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The impact of long-term follow-up care for childhood cancer survivors: A systematic review
Critical Reviews in Oncology/Hematology 114 (2017) 131–138
Contents lists available at ScienceDirect
Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc
Review article
The impact of long-term follow-up care for childhood cancer survivors: A systematic review Christina Signorelli a,b,∗ , Claire E. Wakefield a,b , Joanna E. Fardell a,b , W. Hamish B. Wallace c , Eden G. Robertson a,b , Jordana K. McLoone a,b , Richard J. Cohn a,b a
Discipline of Paediatrics, School of Women’s and Children’s Health, UNSW Australia, Kensington, NSW, Australia Kids Cancer Centre, Sydney Children’s Hospital, NSW, Randwick, Australia c Department of Hematology/Oncology, Royal Hospital for Sick Children, Edinburgh, UK b
Contents 1. 2.
3.
4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.1. Data sources and searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.2. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.3. Screening and extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 2.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.1. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.2. Long term follow-up impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3. Medical impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3.1. Late effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3.2. Screening practices and health behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3.3. Hospitalization/emergency department visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.4. Psychosocial impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.4.1. Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.4.2. Risk perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 3.4.3. Psychological morbidities and HRQoL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 3.5. Follow-up care type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Contributorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Competing interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
a r t i c l e
i n f o
Article history: Received 25 January 2017 Received in revised form 4 April 2017 Accepted 11 April 2017 Keywords: Pediatrics Oncology Survivorship Surveillance Long term follow-up
a b s t r a c t Objectives: Childhood cancer survivors are at risk of developing late treatment-related complications. In response, many hospitals worldwide have established follow-up clinics to monitor survivors as they age. However, there is limited evidence of the efficacy of these clinics in meeting the lifelong healthcare needs of survivors. In this review we collated evidence of the measurable impact of engagement in specialized survivorship care, on survivors’ medical and psychosocial outcomes. Design: We conducted a systematic review according to PRISMA guidelines, and assessed the quality of included studies using ‘QualSyst’. Data sources: We screened 641 abstracts in Medline, Embase and CINAHL, yielding 9 eligible articles (N = 5135 survivors).
∗ Corresponding author at: Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, NSW 2031, Australia. E-mail address: [email protected] (C. Signorelli). http://dx.doi.org/10.1016/j.critrevonc.2017.04.007 1040-8428/© 2017 Elsevier B.V. All rights reserved.
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Eligibility criteria for selecting studies: Articles were eligible if: participants were diagnosed with cancer prior to the age of 21; participants were classified as ‘survivors’ of childhood or adolescent cancer, usually defined as 5 years from diagnosis or 2 years from the end of treatment; studies evaluated the impact of engagement in long term follow-up (LTFU) care on medical, psychosocial or other outcomes in pediatric cancer survivors. Results: One article evaluated primary care physician-led follow-up and the remainder evaluated specialized survivorship clinics. Survivors attending follow-up care tended to demonstrate higher knowledge about their treatment and diagnosis (n = 2), and had more accurate late effects risk perception (n = 3). Attendees also engaged in increased more regular surveillance, had fewer emergency department visits/hospitalizations (n = 1), and more late effects detected (n = 3), than non-attendees. Conclusions: There is a dearth of literature systematically evaluating the medical and psychosocial impact of follow-up care. Research suggests however, survivors engaged in follow-up care have better health and educational outcomes, highlighting the need for lifelong survivorship care and ongoing late effects education for survivors. Recalling survivors who become disengaged with follow-up care is also valuable, as their risk of treatment-related complications rises with age. Further systematic evaluation is urgently needed. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Improvements in survival rates have resulted in growing concerns about childhood cancer survivors’ (CCS) risk of developing treatment-related conditions (Oeffinger et al., 2006). Survivors are vulnerable to medical and psychosocial ‘late effects’ that are often associated with aging (Oeffinger et al., 2006; Signorelli et al., 2016). Three in every four survivors experience a late effect of their cancer treatment, 37% of which may be life threatening (Geenen et al., 2007). However, early intervention may reduce morbidity due to late effects (Schwartz, 1999). Numerous guidelines therefore recommend lifelong care for CCS, sparked by the landmark Institute of Medicine report on the organization of long term follow-up guidelines and clinics (Landier et al., 2004; Wallace et al., 2013; Hewitt et al., 2003). The goal of follow-up care is to reduce the burden of late effects in CCS. Follow-up care is ideally comprehensive and interdisciplinary, focuses on preventing or managing late effects through surveillance, educates survivors on treatment-related complications, and encourages preventative lifestyle behaviors (Hollen and Hobbie, 1995). Risk-based anticipatory care received at long term follow-up clinics is recommended to reduce morbidities and mortality associated with treatment for pediatric cancer (Grossi, 1998). Engagement in follow-up is intended to foster ongoing education, screening, early detection, and where possible prevention, of late complications and second malignancies, facilitating early intervention when complications arise, and ultimately leading to improved medical and psychosocial outcomes in the long-term (Marina, 1997). Follow-up recommendations may differ for survivors, based on their diagnosis, and treatment type(s) and intensity (Edgar et al., 2013). Higher risk survivors often continue receiving their followup care through specialized Long Term Follow-Up (LTFU) clinics, usually at their treating hospital. Medium and low-risk survivors may be referred to their Primary Care Physician (PCP) for a sharedcare (joint participation from PCPs and specialists) or PCP-led model respectively. With demand on pediatric oncology services surpassing supply, other survivors are formally transitioned from their pediatric center to an adult service (primary care or hospitalbased), often depending on how they are risk-stratified (Henderson et al., 2010). Given the strong calls to offer LTFU care to CCS, increasing resources are being allocated worldwide to guideline and resource development (Henderson et al., 2010). Yet, up to 68.5% of long term survivors do not engage in any cancer related follow-up care (Nathan et al., 2008), and there are several patient-, provider-
and system-related barriers to care (Oeffinger, 2003). In particular, young adult survivors of childhood cancer often become disengaged from follow-up following the transition from pediatric to adult healthcare (Henderson et al., 2010; Freyer, 2010). Accordingly, interventions to re-engage CCS into long term follow-up are being developed (Edgar et al., 2012). However the efficacy and costeffectiveness of such care is yet to be established (Oeffinger and McCabe, 2006). A review of the evidence summarizing the impact of receiving long term follow-up care in CCS is therefore overdue (Tonorezos and Oeffinger, 2015). This systematic review aimed to evaluate the medical and psychosocial impact of attending a long term follow-up clinic or receiving specialized cancer care in the childhood cancer survivor population. Specifically, the review aimed to answer the following research questions: 1) What is the impact on CCS of attending LTFU, in comparison to not attending? 2) Is there a difference in the impact of LTFU care received by survivors at specialized survivorship clinics or centers, as compared to care in the primary care setting? 2. Methods 2.1. Data sources and searches This systematic review was guided by Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) procedures (Edgar et al., 2012).We searched three electronic databases (Medline, Embase, and CINAHL), Google Scholar and two grey literature databases (Trove and Open Grey), up to June 2016, and limited to English and human studies (See Supplemental Table 1 for the search algorithm). 2.2. Inclusion criteria Articles were eligible if: 1) Participants were diagnosed with cancer prior to the age of 21 2) Participants were classified as ‘survivors’ of childhood or adolescent cancer, usually defined as 5 years from diagnosis or 2 years from the end of treatment 3) Studies evaluated the impact of engagement in LTFU care on medical, psychosocial or other outcomes in pediatric cancer survivors
