Journal of Medical Imaging and Radiation Oncology 58 (2014) 693–699 bs_bs_banner
R ADIATION O N C O LO GY —O R I G I N AL A RTICLE
Utility of an Australasian registry for children undergoing radiation treatment Verity Ahern* Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia
Abstract V Ahern MBBS, FRANZCR. Correspondence Dr Verity Ahern, Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, PO Box 533, Sydney, NSW 2073, Australia. Email: [email protected] Conflict of interest: None. *On behalf of present and past members of the Paediatric Special Interest Group of the Faculty of Radiation Oncology: Roger Allison, Scott Babington, Martin Borg, Jennifer Chard, Robyn Cheuk, John Childs, Joshua Dass, Mary Dwyer, Anthony Falkov, Sanjiv Gupta, David Hamilton, Chris Harrington, Hien Le, Andrew Potter, Andrew Pullar, Maree Sexton, Robert Smee, Mandy Taylor, Greg Wheeler, Phillip Yuile and Yvonne Zissiadis. Hospitals represented: Adelaide Radiotherapy Centre, Auckland City Hospital, Calvary Mater Newcastle, Christchurch Hospital, Mater Hospital Brisbane, Peter MacCallum Cancer Institute, Royal Adelaide Hospital, Royal Children’s Hospital Brisbane, Royal Perth Hospital, Prince of Wales Hospital, Sir Charles Gairdner Hospital, Wellington Hospital and Westmead Hospital.
Introduction: The aim of this study was to evaluate the utility of an Australasian registry (‘the Registry’) for children undergoing radiation treatment (RT). Methods: Children under the age of 16 years who received a course of radiation between January 1997 and December 2010 and were enrolled on the Registry form the subjects of this study. Results: A total of 2232 courses of RT were delivered, predominantly with radical intent (87%). Registrations fluctuated over time, but around one-half of children diagnosed with cancer undergo a course of RT. The most prevalent age range at time of RT was 10–15 years, and the most common diagnoses were central nervous system tumours (34%) and acute lymphoblastic leukaemia (20%). Conclusions: The Registry provides a reflection of the patterns of care of children undergoing RT in Australia and a mechanism for determining the resources necessary to manage children by RT (human, facilities and emerging technologies, such as proton therapy). It lacks the detail to provide information on radiotherapy quality and disease outcomes which should be the subject of separate audit studies. The utility of the Registry has been hampered by its voluntary nature and varying needs for consent. Completion of registry forms is a logical requirement for inclusion in the definition of a subspecialist in paediatric radiation oncology. Key words: paediatrics; radiotherapy; registries.
Submitted 23 March 2014; accepted 21 June 2014. doi:10.1111/1754-9485.12215
Introduction The Paediatric Radiation Oncology Registry commenced in 1997 to gather information about the number of children in Australia and New Zealand undergoing a course of radiation treatment (RT), their diagnoses and RT site, dose and treatment intent, and whether the child was enrolled on a clinical trial. © 2014 The Royal Australian and New Zealand College of Radiologists
An analysis of the patterns of care for the first 30-month cohort of 348 patients registered was presented at the Annual Scientific Meeting of the Royal Australia and New Zealand College of Radiologists (RANZCR) 1999 (Ahern and Cakir, Patterns of practice in paediatric radiotherapy – a report on the paediatric database) and the International Society of Paediatric Oncology (SIOP) in 2001.1 The key findings were that close to 693
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50% of children with a diagnosis of cancer undergo a course of RT at some stage during their disease course, although there was some variation in this rate according to treating centre resulting in discussions with paediatric oncologists locally. Enrolment of children to the Registry was comprehensive during this initial era. Subsequently, the Registry has been used to identify and report on a cohort of children undergoing RT for medulloblastoma, palliation and total body irradiation.2–4 Over the years, enrolment of children to the Registry has diminished, although the members of the RANZCR Paediatric Special Interest Group (SIG) have supported the Registry’s continuation. The aim of the present study was to evaluate the utility of the Registry in order to inform whether the Registry should remain active.
