did not benefit from formal links with patient/user groups. Members of the CCLG (Children's Cancer and Leukaemia Group, previously the UK Children's Cancer Study Group) were, however, fully involved throughout. More recently with respect to the present research, the acceptability of using patient data without explicit consent (as is the case in this report) has been positively discussed with patient groups and clinicians; and the study website (www.UKCCS.org) contains information about ongoing research activities and fair processing. It is our intention to establish a PPIE group to input into future research when the COVID pandemic permits.

The characteristics of individuals in the original case-control study and in the 5-year survivor cohorts are shown in Table 2 . As expected, the 290 (21%) children with ALL who died within five years of diagnosis were more likely to have had T-cell disease (χ 2 =44.0, p<0.001), have been infants or older children (χ 2 =100.9, p<0.001), and were less likely to have participated in a clinical trial (χ 2 =11.6, p=0.001). Tracking children from around their 9 th year of age through to their 29 th , this reports primary focus is teenage and young adult (TYA) survivors who, again as expected, continued to experience more deaths (cumulative mortality 10.7%, 95% Confidence Interval 9.0-12.8) than their . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.27.21261102 doi: medRxiv preprint general population counterparts (cumulative mortality 0.6%, 95% CI 0.3-1.1); yielding a mortality rate ratio of 21.3 (95% CI 11.2-45.6). Likewise, 5-year ALL survivors were also more likely to have a subsequent cancer registration (non-ALL malignancy Incidence Rate Ratio 9.9, 95% CI 4.1-29.1), although the numbers are small (32 versus 6).

Childhood ALL survivors are regularly monitored throughout their TYA years either in paediatrics, haematology or oncology, as is evidenced in Figure 2A which shows the outpatient activity of 5-year ALL survivors and their corresponding controls for these three clinical specialties combined (specialty-specific outpatient and inpatient data are shown in Supplementary Figure 1 ). At around one visit in 20 years, hospital activity among population controls is very low, and varies little over time. By contrast, for ALL survivors, 8 years after diagnosis outpatient activity is around 35 times higher than the background rate, falling 10 years later to around 0.4 visits per case per year ( Figure  2A ). In all other clinical specialties combined, outpatient activity among childhood ALL survivors are also consistently higher than expected; hazard rates in both cohorts increasing over time at the same steady rate ( Figure 2B ).

More information on hospital activity is presented for the top 15 specialties (excluding paediatrics, haematology and oncology) for males and females separately in Figure 3 (outpatients) and Figure 4 (inpatients). In all figures, cumulative incidence frequencies (outpatient = two or more face-to-face visits to that specialty; inpatient = any admission) are on the left and incidence rates on the right; with the ordering of specialties determined by the magnitude of the incidence rate ratio (IRR). Most specialties are associated with high relative and attributable risks (inpatient and outpatient). Furthermore, although the magnitude of the effect often varies between males and females, the overall pattern is broadly similar. In both sexes, for example, the strongest effects are seen for endocrinology; the IRRs for outpatients and inpatients being 36.7 (95% CI 17.3-93.4) and 19.7 (95% CI 7.9-63.2) respectively for males, and 11.0 (95% CI 6.2-21.1) and 6.2 (95% CI 3.1-13.5) for females. Notable excesses (relative and attributable) are also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine, for both genders. Male survivors were also more likely than their peers to attend gastroenterology, ENT (ear, nose and throat), urology, and dermatology; while female survivors were twice as likely as their controls to be referred to plastic surgery. Interestingly, no case-control differences are evident for trauma and orthopaedics, which has the highest background cumulative incidence in males. Likewise, among females, no differences were detected for obstetrics and gynaecology; however, it is notable that activity is lower than expected in midwifery (outpatient IRR 0.9, 95% CI 0.7-1.2; inpatient IRR 0.6, 95% CI 0.4-0.9).

Detailed inspection of the HES data revealed no evidence of specialty-specific changes in either relative or attributable risks over the 20-year time frame (Supplementary Figure 2) ; possible exceptions being falls in ranking for ophthalmology among males and dermatology among females. Furthermore, no differences between B-and T-cell survivors with respect to any of the outcomes were evident, although the number with T-cell disease was comparatively small (n=70).

Including data on more than 1000 survivors of childhood ALL and twice as many age-and sexmatched general population controls, this national record-linkage study found that survivors continued to experience large excesses in mortality and morbidity throughout their teenage and young adult years. With hospital activity being higher than expected in specialties covering most organ and tissue systems, survivors were more than twice as likely to fall under the care of . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.27.21261102 doi: medRxiv preprint endocrinology, cardiology, respiratory medicine, ophthalmology, neurology and/or gastroenterology specialists. Moreover, aside from a gradual decline in visits to clinical specialties involved in followup monitoring (paediatrics, haematology and oncology), there was little indication of activity returning to general population levels up to 25 years after the initial ALL diagnosis. Among females, it is also notable that midwifery outpatient attendances were not increased, with admissions being lower than expected.