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Articles were not excluded based on the year in which they were published. As survivors may receive their care in either tertiary or primary care settings (or both), LTFU care was defined as any formal cancer-related care received, including from their PCP, through a survivorship clinic, specialized cancer center, or at their treating pediatric hospital (e.g. a LTFU clinic, led by an oncologist or a specialist nurse). Survivors engaged in any regular cancer-related survivorship care are classified as ‘attendees’, whilst those have not been in any such care for at least two years are defined as ‘non-attendees’. 2.3. Screening and extraction Two reviewers (CS and EGR) independently screened 641 abstracts after de-duplication, three of which were eligible for the review. The consistency between reviewers was high and any disagreements resolved by consensus. We sourced a further six articles by screening the reference lists of eligible articles and a general search in Google Scholar. Fig. 1 summarizes the screening and data extraction process, including exclusion reasons. Reviewer one (CS) extracted relevant data from all nine eligible articles. The second reviewer (EGR) extracted data for two included articles to confirm reliable extraction. 2.4. Quality assessment Two reviewers (CS and ER) assessed all eligible articles against a set of 14 criteria included in ‘QualSyst’ (Kmet et al., 2004). All criteria were equally weighted and studies were not excluded on the basis of a quality threshold (Supplemental Table 2). 3. Results 3.1. Study characteristics Nine articles described the impact of LTFU engagement, representing 5135 pediatric cancer survivors (range: 50–3912). Seven studies reported mean ages of survivors at study participation, ranging from 5–57years. Survivors’ mean age at diagnosis ranged from 0–21years, reported in four studies. Four of the nine articles compared outcomes in survivors before and after a follow-up visit(s) (Cherven et al., 2014; Hogan et al., 2013; Landier et al., 2015; Blaauwbroek et al., 2007a), while four articles compared outcomes between attendees and non-attendees (Ford et al., 2013; Ganju et al., 2016; Lindell et al., 2015; Szalda et al., 2015), and one was a retrospective cohort study (Sutradhar et al., 2015). Most studies were conducted in the United States (n = 7). Participants were mainly middle income, well-educated, living in urban areas, and all studies targeted English speakers and, in two studies, Spanish survivors (Cherven et al., 2014; Landier et al., 2015). 3.2. Long term follow-up impact Supplemental Table 3 summarizes the medical and psychosocial impact of LTFU. Primary outcomes included CCS’ knowledge of late effects, medical history and late effects risk (n = 4) (Cherven et al., 2014; Landier et al., 2015; Ganju et al., 2016; Lindell et al., 2015), newly detected late effects (n = 2) (Hogan et al., 2013; Blaauwbroek et al., 2007a), emergency department visits and hospitalization (n = 1) (Sutradhar et al., 2015), overall and mental health (n = 1) (Ford et al., 2013), and healthcare use, including surveillance practices (n = 1) (Szalda et al., 2015). The evidence suggests engagement in LTFU care has a mostly positive impact on CCSs’ outcomes (Table 1).
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3.3. Medical impact 3.3.1. Late effects Four studies assessed the impact of LTFU on prevalence of diagnosed late effects (Cherven et al., 2014; Landier et al., 2015; Ganju et al., 2016; Lindell et al., 2015). All highlighted disengaged CCS may be less aware of the late effects they experience. Two of these studies from the US (n = 213) and The Netherlands (n = 123) showed up to 34% of disengaged survivors attending clinic were diagnosed with previously undetected late effects requiring treatment and/or further surveillance (Hogan et al., 2013; Blaauwbroek et al., 2007a). Newly identified late effects were observed in almost 12% of disengaged survivors with no late effects’ history, including osteoporosis, and second malignancies (Hogan et al., 2013). In another US study (n = 173) attendees had more than twice the incidence of endocrine and hormone-related late effects compared with non-attendees, suggesting non-attendees may have several undiagnosed, and potentially treatable, late effects (Ford et al., 2013). 3.3.2. Screening practices and health behaviors One study assessing survivors’ health behaviors, provided some evidence of LTFU benefits (Ford et al., 2013). Self-reported health was generally high in both clinic attendees and non-attendees, and most reported a biannual general physical examination by their PCP, despite attendance. While many attendees (61%) accurately remembered they had previously visited survivorship clinics for follow-up, only 21% of non-attendees accurately reported their non-attendance. Although not significantly different, attendees reported lower alcohol consumption and current tobacco use, and higher surveillance practices (e.g. breast or dental examinations). 3.3.3. Hospitalization/emergency department visits Evidence of the impact of follow-up attendance on hospitalizations was limited to one retrospective medical record review of almost 4000 Canadian survivors (Sutradhar et al., 2015). Highacuity emergency department (ED; e.g. urgent, resuscitation) visits were significantly lower in clinic attendees. Survivors who had visited a clinic at least once demonstrated a 19% lower rate of ED visits compared with non-attendees, with every additional clinic visit thereafter associated with a 5% reduction in ED visits. At any one time, the cumulative incidence of ED visits remained significantly higher for individuals who had never attended clinic. 3.4. Psychosocial impact 3.4.1. Knowledge Four studies assessed the impact of follow-up on CCS’ knowledge relating to their cancer and late effects (Cherven et al., 2014; Ford et al., 2013; Ganju et al., 2016; Lindell et al., 2015). In one study comparing attendees with non-attendees, survivors’ accuracy of reporting their diagnosis was high and knowledge of treatment information poor, regardless of follow-up engagement (Ford et al., 2013). Non-attendees in two US studies (n = 222 and n = 93) had lower knowledge of their specific diagnosis (Ganju et al., 2016; Lindell et al., 2015), and reported fewer discussions about their late effects risks (Lindell et al., 2015). Although not statistically significant, non-attendees also reported lower knowledge of specific chemotherapy agents received, and surgical treatment (Ganju et al., 2016). Attendees were more accurate in recalling their specific chemotherapeutics and specific radiation treatment (Lindell et al., 2015), and future late effects risk (Ganju et al., 2016). In a pre-post study of survivors newly recruited to clinic, chemotherapy and late effects knowledge increased significantly 3 months postvisit, compared to before their clinic visit (Lindell et al., 2015). No such difference was observed between their one and three month
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Identification
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Records identified through database search: (Medline, Embase, and CINAHL)
762 abstracts meeting search criteria Duplicates excluded: n= 121
Screening
641 records Excluded due to incorrect format (conference abstracts, books, dissertations): n = 213
Eligibility
428 abstracts screened
6 full-texts assessed for eligibility
Excluded: - Not pediatrics (n=3) - Not cancer-related (n=1) - Not evaluating impact of LTFU (n=47) - A combination of 2 or more of the above (n=374)
3 eligible articles Included
Manual search: Reference list of relevant articles screened, and Google Scholar searched, for further eligible articles n=6 9 journal articles Fig. 1. Flow diagram for study selection and reasons for exclusion.
follow-up interview. Although knowledge declined slightly at 12 month follow-up, it remained significantly higher than prior to clinic visits (Lindell et al., 2015).
with time (Landier et al., 2015; Lindell et al., 2015), while accuracy of their perceived late effects risk declined significantly with time (Lindell et al., 2015).
