Cohort Profile: The St. Jude Lifetime Cohort Study (SJLIFE) for paediatric cancer survivors

Innovations in the understanding of childhood cancer biology, treatment and supportive care have dramatically improved cure rates such that 84% of newly diagnosed children and adolescents in high-income countries are expected to survive beyond 5-years from diagnosis.1 As a result, the number of childhood cancer survivors living in the USA surpassed 420 000 in 20131 and is anticipated to approach 500 000 by 2020.2 The medical success manifest by this growing population has been realized at a cost, however, as many survivors experience adverse health outcomes related to cancer and its treatment.3–6 In addition to chronic morbidity, survivors experience premature mortality compared to age- and sex-matched controls.7–10 Current understanding of late health outcomes in adult survivors of childhood cancer has largely been the result of a number of cohort studies that have been instrumental in identifying, quantifying and characterizing cancer treatment-related health risks.11–17 Health outcomes research findings have had a major influence on changes in paediatric cancer therapy and have informed health-screening strategies of childhood cancer survivors. However, in the early years of these studies, many were limited by dependence upon self-reported outcomes or registry data, smaller population sizes and restriction to single disease subsets and/or limited follow-up duration. To address these limitations, some have evolved to include periodic, prospective physical assessments extending beyond the period of cancer centre follow-up for single disease groups,11 nested subsets within the larger cohort14, and more recently for all survivors,12,17 in an effort to gain a better understanding of the true prevalence of disease and contributing risk factors. To this end, St. Jude Children’s Research Hospital (SJCRH) established in 2007 the prospective St. Jude Lifetime (SJLIFE) cohort, open to survivors of all paediatric cancer subtypes representing the spectrum of paediatric, adolescent and young adult cancers, as well as frequency-matched community controls, including collection of comprehensive treatment data on all participants, provision of protocol-based medical assessments, assessment of patient-reported outcomes, validation of self-reported medical events, performance of periodic longitudinal evaluations and collection of biologic specimens.18 Longitudinal, systematic medical assessments facilitate elucidation of the pathophysiology of cancer treatment-related morbidity, identification of biomarkers of subclinical organ dysfunction and characterization of high-risk survivor groups who may benefit from interventions to preserve health. At its inception in 2007, SJLIFE was an institutionally funded resource designed to study adults previously treated for childhood cancer at SJCRH who had survived ≥10 years from cancer diagnosis. In 2015, SJLIFE received extramural support from the National Institutes of Health (CA195547) to expand enrollment to include individuals of any age treated at SJCRH who had survived ≥5 years from cancer diagnosis in order to facilitate: (i) detection of asymptomatic and premorbid conditions; (ii) discovery of early predictors of adverse outcomes; and (iii) to collectively provide the basis for impactful and targeted interventions. These changes significantly increased the number of eligible survivors and aligned eligibility requirements with existing observational cohorts of childhood cancer survivors, expanding the opportunity for novel research initiatives, including replication and validation of previous findings. The study was reviewed by the SJCRH Institutional Review Board and ethical approval was obtained on 25 April 2007. Details regarding study design, recruitment and participant characteristics of the original cohort have been previously published.18 This study is registered at ClinicalTrials.gov under the identifier NCT00760656. The SJLIFE study utilizes a retrospective cohort study design with prospective follow-up and ongoing accrual of patients diagnosed and treated at SJCRH over five decades (1962–2012). Additional information regarding the SJLIFE cohort is available at https://sjlife.stjude.org/. St. Jude provides financial support for transportation, medical evaluations, meals, domiciliary care and monetary compensation for days of study participation. The original inclusion criteria, as established in 2007, were limited to adults ≥18 years of age at the time of evaluation who were treated at SJCRH and had lived ≥10 years from initial cancer diagnosis. In 2015, the criteria were expanded to include survivors of any age at the time of evaluation who had lived ≥5 years post diagnosis and who had been diagnosed through 30 June 2012. Table 1 shows the distribution of characteristics of the pool of survivors eligible for recruitment into the cohort prior to expansion and after expansion. Characteristics of eligible SJLIFE survivors prior to and after expansion Characteristics of eligible SJLIFE survivors prior to and after expansion To be eligible for participation in SJLIFE, individuals must have: (i) a history of childhood cancer diagnosed and have been treated at SJCRH between 1962 and 2012 and (ii) have survived ≥5 years from diagnosis. Whereas SJLIFE does not specify age at cancer diagnosis, SJCRH generally restricts acceptance to children <25 years of age at the time of cancer diagnosis. Recruitment utilizes a centralized process: (i) eligible survivors (through 30 June 2012) were identified via