250
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0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Fig. 1. Number of episodes (N = 2232) of radiation treatment registered by year of registration. , all episodes; , episode 1.
Methods The prospective Registry commenced in January 1997, and the current analysis included all children under the age of 16 years at the time of RT, enrolled to the end of December 2010. Enrolment of a child to the Registry has been a voluntary activity. New Zealand regulations mandated patient or delegate consent for enrolment to the Registry throughout this time period, although privacy laws requiring patient or delegate consent only became enacted in Australia in around 2001. Since then, each jurisdiction enrolling patients on the Registry has gained approval from their ethics committee to do so. Patients or their delegates are provided with a patient information sheet as a component of obtaining consent for enrolment on the Registry. Approval for the Registry itself was obtained from the Human Research Ethics Committee of Western Sydney Area Health Service when that became necessary. The data collection form did not change over the study period and has remained a hard copy document forwarded to the Crown Princess Mary Cancer Centre. It included fields for gender, age at diagnosis and RT, tumour diagnosis, treatment centre, enrolment on a clinical trial, treatment intent (cure or palliation), dates of RT, site treated, and dose and fractionation schedule. A field to record treatment technique and the use of sedation or anaesthesia was added in January 2012. The data collection form has been available on the RANZCR website previously. Each course of treatment required completion of a separate data collection form. Members of the Paediatric SIG were contacted on multiple occasions during 2010 and 2011 to complete data collection forms, and a RANZCR College Research Grant was available for sites to offset data management time for this activity. The quantitative data were analysed using standard descriptive statistics, mean, median, minimum and maximum, where appropriate. The categorical data were analysed using counts and percentage frequency. 694
Results A total of 2232 courses of RT were delivered during the study period, 88% (N = 1962) of which were first courses. Registrations varied by year and treatment centre, with most occurring in the initial three-year time period (Figs 1,2). Of those children receiving a first course of RT, 59% (N = 1151) were male. The most prevalent age range at time of diagnosis and RT was 10–15 years (Fig. 3). Just over 200 children under the age of three years received a course of RT, although a greater number of children were diagnosed in this young age group indicating RT was deferred for some children until over the age of three years.
Fig. 2. Number of first courses of radiation treatment (N = 1962) registered by , Centre 1; , Centre 2; treatment centre and year of registration. , Centre 3; , Centre 4; , Centre 5; , Centre 6; , Centre 7; , Centre NZ; , all others combined. © 2014 The Royal Australian and New Zealand College of Radiologists
Utility of a paediatric radiotherapy registry
900
14, 2%
41% 800
59, 9%
16, 2% 34%
700
33%
19, 3%
30%
600
185, 28% 500
41, 6%
19%
400
17%
16%
300 10% 200
67, 10% 100 0 Age at diagnosis
Age at radiaon
Fig. 3. Age of children at diagnosis and radiation treatment (N = 1962). years; , 3–5 years; , 5–10 years; , 10–16 years.
100, 15% , 0–3
72, 11%
90, 14% The most prevalent diagnosis was acute lymphoblastic leukaemia or a central nervous system tumour, most often medulloblastoma (Figs 4,5). A total of 55 episodes of RT were delivered for benign tumours (craniopharyngioma, N = 25; arterio-venous malformation, N = 16; meningioma, N = 10; Langerhans cell histiocytosis, N = 4). Of interest, 13 children received RT for nasopharyngeal cancer, six for malignant thyroid tumours and three for melanoma.