3.4.2. Risk perception Attendees more accurately reported their late effects risk than non-attendees. However both groups underestimated their overall self-reported late effects risk, compared with physician-reported risk (Ford et al., 2013; Lindell et al., 2015). US adolescent survivors’ (n = 50) late effects knowledge increased significantly following their first follow-up visit (Cherven et al., 2014). Another study showed survivors prompted with a complete list of potential late effects identified themselves as being at risk of late effects for which they were not personally at risk of (Lindell et al., 2015). Late effects awareness in 369 previously disengaged US survivors almost doubled after three clinic visits, although knowledge gains plateaued after the third visit (Landier et al., 2015). Attendees’ accuracy of reporting their diagnosis and treatment history did not improve
3.4.3. Psychological morbidities and HRQoL No significant differences were observed between attendees and non-attendees in psychological morbidities, including post-traumatic stress disorder (Ford et al., 2013). Although not significant either, attendees tended to report higher distress levels than non-attendees. Survivors disengaged from follow-up with moderate/severe late effects, had significantly lower HRQoL than survivors with no/mild late effects, worst on physical and social functioning, vitality and general health perceptions scales (Blaauwbroek et al., 2007a).
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Table 1 Strength of evidence of the main impact of engagement in LTFU care. Negative findings Medical impact
Neutral findings
Late effects detected
Healthcare use
No difference in number of general physical exams (Blaauwbroek et al., 2007a) No difference in healthcare use, including complementary support services (Lindell et al., 2015) High self-reported overall health in all survivors (Blaauwbroek et al., 2007a)
General health Health behaviors
Psychological impact
Health-related quality of life Knowledge
Decline in knowledge 12 months post-visit (still higher than non-attendees) (Ganju et al., 2016)
Risk perception
Incorrectly reported late effects risk when prompted with a list (Ganju et al., 2016)
Impact of type of follow-up care
Many survivors became disengaged following transition to adult care (Lindell et al., 2015) Fewer discussions about diagnosis, treatment, late effects and screening in PCP versus specialized setting (Lindell et al., 2015)
No differences in psychological morbidities or PTSD (Blaauwbroek et al., 2007a) Accuracy of reporting general diagnosis high and treatment history low, in all survivors (Blaauwbroek et al., 2007a) Knowledge gained about late effects plateaued after the third visit (Hogan et al., 2013) Both groups underestimated their risk of late effects (Blaauwbroek et al., 2007a; Ganju et al., 2016) Satisfaction with care equally as high in survivors receiving care from PCP versus specialized cancer setting (Lindell et al., 2015)
Positive findings Increased detection (Cherven et al., 2014; Landier et al., 2015) Twice the incidence of endocrine and hormone-related late effects (Blaauwbroek et al., 2007a) Fewer hospitalizations and high acuity ED admissions (Szalda et al., 2015) More accurate reporting of attendance (Blaauwbroek et al., 2007a) Higher surveillance practices (Blaauwbroek et al., 2007a)
Lower alcohol consumption and current tobacco use (NS) (Blaauwbroek et al., 2007a) Better distress levels (Blaauwbroek et al., 2007a) Higher knowledge of specific diagnosis (Ford et al., 2013; Ganju et al., 2016) More discussions about late effects25 Higher knowledge of specific treatments (NS) (Ford et al., 2013; Ganju et al., 2016) Higher accuracy reporting risk of late effects (Kmet et al., 2004; Hogan et al., 2013; Ford et al., 2013; Ganju et al., 2016) No difference in knowledge gained when delivered by nurse or PCP (Hogan et al., 2013) Reduced ED visits even when adjusting for PCP-led care (Szalda et al., 2015)
Abbreviations: ED, Emergency Department; NS, not significant; PCP, Primary care physician; PTSD, post-traumatic stress disorder.
3.5. Follow-up care type Four of the survivorship clinics assessed were oncologist-led (Hogan et al., 2013; Blaauwbroek et al., 2007a; Ford et al., 2013; Lindell et al., 2015), one led by both an oncologist and nurse practitioner (Landier et al., 2015), and one led by a multidisciplinary team (Cherven et al., 2014). Two did not specify a lead clinician (Ganju et al., 2016; Sutradhar et al., 2015). Of the six studies which reported referring to LTFU guidelines, all used the Children’s Oncology Group (COG) risk-based guidelines, either formally or to some degree to inform their practice (Landier et al., 2004). All articles evaluated the impact of follow-up attendance at a specialized survivorship clinic, with one also including a comparison to PCP-led follow-up (Szalda et al., 2015). The delivery and setting did not appear to impact outcomes in CCS engaged in care, however few differences in the care received were observed. In one study examining ED visits in survivors, the link between clinic attendance and reduced ED visits remained strong, even after adjusting for annual physical examinations from a PCP and for continuity of primary care (Sutradhar et al., 2015). There were few differences in healthcare use between attendees and non-attendees. Forty-five percent of 80 US survivors became disengaged from specialized cancer care after transitioning from pediatric to adult care (Szalda et al., 2015). General healthcare use, and use of support services (support groups, physical/occupational therapy, financial assistance), in those who became disengaged was no different to those who remained in survivorship-focused care. However follow-up in the primary care setting appeared less survivorship-focused and survivors reported fewer cancer-related discussions with their PCP, significantly lower among survivors dis-
engaged from specialized follow-up (Szalda et al., 2015). However satisfaction with care was rated equally high in survivors receiving cancer-related follow-up from a PCP or specialist. Another study showed PCP-delivered care did not influence post-visit knowledge gains in previously disengaged survivors, compared with nursedelivered care (Landier et al., 2015). 4. Discussion Specialized follow-up was developed in response to growing concerns for survivors’ health and wellbeing following treatment for childhood cancer. Results of the nine studies eligible for our review generally supported improved detection of late effects, better health behaviors, improved knowledge, lower distress-levels, more accurate risk perception, and more appropriate healthcare use (for example seeking recommended screening, and reducing unnecessary use of services) in CCS engaged in LTFU. There was no difference in CCS’ self-reported overall health, satisfaction with care, and psychological morbidities or PTSD, and both attendees and non-attendees tended to underestimate their risk of late effects. There appeared to be no effect of the type of care offered on CCS’ outcomes, although there was some evidence that survivors receive less survivorship-focused care when cared for in non-specialized settings, suggesting follow-up in these settings may not be meeting their survivorship needs. Two studies in our review showed survivors re-engaging with a survivorship clinic had previously undiagnosed moderate to severe late effects (Hogan et al., 2013; Blaauwbroek et al., 2007a). Many survivors had a chronic condition, limited late effects knowledge, and some were completely unaware of their cancer history (Maeda
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et al., 2010). Given the prevalence and severity of late effects increase with time since diagnosis (Nathan et al., 2008; Oeffinger et al., 2004), which do not plateau with age (Blaauwbroek et al., 2007b), it may be worthwhile to provide additional late effects training and education to all survivors and follow-up care providers to improve appreciation of symptoms pointing to such complications and potentially reduce the burden of unmet information needs (Vetsch et al., 2016). Attendees demonstrated reduced ED visits and ED hospitalizations rates (Sutradhar et al., 2015). However it remains unclear if reduced ED visits can be attributed to clinic attendance specifically, and this Canadian study did not account for participants’ age at study participation or time of hospitalization as a potential confounding factor for increased visits and admissions. Previous research does show significantly greater healthcare use in attendees, and potentially higher satisfaction with care (Nathan et al., 2008; Kaul et al., 2016). Despite some evidence of an association between clinic attendance and reduced ED visits after adjusting for annual physical examinations from a PCP and continuity of primary care (Sutradhar et al., 2015), further research is also needed to evaluate whether ED visits are also reduced in those who seek follow-up from a PCP, compared with specialized cancer care. The paucity of data relating to the efficacy of PCP led follow-up should be addressed more generally, as well as internationally to account for differences in primary care delivery across countries. Poorer cancer-related knowledge among non-attendees (Ganju et al., 2016; Lindell et al., 2015), survivors’ declining understanding of late effects over time (Lindell et al., 2015), and underestimation of their risk of late effects (Cherven et al., 2014; Lindell et al., 2015), highlight the importance of regularly educating survivors about their treatment history, in order to reinforce their knowledge and understanding of risk of