predetermined queries of medical record data in the SJCRH Clinical Research Informatics System; (ii) personalized invitation letters that provide mechanisms to respond electronically or via mail are sent to the survivor’s last known address; (iii) if there is no response after 2 weeks, a study interviewer calls to determine the survivor’s level of interest in participating; (iv) those interested in participating are transferred to a visit coordinator who describes the study and schedules the survivor for an on-campus visit (average duration of 3–4 days). If participants cannot be reached via voice call, electronic communications (i.e. email and text messaging) are attempted. To minimize loss to follow-up (both for original recruitment and for subsequent visits), the study team uses a combination of tracing procedures (e.g. patient and family contact information, postal forwarding addresses and internet queries) to locate participants, and verifies participant addresses at each point of contact (e.g. at the time of on-campus visit and follow-up phone calls). To facilitate estimates of risk associated with cancer and its treatment, SJLIFE is recruiting age-, sex- and race-frequency matched individuals without a history of childhood cancer to complete the same clinical assessment as survivors. We refer to these individuals as ‘community controls’ since they are being recruited through a variety of approaches from the same general geographic area as the SJLIFE survivor population (Figure 1). To achieve the desired geographic distribution, we offer the SJLIFE survivor participant the opportunity to identify a friend or non-first degree relative to accompany them to their on-campus visit and enrol as a community control. Additional community controls are recruited from the Memphis area through advertisements. As of 12 March 2020, 736 (target accrual of 1250) community controls have completed on-campus evaluations. The geographical distribution of eligible survivor and control participants is shown in Figure 1. Geographical distribution of survivors and controls in the St. Jude Lifetime Cohort in the conterminous USA. Note that participants from Alaska (n = 4), Hawaii (n = 6) and International (n = 68) participants are not shown Geographical distribution of survivors and controls in the St. Jude Lifetime Cohort in the conterminous USA. Note that participants from Alaska (n = 4), Hawaii (n = 6) and International (n = 68) participants are not shown The following categories are used to classify participants: (i) ‘eligible participants’ are individuals meeting eligibility criteria and alive at the time of recruitment; (ii) ‘enrolled participants’ are those who have signed consent to participate; (iii) ‘confirmed interest participants’ have been contacted and are interested, but have not yet signed consent to participate; (iv) ‘non-participants’ have declined participation, failed to respond after initially indicating interest or were not able to be contacted. As of 12 March 2020, 73.3% (6005/8192) of all living, eligible survivors have enrolled and 80.1% have enrolled or confirmed their interest in participating. Among those approached for study participation, 80.3% (6005/7471) have been successfully enrolled, 87.8% have enrolled or have confirmed interest in participating and 94.9% of those enrolled have elected to complete an on-campus assessment (Figure 2). Differences between participants and non-participants are detailed in Supplementary Table 1, available as Supplementary data at IJE online. Participant flow for recruitment of survivors into the St. Jude Lifetime Cohort. Of the 9369 survivors, 8192 were eligible for recruitment, with 5223 completing a campus assessment as of 12 March 2020. Response rate is defined as those who have completed a campus visit (n = 5223)/those contacted for recruitment (n = 7471) = 69.9% Participant flow for recruitment of survivors into the St. Jude Lifetime Cohort. Of the 9369 survivors, 8192 were eligible for recruitment, with 5223 completing a campus assessment as of 12 March 2020. Response rate is defined as those who have completed a campus visit (n = 5223)/those contacted for recruitment (n = 7471) = 69.9% The timing and sequence of participant data acquisition for events occurring prior to and after study enrollment are reflected in Figure 3. During and following treatment of paediatric cancer, remission status and treatment-related toxicities are routinely monitored by the primary oncology team and/or the long-term follow-up (after completion of therapy) clinic until the survivor is ≥10 years from diagnosis and ≥18 years of age, whichever occurs later. Data abstracted from medical records for all participants include demographics, cumulative chemotherapy doses, radiation fields and cumulative doses, information on surgical interventions, primary cancer recurrences and subsequent neoplasms, and acute and late organ-specific toxicity. Timing and sequence of participant data acquisition for events prior to and after study enrollment in the St. Jude Lifetime Cohort Timing and sequence of participant data acquisition for events prior to and after study enrollment in the St. Jude Lifetime Cohort The health and vital status of potential participants are monitored by the St. Jude Cancer Registry and supplemented by National Death Index (NDI) searches. The NDI provides a centralized database of death record information ascertained by state vital statistics offices. The SJLIFE study team periodically submits a request to NDI for vital statistics on study participants known to have died or without known