397 (20%)
663 (34%)
156 (8%)
141 (7%)
45 (2%)
123, (%)
115 (6%) 95 (5%)
98 (5%)
69 (4%) 60 (3%) Fig. 4. Frequency of diagnoses (N = 1962). , acute leukaemias; , neuroblastoma; , rhabdomyosarcoma; , Wilms; , Ewing sarcoma; , other sarcoma; , Hodgkin lymphoma; , other lymphoma, leukaemia, anaemia; , other; , benign; , central nervous system. © 2014 The Royal Australian and New Zealand College of Radiologists
Fig. 5. Frequency of central nervous system tumours (N = 663). , medulloblastoma; , brainstem glioma; , ependymoma; , glioma, high grade; , intracranial germ cell tumour; , glioma, low grade; , spinal cord tumour; , visual pathway glioma; , atypical teratoid rhabdoid tumour; , other.
Craniospinal RT was the technique employed for 13% of all treatment episodes (284/2232), total body irradiation for 13% (291/2232), and prophylactic cranial RT for 6% (135/2232). RT intent was palliative for 380 of 2232 episodes (17%), representing 10% of first RT episodes (202/ 1962) and 58% of second episodes (120/206). The third episode of RT was still given with curative intent on 14% of occasions (6/42). A small number of children received more than three courses of RT (N = 12), all with palliative intent. A majority of children receiving a first course of treatment were recorded as being ‘entered to a protocol’ (55%, 1079/1962), with 31% of these patients entered to ANZCHOG studies (N = 332), 23% to Children’s Oncology Group of North America studies (N = 252), 7% to St Jude Children’s Hospital studies (N = 71) and 4% to SIOP studies (N = 42). It is probable that some or many of these patients were treated ‘according to’ a protocol rather than enrolled on a study.
Discussion In the 14 years to the end of 2010, the Registry recorded 2232 courses of RT delivered to children under the age of 16 years in Australia and New Zealand, an annual rate of around 160 courses. Almost all registrations were from Australia, and annual registration numbers varied considerably. The vast majority of treatments were deliv695
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ered with radical intent, and the most commonly treated tumours were acute lymphoblastic leukaemia and medulloblastoma.
Comparison with other registries The Australian Paediatric Cancer Registry (APCR) is ‘one of the few population-based childhood cancer registries in the world’ and records a stable annual incidence of cancer after the mid-1990s at around 620 cases annually for children under15 years of age.5 We are not aware of any population-based registry other than our own which records courses of RT delivered to children, although population-based cancer registries for children are advocated because of the rarity of childhood cancer.6
Strengths and limitations of the Registry The registry is not complete, and the variation in annual registrations is not likely to be a reflection of changes in RT practice over the study period for two reasons. First, there were 194 enrolments during 2010 when there was a significant effort at all centres to enrol patients due to the College research grant, and this is around the same number of children who were enrolled during each of the first three years of the registry. Second, NSW Health records all courses of RT delivered through the Radiotherapy Management System (RMIS).7 During 2008, RMIS records that 99 children under the age of 15 years underwent a course of RT, while the Registry records that 30 patients received a course of RT, and there were 172 new cases of cancer in children less than 15 years of age in NSW.8 This indicates a true RT utilisation rate of 57% and that only around one-third of RT courses in NSW children were recorded in the Registry in 2008. The 57% RT utilisation rate concords with the rate determined from the first three years of the Registry.1 Courses of RT recorded in the Registry are not crosslinked with APCR records. Patients under the age of 16 years are enrolled in the Registry, while APCR enrols patients less than 15 years of age. The APCR categorises patients according to the International Classification of Childhood Cancers-3 which includes non-malignant intracranial and intraspinal tumours.9 We have not retrospectively re-classified diagnoses for Registry patients. The differences in age and tumour diagnoses between the Registry and the APCR will lead to some inaccuracies in our evaluation, but this is not likely to be large. There are several possible reasons why enrolments to the Registry are incomplete. Enrolment is a voluntary activity with no incentive attached for radiation oncologists. Furthermore, not all radiation oncologists managing children may agree with enrolling patients on a Registry for which they do not feel ownership. Some children may be managed by radiation oncologists who are unaware of the Registry. Consent to the Registry is necessary with different Human Research and Ethics 696