future late effects. Misreporting of late effects’ risks indicates survivors may not necessarily understand which late effects are personally relevant (Lindell et al., 2015). Empowering survivors with knowledge and selfmanagement skills have been linked to improved health, more appropriate health service use, and reduced healthcare costs (Lorig et al., 1999). Further resources and health provider time could therefore be allocated to address survivor and parent inaccuracies in risk perception (Cherven et al., 2014). Survivors with no/mild late effects, and engaged in follow-up (Blaauwbroek et al., 2007a), reported higher HRQoL, suggesting early detection and prevention of late effects, as well as recalling disengaged survivors to follow-up, may improve survivors’ wellbeing. PTSD has also been linked to HRQoL in other populations (Stoll et al., 2000). The lifetime prevalence of PTSD in healthy adults is 6.8% (Kessler et al., 2005), similar to that of CCS in this review, regardless of their attendance patterns (Ford et al., 2013). Lower HRQoL in non-attendees however indicates follow-up engagement may prevent psychological morbidities and improve survivors’ emotional wellbeing. Although attendees did not report higher anxiety in the included studies (Ford et al., 2013), care should be taken not to undermine survivors’ confidence and psychological recovery in the long term by overemphasizing their risks (Taylor et al., 2004). Only one eligible study in this review assessed the effectiveness of survivorship care in the primary care setting, or compared outcomes in survivors attending a specialized clinic versus PCP (Szalda et al., 2015), highlighting the importance of future research comparing different models of care. Information provision by a physician versus nurse practitioner did not appear to impact knowledge gains in previously disengaged survivors (Landier et al., 2015). Oncologist-led follow-up models of care are generally favored by survivors (Michel et al., 2009; Fardell, 2016), however purely hospital-based models may be unsustainable due to the growing population of long term survivors of childhood cancer
requiring lifelong care and regular surveillance. Risk-stratification of survivors to other settings, such as primary care, may help to alleviate these pressures. However, few studies systematically address the ‘effectiveness’ of receiving follow-up care from a PCP or in shared care, as compared with specialized survivorship care, although the area is gaining increasing attention in adult and pediatric oncology (Overholser et al., 2015; Grunfeld et al., 2006). The findings of this review suggest engagement in any type of follow-up is mostly beneficial for survivors, however the ideal model of care may vary based on different health care settings and local resources (e.g. private versus public, or geographical location). Less survivor-focused care, and fewer risk-based discussions, in the primary care setting may be explained by PCPs lack of familiarity with LTFU guidelines (Nathan et al., 2013; Suh et al., 2014), potentially improved through greater support and better communication with PCPs. Regardless of follow-up type, survivors rated their satisfaction with care highly (Szalda et al., 2015), indicating they may be unaware that such issues should be addressed or do not have the capacity/confidence to raise them. This highlights the need to also better equip survivors nearing transition, with clearer expectations of ongoing survivorship care and how to advocate for themselves in the adult setting. Previous research supports the notion that good communication with their health care provider, experienced in survivorship, increases survivor knowledge and understanding of their late effects and has prepared them to be advocates for their health, especially as they navigate the adult health care system (Fardell, 2016). Further efforts in evaluating the cost effectiveness of running specialized cancer clinics in comparison to follow-up in the primary care setting would also be valuable (Hollen and Hobbie, 1995), should the latter be shown to be equally as effective. This will provide a more sustainable alternative to survivorship centers which are resource-intensive and underfunded, helping manage the growing population of CCS. PCPs are well placed to provide holistic care, and have the potential to reduce unmet needs in this population (Emery, 2014). A limitation of this review is that it could not evaluate the potential impact of complementary support programs on survivors (Schultz and Mir, 2012; Martiniuk et al., 2011; Curran et al., 2012; Carter et al., 2012), since no studies systematically compared such differences, despite many survivors seeking such services alongside formal follow-up (Szalda et al., 2015). It was also beyond the scope of this review to consider benefits to future survivors, or survivorreported benefits or burdens, such as meeting other CCSs (Earle et al., 2005). Attending follow-up may be personally and emotionally valuable to survivors, but these factors were not captured by the studies eligible for this review. An inherent bias that cannot necessarily be controlled for was survivors’ motivation, which may have been higher among attendees, therefore impacting their outcomes. Whilst it may be expected that engaged survivors may be more motivated, it is possible that they may also be less or equally as motivated as compared to disengaged survivors. For example, they may attend clinic for reassurance that the cancer is not returning, but perceive themselves to be at low risk of other medical and psychosocial late effects, reducing their motivation to seek additional surveillance and specialist care (Cherven et al., 2014). This demonstrates a clear need for future research on the impact of motivation to attend on survivor outcomes, and its consequences for health during long term survivorship. A number of predictors of clinic attendance (younger age, higher socioeconomic status, living closer) may have also been associated with survivors’ outcomes (Klosky et al., 2008). While some studies did adjust for such factors, not all did, and there was little consistency between studies making direct comparisons difficult. However, considering few studies had conflicting findings, trends in the available evidence do suggest positive benefits for remaining engaged in regular follow-up. We were unable to comment
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on survivors’ outcomes after engagement in primarily oncologistled care, compared to attendance at a formal or multidisciplinary survivorship clinic, due to a lack of detail in the included articles. For the same reason, we cannot be sure that any type of care was received exclusively (e.g. primary care alone vs shared care with input from a survivorship clinic to the PCP) unless strictly reported. Future research is needed which clearly reports on these types of care, and evaluates the relative benefit of each model. Finally, the generalizability may be influenced, or limited by the fact that the majority of studies were conducted in the US. 5. Conclusion This review evaluating the impact of LTFU care is important and timely given the resources globally allocated to CCS follow-up care infrastructure, physician training, and guidelines. The healthrelated outcomes of CCS who do not remain in care are largely unknown. Whilst LTFU care is frequently recommended in the literature (Landier et al., 2004), few studies systematically and longitudinally evaluate the potential impact of LTFU attendance in pediatric cancer survivors. The results generally support the positive impact of follow-up on CCS’ physical and mental wellbeing, and highlight the potential gains of ensuring survivors are engaged in essential lifelong care following treatment for childhood cancer. These findings appear consistent across different models of care implemented, an important finding given the unsustainability of oncologist-led, hospital-based care, given the increasing numbers of survivors. However more research is essential. The findings also highlight the importance of streamlining the delivery of LTFU to ensure consistency with guidelines. It is also important for future research to measure clinical and psychosocial outcomes in survivors using validated and reliable measures. This will enable ongoing and more rigorous evaluations of the impact of different models of LTFU care. This will ultimately ensure follow-up care meets the needs of survivors, whilst reducing the long-term impact of childhood cancer and its treatment. Role of the funding source The funding bodies had no involvement in the execution of the study or preparation of this manuscript. Contributorship statement All authors were involved in the preparation of the manuscript, including data interpretation, editing and review. Authors CS, CW, RC and JF were involved in the conception and design of the study, as well as data analysis and interpretation, manuscript preparation, editing and review. CS and ER led the data acquisition, quality assessments and algorithms. Funding The Behavioural Sciences Unit is proudly supported by the Kids with Cancer Foundation, and its survivorship program is funded by a Cancer Council NSW Program Grant (PG16-02) with the support of the Estate of the Late Harry McPaul. Christina Signorelli and Joanna Fardell are supported by The Kids Cancer Project. Claire Wakefield is supported by a Career Development Fellowship from the NHMRC of Australia (APP1067501). Eden Robertson is supported by the Cancer Institute NSW Translational Program Grant (10/TPG/1-13). Competing interest statement The authors have no conflicts of interest to declare.