contact since the last query. The NDI then returns a list of probabilistic matches to the SJLIFE team using a standardized algorithm.19 The results are then processed by the SJLIFE team via the Center for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) data linkage process.20 The combined findings of both NDI and NPCR are then centrally reviewed and a final match status assigned. The Cancer Registry is an established SJCRH resource designed to maintain systematic, life-time annual follow-up for all SJCRH patients, irrespective of participation in SJLIFE. Yearly attempts to contact all prior patients, with the primary purpose of assessing vital status and cancer status (no evidence of disease, recurrence, subsequent primary cancers), are made via written or verbal communication with patients, registries, emergency contacts, newspapers, vital status sites and local providers, with a goal follow-up rate of 90–95%. Delinquent cases remain in follow-up until contacted or confirmation of death is obtained. Following provision of informed consent, SJLIFE participants (both in the original and expanded cohorts) are invited to return to SJCRH at least once every 5 years for protocol-based medical evaluations and assessments of neurocognitive function, physical performance status and patient-reported outcomes. Permission for release of medical records for designated facilities up to 1 year from the campus visit is requested at each evaluation to validate interim, survivor-reported medical events, in particular those relating to the most recent campus visit (e.g. follow-up biopsy and breast cancer diagnosis after a screening imaging abnormality identified during a SJLIFE visit). In addition, two study-team members have the sole responsibility of following-up on health events identified during SJLIFE evaluations and those self-reported between campus visits, and their contact supplements the annual contact by the Cancer Registry. When new interval events are reported, additional permission to seek medical records is obtained on a case-by-case basis. Records are routinely requested for events involving imaging, tissue biopsies, surgical and diagnostic procedures, or interventions specifically impacting gradable conditions (e.g. skin biopsies, outside breast imaging) and/or clinical management (e.g. suspected cancer recurrence, chronic kidney disease, chronic hepatitis C). With the exception of vital status, interval events not coinciding with a campus visit (e.g. a self-reported myocardial infarction occurring 3 years after the last SJLIFE campus assessment) are censored from research analyses until the next subsequent campus visit occurs for uniform cross-sectional validation of events. As of 12 March 2020, 51.3% (2680/5223) of survivors who had completed a baseline clinical assessment have returned for one or more subsequent follow-up assessments. Supplementary Table 2, available as Supplementary data at IJE online, describes baseline characteristics as well as providing a comparison between those who have returned for a subsequent visit and those who declined additional visits. Table 2 describes grade 3–4 chronic conditions by organ system prevalent at baseline. Modified CTCAE21 defined chronic condition prevalence in individuals who have completed a baseline SJLIFE assessment (n = 5223) Modified CTCAE21 defined chronic condition prevalence in individuals who have completed a baseline SJLIFE assessment (n = 5223) Two levels of participation are offered in SJLIFE and have been applied to both the original and expanded cohorts: (i) an on-campus, comprehensive health evaluation (including health questionnaires and direct assessment) or (ii) comprehensive health questionnaires only, that are completed by mail or phone interview (Table 3). Detailed methodology on data collection, including medical record abstraction, questionnaires and medical assessments have been previously published for the original cohort.18 On campus study participation involves travel to the SJCRH campus for a comprehensive assessment averaging 3–4 days, during which biologic specimens (e.g. blood, urine) are collected; metabolic, cognitive and neuromuscular functional status are systematically evaluated; and screening of organ function is performed (Supplementary Table 3, available as Supplementary data at IJE online). These uniform assessments (Table 3) include identification and grading of chronic conditions using modified Common Terminology Criteria for Adverse Events (CTCAE) criteria,21 assessment of patient-reported outcomes, whole genome and exome sequencing, and linkage to the NDI for mortality follow-up. Relevant findings are summarized on a survivorship care plan and mailed to the survivor after the on-campus assessment, with direct phone contact by a study nurse or healthcare provider for critical findings that should be followed up by the participant’s community providers (e.g. suspicious lesions found on breast mammography). On-campus assessments are funded by institutional and extramural support. No study-related costs are submitted to healthcare insurance agencies. Study measures and clinical assessments for the SJLIFE cohort Modified versions of questionnaires are administered to participants who are <18 years of age; for participants 11–18 years of age, parents and participants complete the questionnaires; for participants <11 years of age, parents answer the questions on behalf of the child. Study measures and clinical assessments for the SJLIFE cohort Modified versions of questionnaires are administered to participants who are <18 years of