Our study, which uses linked rather than self-reported data and population controls, is one of only two (17) to separate secondary care activity associated with cancer follow-up from activity associated with other morbidities; finding that survivors not only experienced higher rates of admission but also higher rates of outpatient visits, neither of which abated over their TYA years. Reported less often are the types of conditions underlying these associations, with four studies assessing risks by organ system (8, 12, 14, 17) . Survivors in these studies were diagnosed over a wider period than the study reported here, and had median follow-up times that were shorter; 9 to 17 years from diagnosis, compared to 25 years here. These studies found that survivors were at increased risk of being hospitalised with endocrine or infectious diseases, as well as diseases involving the nervous, circulatory, skin, digestive, genitourinary, respiratory or musculoskeletal systems. With the information source mostly being inpatient records, reports using data from other healthcare settings are sparse (17) and not specific to survivors of ALL (18) . Importantly, while our findings are broadly consistent with these studies, our methods also highlight excesses in ophthalmology, ENT (ear, nose and throat), and oral/dental specialties, as well as decreases in midwifery.

Ensuring homogeneity of treatment, the original study's diagnostic dates were contemporaneous with the national UKALL XI randomized controlled trial (RCT), within which 90.5% of UKCCS 5-year survivors were enrolled (20, 25) . This comparatively high-intensity RCT was the last UK childhood ALL trial prior to the stratification of patient treatment based on early bone marrow response to induction treatment (measured by percentage of leukaemia cells in the marrow) (21, 26) . Information on UKALL XI's scheduling of drugs is provided in the report by Hann and colleagues (20) , several of which have been implicated, either singly or combined, in therapy-related effects (Table  1) . It is, however, important to note that several of the UKALL XI drugs are no longer used (e.g. etoposide, 6-thioguanine) or are used more sparingly (e.g. daunorubicin, cyclophosphamide, corticosteroids), and that cranial irradiation is no longer routinely administered, being reserved for infrequent particular indications (27). Hence, the nature of the UKCCS cohort means that it is well placed to provide baseline data against which to evaluate the impact of treatment de-escalation and other protocol modifications. Other major strengths include its national coverage, completeness of case ascertainment, and large in-built general population comparator (22) (23) (24) ; the latter obviating the need to rely on published national rates, as has been the case in the UK thus far (9, 14, (28) (29) (30) .

With regard to weaknesses, the lack of data from other parts of the NHS, including primary care and adolescent psychosocial services, is an obvious deficiency that currently affects all UK record-linkage studies of the type described here. The relative paucity of information on psychological morbidities is particularly relevant to childhood cancer survivors, who are known to be at increased risk of a number of such disorders (4,31,32). Missing information within the HES datasets is also an issue; diagnostic data, for example, is largely absent from outpatient HES. Furthermore, although steps to mitigate surveillance bias were taken by requiring at least two face-to-face visits to a given specialty, we cannot rule out the possibility that childhood cancer survivors were more likely to be referred to secondary care than their peers.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.27.21261102 doi: medRxiv preprint Adding to a large excess risk for death and cancer, survivors of childhood ALL also experience excess outpatient and inpatient activity across their teenage and young adult years. Involving most clinical specialties, the observed effects are striking; showing no signs of diminishing over the first 25 years of follow-up. The main exception is the comparatively low midwifery contact seen among female ALL survivors. These findings underscore the important need to take prior ALL drug and or radiation treatments into account when interpreting seemingly unrelated symptoms in later life. With virtually complete linkage to existing national databases established, our future research will continue to monitor the health of cancer survivors across their life-span.

What is already known on this topic − In high income countries, improvements in diagnostics and therapeutic approaches mean that 90% of children with acute lymphoblastic leukaemia (ALL) are now cured of their cancer − ALL is the commonest paediatric malignancy, and the prevalence of survivors is increasing

year-on-year as treatments advance and populations age − ALL treatment is prolonged and survivors may suffer health consequences in later life

− Covering most organ and tissue systems, ALL survivors experience marked excesses in outpatient activity and inpatient admissions across their teenage and young adult years − Excess morbidity did not diminish over the first 25 years of follow-up − Individuals previously treated for ALL as a child may present with unusual or seemingly nonassociated symptomatology later in life Contributors: ER, SK, and JS contributed to the design of the original study; and ER and EK instigated the present investigation and prepared the report. EK conducted the analyses, and all authors (ER, EK, SK, AB, TJ, JS, DH, AS) were involved in the development, reviewing, and approving the final manuscript. ER is the principal investigator and guarantor. The corresponding author (ER) attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted. Data sharing: Reasonable requests for data sharing will be considered by the authors.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 29, 2021. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 29, 2021. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 29, 2021. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 29, 2021. ; https://doi.org/10.1101/2021.07.27.21261102 doi: medRxiv preprint : Cumulative incidence (%), incidence rates (per 1000 person-years), attributable risks, and incidence rate ratios for the top 15 outpatient specialties (excluding paediatrics, haematology and oncology) with two of more face-to-face speciality-specific visits in the 5 to 25 years following diagnosis (cases diagnosed <15 years, 1992-96) and their matched population controls.

A Males Figure 4 : Cumulative incidence (%), incidence rates (per 1000 person-years) and incidence rate ratios for the top 15 inpatient specialties (excluding paediatrics, haematology and oncology) in the 5 to 25 years following diagnosis (cases diagnosed aged<15 years, 1992-96) and their matched population controls. Cumulative incidence (%), incidence rates (per 1000 person-years), attributable risks and incidence rate ratios for the top 15 outpatient specialties (excluding paediatrics, haematology and oncology) with two of more face-to-face speciality-specific visits in the 5 to 15 years and 15 to 25 years following diagnosis (cases diagnosed <15 years, 1992-96) and their matched population controls.

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