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Contents lists available at ScienceDirect
Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc
Review article
The impact of long-term follow-up care for childhood cancer survivors: A systematic review Christina Signorelli a,b,∗ , Claire E. Wakefield a,b , Joanna E. Fardell a,b , W. Hamish B. Wallace c , Eden G. Robertson a,b , Jordana K. McLoone a,b , Richard J. Cohn a,b a
Discipline of Paediatrics, School of Women’s and Children’s Health, UNSW Australia, Kensington, NSW, Australia Kids Cancer Centre, Sydney Children’s Hospital, NSW, Randwick, Australia c Department of Hematology/Oncology, Royal Hospital for Sick Children, Edinburgh, UK b
Contents 1. 2.
3.
4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.1. Data sources and searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.2. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 2.3. Screening and extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 2.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.1. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.2. Long term follow-up impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3. Medical impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3.1. Late effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3.2. Screening practices and health behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.3.3. Hospitalization/emergency department visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.4. Psychosocial impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.4.1. Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 3.4.2. Risk perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 3.4.3. Psychological morbidities and HRQoL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 3.5. Follow-up care type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Contributorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Competing interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
a r t i c l e
i n f o
Article history: Received 25 January 2017 Received in revised form 4 April 2017 Accepted 11 April 2017 Keywords: Pediatrics Oncology Survivorship Surveillance Long term follow-up
a b s t r a c t Objectives: Childhood cancer survivors are at risk of developing late treatment-related complications. In response, many hospitals worldwide have established follow-up clinics to monitor survivors as they age. However, there is limited evidence of the efficacy of these clinics in meeting the lifelong healthcare needs of survivors. In this review we collated evidence of the measurable impact of engagement in specialized survivorship care, on survivors’ medical and psychosocial outcomes. Design: We conducted a systematic review according to PRISMA guidelines, and assessed the quality of included studies using ‘QualSyst’. Data sources: We screened 641 abstracts in Medline, Embase and CINAHL, yielding 9 eligible articles (N = 5135 survivors).
∗ Corresponding author at: Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, NSW 2031, Australia. E-mail address: [email protected] (C. Signorelli). http://dx.doi.org/10.1016/j.critrevonc.2017.04.007 1040-8428/© 2017 Elsevier B.V. All rights reserved.
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Eligibility criteria for selecting studies: Articles were eligible if: participants were diagnosed with cancer prior to the age of 21; participants were classified as ‘survivors’ of childhood or adolescent cancer, usually defined as 5 years from diagnosis or 2 years from the end of treatment; studies evaluated the impact of engagement in long term follow-up (LTFU) care on medical, psychosocial or other outcomes in pediatric cancer survivors. Results: One article evaluated primary care physician-led follow-up and the remainder evaluated specialized survivorship clinics. Survivors attending follow-up care tended to demonstrate higher knowledge about their treatment and diagnosis (n = 2), and had more accurate late effects risk perception (n = 3). Attendees also engaged in increased more regular surveillance, had fewer emergency department visits/hospitalizations (n = 1), and more late effects detected (n = 3), than non-attendees. Conclusions: There is a dearth of literature systematically evaluating the medical and psychosocial impact of follow-up care. Research suggests however, survivors engaged in follow-up care have better health and educational outcomes, highlighting the need for lifelong survivorship care and ongoing late effects education for survivors. Recalling survivors who become disengaged with follow-up care is also valuable, as their risk of treatment-related complications rises with age. Further systematic evaluation is urgently needed. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Improvements in survival rates have resulted in growing concerns about childhood cancer survivors’ (CCS) risk of developing treatment-related conditions (Oeffinger et al., 2006). Survivors are vulnerable to medical and psychosocial ‘late effects’ that are often associated with aging (Oeffinger et al., 2006; Signorelli et al., 2016). Three in every four survivors experience a late effect of their cancer treatment, 37% of which may be life threatening (Geenen et al., 2007). However, early intervention may reduce morbidity due to late effects (Schwartz, 1999). Numerous guidelines therefore recommend lifelong care for CCS, sparked by the landmark Institute of Medicine report on the organization of long term follow-up guidelines and clinics (Landier et al., 2004; Wallace et al., 2013; Hewitt et al., 2003). The goal of follow-up care is to reduce the burden of late effects in CCS. Follow-up care is ideally comprehensive and interdisciplinary, focuses on preventing or managing late effects through surveillance, educates survivors on treatment-related complications, and encourages preventative lifestyle behaviors (Hollen and Hobbie, 1995). Risk-based anticipatory care received at long term follow-up clinics is recommended to reduce morbidities and mortality associated with treatment for pediatric cancer (Grossi, 1998). Engagement in follow-up is intended to foster ongoing education, screening, early detection, and where possible prevention, of late complications and second malignancies, facilitating early intervention when complications arise, and ultimately leading to improved medical and psychosocial outcomes in the long-term (Marina, 1997). Follow-up recommendations may differ for survivors, based on their diagnosis, and treatment type(s) and intensity (Edgar et al., 2013). Higher risk survivors often continue receiving their followup care through specialized Long Term Follow-Up (LTFU) clinics, usually at their treating hospital. Medium and low-risk survivors may be referred to their Primary Care Physician (PCP) for a sharedcare (joint participation from PCPs and specialists) or PCP-led model respectively. With demand on pediatric oncology services surpassing supply, other survivors are formally transitioned from their pediatric center to an adult service (primary care or hospitalbased), often depending on how they are risk-stratified (Henderson et al., 2010). Given the strong calls to offer LTFU care to CCS, increasing resources are being allocated worldwide to guideline and resource development (Henderson et al., 2010). Yet, up to 68.5% of long term survivors do not engage in any cancer related follow-up care (Nathan et al., 2008), and there are several patient-, provider-
and system-related barriers to care (Oeffinger, 2003). In particular, young adult survivors of childhood cancer often become disengaged from follow-up following the transition from pediatric to adult healthcare (Henderson et al., 2010; Freyer, 2010). Accordingly, interventions to re-engage CCS into long term follow-up are being developed (Edgar et al., 2012). However the efficacy and costeffectiveness of such care is yet to be established (Oeffinger and McCabe, 2006). A review of the evidence summarizing the impact of receiving long term follow-up care in CCS is therefore overdue (Tonorezos and Oeffinger, 2015). This systematic review aimed to evaluate the medical and psychosocial impact of attending a long term follow-up clinic or receiving specialized cancer care in the childhood cancer survivor population. Specifically, the review aimed to answer the following research questions: 1) What is the impact on CCS of attending LTFU, in comparison to not attending? 2) Is there a difference in the impact of LTFU care received by survivors at specialized survivorship clinics or centers, as compared to care in the primary care setting? 2. Methods 2.1. Data sources and searches This systematic review was guided by Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) procedures (Edgar et al., 2012).We searched three electronic databases (Medline, Embase, and CINAHL), Google Scholar and two grey literature databases (Trove and Open Grey), up to June 2016, and limited to English and human studies (See Supplemental Table 1 for the search algorithm). 2.2. Inclusion criteria Articles were eligible if: 1) Participants were diagnosed with cancer prior to the age of 21 2) Participants were classified as ‘survivors’ of childhood or adolescent cancer, usually defined as 5 years from diagnosis or 2 years from the end of treatment 3) Studies evaluated the impact of engagement in LTFU care on medical, psychosocial or other outcomes in pediatric cancer survivors