age; for participants 11–18 years of age, parents and participants complete the questionnaires; for participants <11 years of age, parents answer the questions on behalf of the child. Since the inception of the SJLIFE study, 120 manuscripts have been published featuring results of late health outcomes. These publications have yielded a number of important findings based on analyses of on-campus participants, including clinically ascertained and validated prevalence6 and cumulative burden estimates4 for cancer treatment-related organ dysfunction, and documentation of novel late health outcomes.43–47 Prior to SJLIFE, prospective clinical ascertainment of a large population of childhood cancer survivors to determine prevalence of chronic conditions had not been performed. Hudson et al. reported the prevalence of chronic conditions and the proportion associated with treatment exposures in the first 1713 adult SJLIFE survivors who had completed a baseline assessment. Pulmonary, auditory, endocrine, reproductive, cardiac and neurocognitive adverse health outcomes were common, with the cumulative prevalence of chronic conditions by organ-specific outcomes by age 50.6 Bhatka et al.4 subsequently expanded upon these findings by applying the mean cumulative count method,48 which estimates the mean number of recurrent or multiple health events occurring in a cohort over time in the presence of competing risk events, in order to describe the unique patterns and excess cumulative burden of chronic health conditions experienced by childhood cancer survivors compared with community controls. By age 50 years, survivors experienced, on average, 17.1 grade 1–5 and 4.7 grade 3–5 chronic health conditions compared with 9.2 and 2.3, respectively, among community controls. Most recently, Wang et al.49 utilized whole genome and exome sequencing to assess the contribution of germline genetic abnormalities to subsequent neoplasm risk in survivors assessed for mutations in cancer predisposition genes. Pathogenic/likely pathogenic mutations were identified in 5.8% of survivors and were associated with increased risk of breast cancer and sarcoma in irradiated survivors and for developing any subsequent neoplasm, breast cancer, non-melanoma skin cancer and two or more histologically subsequent among survivors. systematic, prospective medical assessments and longitudinal the SJLIFE cohort provides the opportunity to of treatment, genetic and to the health status of childhood cancer survivors. major of SJLIFE is the to direct and longitudinal medical assessments on a large cohort of monitored childhood cancer survivors. characterization of health outcomes and cancer and health exposures provide an opportunity to identify novel and to understanding of the of cancer and its treatment on the health of survivors. The SJLIFE study must be in the of a number of SJLIFE is a study, late and detection may be by institutional population and may not be to the of the USA. In addition, was not established until 2007, many survivors treated in decades were no living at study the potential for participation rates in survivorship research are that survivors with the burden of late are more to participation. However, to treatment records for eligible non-participants and linkage to NDI records SJLIFE to better these as the SJLIFE are of the population at the study is limited in its to analyses on of the findings should be in the of SJCRH has established the St. Jude to provide and of large and to facilitate research paediatric cancer and The St. Jude as a between and is a and Data are at the patient providing to an of paediatric cancer data, data and Data be made on the and a The St. Jude provides sequencing data to the research available through a collection of designed to both and SJLIFE data of survivor and community whole and whole are available to the community on the St. Jude SJLIFE data are to the on the St. Jude and include detailed information (i) and age at diagnosis, of and treatment including and organ-specific radiation surgical procedures and including cumulative for and (ii) data and health (e.g. physical and and (iii) outcomes and grading for medical and (e.g. and assessments (e.g. function, data through physical function and neurocognitive assessments, and survivor-reported data obtained via the of SJLIFE The St. Jude Lifetime Cohort was designed to a cohort of childhood cancer survivors in which to prospective health outcomes assessments. cancer survivors were recruited from 8192 survivors diagnosed between 1962 and 2012 with paediatric cancer and treated at St. Jude Children’s Research Hospital in Of the 8192 survivors, have to and 5223 have completed a baseline clinical assessment. are invited to return for follow-up assessment every 5 As of 12 March 2020, of survivors who have completed a baseline assessment have returned for one or more subsequent follow-up assessments. Data detailed medical record of exposures identification and grading of chronic conditions using modified Common Terminology Criteria for Adverse Events (CTCAE) criteria, collection of biologic specimens (e.g. blood, assessment of patient-reported outcomes, physical neurocognitive function, whole genome and exome sequencing, and linkage to the National Death Index (NDI) for mortality follow-up. Study and data are available at and Supplementary data are available at IJE online. This was by the National Cancer at the National Institutes of Health Cancer Center and the St. Jude Lifetime Cohort Study and the at The is the responsibility of the and does not the of the National Institutes of