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Articles were not excluded based on the year in which they were published. As survivors may receive their care in either tertiary or primary care settings (or both), LTFU care was defined as any formal cancer-related care received, including from their PCP, through a survivorship clinic, specialized cancer center, or at their treating pediatric hospital (e.g. a LTFU clinic, led by an oncologist or a specialist nurse). Survivors engaged in any regular cancer-related survivorship care are classified as ‘attendees’, whilst those have not been in any such care for at least two years are defined as ‘non-attendees’. 2.3. Screening and extraction Two reviewers (CS and EGR) independently screened 641 abstracts after de-duplication, three of which were eligible for the review. The consistency between reviewers was high and any disagreements resolved by consensus. We sourced a further six articles by screening the reference lists of eligible articles and a general search in Google Scholar. Fig. 1 summarizes the screening and data extraction process, including exclusion reasons. Reviewer one (CS) extracted relevant data from all nine eligible articles. The second reviewer (EGR) extracted data for two included articles to confirm reliable extraction. 2.4. Quality assessment Two reviewers (CS and ER) assessed all eligible articles against a set of 14 criteria included in ‘QualSyst’ (Kmet et al., 2004). All criteria were equally weighted and studies were not excluded on the basis of a quality threshold (Supplemental Table 2). 3. Results 3.1. Study characteristics Nine articles described the impact of LTFU engagement, representing 5135 pediatric cancer survivors (range: 50–3912). Seven studies reported mean ages of survivors at study participation, ranging from 5–57years. Survivors’ mean age at diagnosis ranged from 0–21years, reported in four studies. Four of the nine articles compared outcomes in survivors before and after a follow-up visit(s) (Cherven et al., 2014; Hogan et al., 2013; Landier et al., 2015; Blaauwbroek et al., 2007a), while four articles compared outcomes between attendees and non-attendees (Ford et al., 2013; Ganju et al., 2016; Lindell et al., 2015; Szalda et al., 2015), and one was a retrospective cohort study (Sutradhar et al., 2015). Most studies were conducted in the United States (n = 7). Participants were mainly middle income, well-educated, living in urban areas, and all studies targeted English speakers and, in two studies, Spanish survivors (Cherven et al., 2014; Landier et al., 2015). 3.2. Long term follow-up impact Supplemental Table 3 summarizes the medical and psychosocial impact of LTFU. Primary outcomes included CCS’ knowledge of late effects, medical history and late effects risk (n = 4) (Cherven et al., 2014; Landier et al., 2015; Ganju et al., 2016; Lindell et al., 2015), newly detected late effects (n = 2) (Hogan et al., 2013; Blaauwbroek et al., 2007a), emergency department visits and hospitalization (n = 1) (Sutradhar et al., 2015), overall and mental health (n = 1) (Ford et al., 2013), and healthcare use, including surveillance practices (n = 1) (Szalda et al., 2015). The evidence suggests engagement in LTFU care has a mostly positive impact on CCSs’ outcomes (Table 1).
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3.3. Medical impact 3.3.1. Late effects Four studies assessed the impact of LTFU on prevalence of diagnosed late effects (Cherven et al., 2014; Landier et al., 2015; Ganju et al., 2016; Lindell et al., 2015). All highlighted disengaged CCS may be less aware of the late effects they experience. Two of these studies from the US (n = 213) and The Netherlands (n = 123) showed up to 34% of disengaged survivors attending clinic were diagnosed with previously undetected late effects requiring treatment and/or further surveillance (Hogan et al., 2013; Blaauwbroek et al., 2007a). Newly identified late effects were observed in almost 12% of disengaged survivors with no late effects’ history, including osteoporosis, and second malignancies (Hogan et al., 2013). In another US study (n = 173) attendees had more than twice the incidence of endocrine and hormone-related late effects compared with non-attendees, suggesting non-attendees may have several undiagnosed, and potentially treatable, late effects (Ford et al., 2013). 3.3.2. Screening practices and health behaviors One study assessing survivors’ health behaviors, provided some evidence of LTFU benefits (Ford et al., 2013). Self-reported health was generally high in both clinic attendees and non-attendees, and most reported a biannual general physical examination by their PCP, despite attendance. While many attendees (61%) accurately remembered they had previously visited survivorship clinics for follow-up, only 21% of non-attendees accurately reported their non-attendance. Although not significantly different, attendees reported lower alcohol consumption and current tobacco use, and higher surveillance practices (e.g. breast or dental examinations). 3.3.3. Hospitalization/emergency department visits Evidence of the impact of follow-up attendance on hospitalizations was limited to one retrospective medical record review of almost 4000 Canadian survivors (Sutradhar et al., 2015). Highacuity emergency department (ED; e.g. urgent, resuscitation) visits were significantly lower in clinic attendees. Survivors who had visited a clinic at least once demonstrated a 19% lower rate of ED visits compared with non-attendees, with every additional clinic visit thereafter associated with a 5% reduction in ED visits. At any one time, the cumulative incidence of ED visits remained significantly higher for individuals who had never attended clinic. 3.4. Psychosocial impact 3.4.1. Knowledge Four studies assessed the impact of follow-up on CCS’ knowledge relating to their cancer and late effects (Cherven et al., 2014; Ford et al., 2013; Ganju et al., 2016; Lindell et al., 2015). In one study comparing attendees with non-attendees, survivors’ accuracy of reporting their diagnosis was high and knowledge of treatment information poor, regardless of follow-up engagement (Ford et al., 2013). Non-attendees in two US studies (n = 222 and n = 93) had lower knowledge of their specific diagnosis (Ganju et al., 2016; Lindell et al., 2015), and reported fewer discussions about their late effects risks (Lindell et al., 2015). Although not statistically significant, non-attendees also reported lower knowledge of specific chemotherapy agents received, and surgical treatment (Ganju et al., 2016). Attendees were more accurate in recalling their specific chemotherapeutics and specific radiation treatment (Lindell et al., 2015), and future late effects risk (Ganju et al., 2016). In a pre-post study of survivors newly recruited to clinic, chemotherapy and late effects knowledge increased significantly 3 months postvisit, compared to before their clinic visit (Lindell et al., 2015). No such difference was observed between their one and three month
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Identification
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Records identified through database search: (Medline, Embase, and CINAHL)
762 abstracts meeting search criteria Duplicates excluded: n= 121
Screening
641 records Excluded due to incorrect format (conference abstracts, books, dissertations): n = 213
Eligibility
428 abstracts screened
6 full-texts assessed for eligibility
Excluded: - Not pediatrics (n=3) - Not cancer-related (n=1) - Not evaluating impact of LTFU (n=47) - A combination of 2 or more of the above (n=374)
3 eligible articles Included
Manual search: Reference list of relevant articles screened, and Google Scholar searched, for further eligible articles n=6 9 journal articles Fig. 1. Flow diagram for study selection and reasons for exclusion.
follow-up interview. Although knowledge declined slightly at 12 month follow-up, it remained significantly higher than prior to clinic visits (Lindell et al., 2015).
with time (Landier et al., 2015; Lindell et al., 2015), while accuracy of their perceived late effects risk declined significantly with time (Lindell et al., 2015).
3.4.2. Risk perception Attendees more accurately reported their late effects risk than non-attendees. However both groups underestimated their overall self-reported late effects risk, compared with physician-reported risk (Ford et al., 2013; Lindell et al., 2015). US adolescent survivors’ (n = 50) late effects knowledge increased significantly following their first follow-up visit (Cherven et al., 2014). Another study showed survivors prompted with a complete list of potential late effects identified themselves as being at risk of late effects for which they were not personally at risk of (Lindell et al., 2015). Late effects awareness in 369 previously disengaged US survivors almost doubled after three clinic visits, although knowledge gains plateaued after the third visit (Landier et al., 2015). Attendees’ accuracy of reporting their diagnosis and treatment history did not improve
3.4.3. Psychological morbidities and HRQoL No significant differences were observed between attendees and non-attendees in psychological morbidities, including post-traumatic stress disorder (Ford et al., 2013). Although not significant either, attendees tended to report higher distress levels than non-attendees. Survivors disengaged from follow-up with moderate/severe late effects, had significantly lower HRQoL than survivors with no/mild late effects, worst on physical and social functioning, vitality and general health perceptions scales (Blaauwbroek et al., 2007a).
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Table 1 Strength of evidence of the main impact of engagement in LTFU care. Negative findings Medical impact
Neutral findings
Late effects detected
Healthcare use
No difference in number of general physical exams (Blaauwbroek et al., 2007a) No difference in healthcare use, including complementary support services (Lindell et al., 2015) High self-reported overall health in all survivors (Blaauwbroek et al., 2007a)
General health Health behaviors
Psychological impact
Health-related quality of life Knowledge
Decline in knowledge 12 months post-visit (still higher than non-attendees) (Ganju et al., 2016)
Risk perception
Incorrectly reported late effects risk when prompted with a list (Ganju et al., 2016)
Impact of type of follow-up care
Many survivors became disengaged following transition to adult care (Lindell et al., 2015) Fewer discussions about diagnosis, treatment, late effects and screening in PCP versus specialized setting (Lindell et al., 2015)
No differences in psychological morbidities or PTSD (Blaauwbroek et al., 2007a) Accuracy of reporting general diagnosis high and treatment history low, in all survivors (Blaauwbroek et al., 2007a) Knowledge gained about late effects plateaued after the third visit (Hogan et al., 2013) Both groups underestimated their risk of late effects (Blaauwbroek et al., 2007a; Ganju et al., 2016) Satisfaction with care equally as high in survivors receiving care from PCP versus specialized cancer setting (Lindell et al., 2015)
Positive findings Increased detection (Cherven et al., 2014; Landier et al., 2015) Twice the incidence of endocrine and hormone-related late effects (Blaauwbroek et al., 2007a) Fewer hospitalizations and high acuity ED admissions (Szalda et al., 2015) More accurate reporting of attendance (Blaauwbroek et al., 2007a) Higher surveillance practices (Blaauwbroek et al., 2007a)
Lower alcohol consumption and current tobacco use (NS) (Blaauwbroek et al., 2007a) Better distress levels (Blaauwbroek et al., 2007a) Higher knowledge of specific diagnosis (Ford et al., 2013; Ganju et al., 2016) More discussions about late effects25 Higher knowledge of specific treatments (NS) (Ford et al., 2013; Ganju et al., 2016) Higher accuracy reporting risk of late effects (Kmet et al., 2004; Hogan et al., 2013; Ford et al., 2013; Ganju et al., 2016) No difference in knowledge gained when delivered by nurse or PCP (Hogan et al., 2013) Reduced ED visits even when adjusting for PCP-led care (Szalda et al., 2015)
Abbreviations: ED, Emergency Department; NS, not significant; PCP, Primary care physician; PTSD, post-traumatic stress disorder.
3.5. Follow-up care type Four of the survivorship clinics assessed were oncologist-led (Hogan et al., 2013; Blaauwbroek et al., 2007a; Ford et al., 2013; Lindell et al., 2015), one led by both an oncologist and nurse practitioner (Landier et al., 2015), and one led by a multidisciplinary team (Cherven et al., 2014). Two did not specify a lead clinician (Ganju et al., 2016; Sutradhar et al., 2015). Of the six studies which reported referring to LTFU guidelines, all used the Children’s Oncology Group (COG) risk-based guidelines, either formally or to some degree to inform their practice (Landier et al., 2004). All articles evaluated the impact of follow-up attendance at a specialized survivorship clinic, with one also including a comparison to PCP-led follow-up (Szalda et al., 2015). The delivery and setting did not appear to impact outcomes in CCS engaged in care, however few differences in the care received were observed. In one study examining ED visits in survivors, the link between clinic attendance and reduced ED visits remained strong, even after adjusting for annual physical examinations from a PCP and for continuity of primary care (Sutradhar et al., 2015). There were few differences in healthcare use between attendees and non-attendees. Forty-five percent of 80 US survivors became disengaged from specialized cancer care after transitioning from pediatric to adult care (Szalda et al., 2015). General healthcare use, and use of support services (support groups, physical/occupational therapy, financial assistance), in those who became disengaged was no different to those who remained in survivorship-focused care. However follow-up in the primary care setting appeared less survivorship-focused and survivors reported fewer cancer-related discussions with their PCP, significantly lower among survivors dis-
engaged from specialized follow-up (Szalda et al., 2015). However satisfaction with care was rated equally high in survivors receiving cancer-related follow-up from a PCP or specialist. Another study showed PCP-delivered care did not influence post-visit knowledge gains in previously disengaged survivors, compared with nursedelivered care (Landier et al., 2015). 4. Discussion Specialized follow-up was developed in response to growing concerns for survivors’ health and wellbeing following treatment for childhood cancer. Results of the nine studies eligible for our review generally supported improved detection of late effects, better health behaviors, improved knowledge, lower distress-levels, more accurate risk perception, and more appropriate healthcare use (for example seeking recommended screening, and reducing unnecessary use of services) in CCS engaged in LTFU. There was no difference in CCS’ self-reported overall health, satisfaction with care, and psychological morbidities or PTSD, and both attendees and non-attendees tended to underestimate their risk of late effects. There appeared to be no effect of the type of care offered on CCS’ outcomes, although there was some evidence that survivors receive less survivorship-focused care when cared for in non-specialized settings, suggesting follow-up in these settings may not be meeting their survivorship needs. Two studies in our review showed survivors re-engaging with a survivorship clinic had previously undiagnosed moderate to severe late effects (Hogan et al., 2013; Blaauwbroek et al., 2007a). Many survivors had a chronic condition, limited late effects knowledge, and some were completely unaware of their cancer history (Maeda
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et al., 2010). Given the prevalence and severity of late effects increase with time since diagnosis (Nathan et al., 2008; Oeffinger et al., 2004), which do not plateau with age (Blaauwbroek et al., 2007b), it may be worthwhile to provide additional late effects training and education to all survivors and follow-up care providers to improve appreciation of symptoms pointing to such complications and potentially reduce the burden of unmet information needs (Vetsch et al., 2016). Attendees demonstrated reduced ED visits and ED hospitalizations rates (Sutradhar et al., 2015). However it remains unclear if reduced ED visits can be attributed to clinic attendance specifically, and this Canadian study did not account for participants’ age at study participation or time of hospitalization as a potential confounding factor for increased visits and admissions. Previous research does show significantly greater healthcare use in attendees, and potentially higher satisfaction with care (Nathan et al., 2008; Kaul et al., 2016). Despite some evidence of an association between clinic attendance and reduced ED visits after adjusting for annual physical examinations from a PCP and continuity of primary care (Sutradhar et al., 2015), further research is also needed to evaluate whether ED visits are also reduced in those who seek follow-up from a PCP, compared with specialized cancer care. The paucity of data relating to the efficacy of PCP led follow-up should be addressed more generally, as well as internationally to account for differences in primary care delivery across countries. Poorer cancer-related knowledge among non-attendees (Ganju et al., 2016; Lindell et al., 2015), survivors’ declining understanding of late effects over time (Lindell et al., 2015), and underestimation of their risk of late effects (Cherven et al., 2014; Lindell et al., 2015), highlight the importance of regularly educating survivors about their treatment history, in order to reinforce their knowledge and understanding of risk of future late effects. Misreporting of late effects’ risks indicates survivors may not necessarily understand which late effects are personally relevant (Lindell et al., 2015). Empowering survivors with knowledge and selfmanagement skills have been linked to improved health, more appropriate health service use, and reduced healthcare costs (Lorig et al., 1999). Further resources and health provider time could therefore be allocated to address survivor and parent inaccuracies in risk perception (Cherven et al., 2014). Survivors with no/mild late effects, and engaged in follow-up (Blaauwbroek et al., 2007a), reported higher HRQoL, suggesting early detection and prevention of late effects, as well as recalling disengaged survivors to follow-up, may improve survivors’ wellbeing. PTSD has also been linked to HRQoL in other populations (Stoll et al., 2000). The lifetime prevalence of PTSD in healthy adults is 6.8% (Kessler et al., 2005), similar to that of CCS in this review, regardless of their attendance patterns (Ford et al., 2013). Lower HRQoL in non-attendees however indicates follow-up engagement may prevent psychological morbidities and improve survivors’ emotional wellbeing. Although attendees did not report higher anxiety in the included studies (Ford et al., 2013), care should be taken not to undermine survivors’ confidence and psychological recovery in the long term by overemphasizing their risks (Taylor et al., 2004). Only one eligible study in this review assessed the effectiveness of survivorship care in the primary care setting, or compared outcomes in survivors attending a specialized clinic versus PCP (Szalda et al., 2015), highlighting the importance of future research comparing different models of care. Information provision by a physician versus nurse practitioner did not appear to impact knowledge gains in previously disengaged survivors (Landier et al., 2015). Oncologist-led follow-up models of care are generally favored by survivors (Michel et al., 2009; Fardell, 2016), however purely hospital-based models may be unsustainable due to the growing population of long term survivors of childhood cancer
requiring lifelong care and regular surveillance. Risk-stratification of survivors to other settings, such as primary care, may help to alleviate these pressures. However, few studies systematically address the ‘effectiveness’ of receiving follow-up care from a PCP or in shared care, as compared with specialized survivorship care, although the area is gaining increasing attention in adult and pediatric oncology (Overholser et al., 2015; Grunfeld et al., 2006). The findings of this review suggest engagement in any type of follow-up is mostly beneficial for survivors, however the ideal model of care may vary based on different health care settings and local resources (e.g. private versus public, or geographical location). Less survivor-focused care, and fewer risk-based discussions, in the primary care setting may be explained by PCPs lack of familiarity with LTFU guidelines (Nathan et al., 2013; Suh et al., 2014), potentially improved through greater support and better communication with PCPs. Regardless of follow-up type, survivors rated their satisfaction with care highly (Szalda et al., 2015), indicating they may be unaware that such issues should be addressed or do not have the capacity/confidence to raise them. This highlights the need to also better equip survivors nearing transition, with clearer expectations of ongoing survivorship care and how to advocate for themselves in the adult setting. Previous research supports the notion that good communication with their health care provider, experienced in survivorship, increases survivor knowledge and understanding of their late effects and has prepared them to be advocates for their health, especially as they navigate the adult health care system (Fardell, 2016). Further efforts in evaluating the cost effectiveness of running specialized cancer clinics in comparison to follow-up in the primary care setting would also be valuable (Hollen and Hobbie, 1995), should the latter be shown to be equally as effective. This will provide a more sustainable alternative to survivorship centers which are resource-intensive and underfunded, helping manage the growing population of CCS. PCPs are well placed to provide holistic care, and have the potential to reduce unmet needs in this population (Emery, 2014). A limitation of this review is that it could not evaluate the potential impact of complementary support programs on survivors (Schultz and Mir, 2012; Martiniuk et al., 2011; Curran et al., 2012; Carter et al., 2012), since no studies systematically compared such differences, despite many survivors seeking such services alongside formal follow-up (Szalda et al., 2015). It was also beyond the scope of this review to consider benefits to future survivors, or survivorreported benefits or burdens, such as meeting other CCSs (Earle et al., 2005). Attending follow-up may be personally and emotionally valuable to survivors, but these factors were not captured by the studies eligible for this review. An inherent bias that cannot necessarily be controlled for was survivors’ motivation, which may have been higher among attendees, therefore impacting their outcomes. Whilst it may be expected that engaged survivors may be more motivated, it is possible that they may also be less or equally as motivated as compared to disengaged survivors. For example, they may attend clinic for reassurance that the cancer is not returning, but perceive themselves to be at low risk of other medical and psychosocial late effects, reducing their motivation to seek additional surveillance and specialist care (Cherven et al., 2014). This demonstrates a clear need for future research on the impact of motivation to attend on survivor outcomes, and its consequences for health during long term survivorship. A number of predictors of clinic attendance (younger age, higher socioeconomic status, living closer) may have also been associated with survivors’ outcomes (Klosky et al., 2008). While some studies did adjust for such factors, not all did, and there was little consistency between studies making direct comparisons difficult. However, considering few studies had conflicting findings, trends in the available evidence do suggest positive benefits for remaining engaged in regular follow-up. We were unable to comment
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on survivors’ outcomes after engagement in primarily oncologistled care, compared to attendance at a formal or multidisciplinary survivorship clinic, due to a lack of detail in the included articles. For the same reason, we cannot be sure that any type of care was received exclusively (e.g. primary care alone vs shared care with input from a survivorship clinic to the PCP) unless strictly reported. Future research is needed which clearly reports on these types of care, and evaluates the relative benefit of each model. Finally, the generalizability may be influenced, or limited by the fact that the majority of studies were conducted in the US. 5. Conclusion This review evaluating the impact of LTFU care is important and timely given the resources globally allocated to CCS follow-up care infrastructure, physician training, and guidelines. The healthrelated outcomes of CCS who do not remain in care are largely unknown. Whilst LTFU care is frequently recommended in the literature (Landier et al., 2004), few studies systematically and longitudinally evaluate the potential impact of LTFU attendance in pediatric cancer survivors. The results generally support the positive impact of follow-up on CCS’ physical and mental wellbeing, and highlight the potential gains of ensuring survivors are engaged in essential lifelong care following treatment for childhood cancer. These findings appear consistent across different models of care implemented, an important finding given the unsustainability of oncologist-led, hospital-based care, given the increasing numbers of survivors. However more research is essential. The findings also highlight the importance of streamlining the delivery of LTFU to ensure consistency with guidelines. It is also important for future research to measure clinical and psychosocial outcomes in survivors using validated and reliable measures. This will enable ongoing and more rigorous evaluations of the impact of different models of LTFU care. This will ultimately ensure follow-up care meets the needs of survivors, whilst reducing the long-term impact of childhood cancer and its treatment. Role of the funding source The funding bodies had no involvement in the execution of the study or preparation of this manuscript. Contributorship statement All authors were involved in the preparation of the manuscript, including data interpretation, editing and review. Authors CS, CW, RC and JF were involved in the conception and design of the study, as well as data analysis and interpretation, manuscript preparation, editing and review. CS and ER led the data acquisition, quality assessments and algorithms. Funding The Behavioural Sciences Unit is proudly supported by the Kids with Cancer Foundation, and its survivorship program is funded by a Cancer Council NSW Program Grant (PG16-02) with the support of the Estate of the Late Harry McPaul. Christina Signorelli and Joanna Fardell are supported by The Kids Cancer Project. Claire Wakefield is supported by a Career Development Fellowship from the NHMRC of Australia (APP1067501). Eden Robertson is supported by the Cancer Institute NSW Translational Program Grant (10/TPG/1-13). Competing interest statement The authors have no conflicts of interest to declare.
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