Committees (HREC) developing their own versions of a consent form, including the need for separate patient information sheets and consent forms appropriate for 14-year-olds and eight-year-olds requested by one HREC. Interpretation of New Zealand privacy laws has varied, with some jurisdictions failing to allow de-identified patient information to be sent to an Australian centre. In one small Australian survey of medical oncologists, bureaucratic ethics processes was identified as a barrier to recruitment to clinical trials, as were lack of infrastructure support and lack of time.10 Clinician behaviour may be an another hindrance to recruitment to the Registry, as identified in a systematic review of the literature on obstacles to recruitment to cancer clinical trials.11 The Registry does not record patient outcomes, namely, disease control or RT toxicity. To do so would require additional time from clinicians and data management time centrally. However, this means that any research study requiring outcome information from a cohort of registered patients will need submission of a separate request to the HREC of each jurisdiction. Without knowing patient outcomes, we do not know whether the standard of paediatric radiation therapy varies between centres across Australia and New Zealand or meets international standards. This is the strongest reason for universal participation in the Registry and expanding the Registry to include a core set of outcome measures such as acute radiotherapy toxicity, local control, disease-free survival and late radiotherapy toxicity. Nevertheless, the five-year survival rate for all children with cancer treated 1997–2006 in Australia (79%) is similar to rates in other high-income nations; radiotherapy quality contributes to this achievement.12
How the Registry could be used The large patient cohort can provide meaningful information to the paediatric RT community locally and internationally in a number of areas. For example, we can identify where prospective studies are feasible across Australasia, and we can provide an estimate of patient numbers available for international collaborative studies. The Registry could be used as a source of identifying patients for audits such as local control outcomes in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma where our heterogeneous group of patients with a range of tumour characteristics and treatments could provide value. Long-term effects of RT could also be evaluated as demonstrated by a publication from the German Group of Pediatric Radiation Oncology.13 Such reports have not resulted from the Registry. This may be due to the complex issues of consent but also to the lack of clinician time. The Registry demonstrates that radiation oncologists managing children in Australia are willing to enrol children on clinical trials, but their clinical workload is probably greater than average; little account is taken of © 2014 The Royal Australian and New Zealand College of Radiologists
Utility of a paediatric radiotherapy registry
subspecialisation in paediatrics in workload calculations in Faculty of Radiation Oncology documents.14 Our group estimates that the time required to assess, plan and treat a new paediatric cancer patient for RT compared with a new adult cancer patient is a 3:1 ratio. The only Australian data to support this opinion at least in part come from the NSW RMIS where a paediatric case under sedation is allocated treatment time equivalent to three adult patients.7 The German Society of Radiation Oncology (DEGRO) has recently published the results of the QUIRO study to document the resource requirements for delivery of high-quality RT to paediatric and adolescent patients.15 Across three radiotherapy centres, the consultant time required to manage children undergoing RT without general anaesthesia was 42 minutes for first consultation, 87 minutes attending multidisciplinary meetings, 38 minutes defining organs at risk and target volumes, 27 minutes obtaining consent, and 366 minutes for all activities combined. This compares, allowing for some differences in resources examined, to 144 minutes consultant time for a breast cancer patient who will receive 25-fraction course of breast RT and 244 minutes consultant time for patients undergoing hypofractionated intracranial stereotactic radiotherapy (19% of 21.43 hours).16,17 An audit tool or a component of a reflective diary for continuing medical education is an obvious application of enrolling patients on the Registry. An informal survey of radiation oncologists managing children in Australia and New Zealand in 2013 found that only four of 11 respondents had undertaken a postgraduate fellowship in paediatrics (V. Ahern, pers. comm., 2013), indicating a need for continuing education and peer review in managing children. The paediatric SIG of the Faculty of Radiation Oncology of the RANZCR recently instituted a fortnightly case conference by video or teleconference in recognition of the need for peer review, following the Swedish model.18 Adding a core set of outcome measures to the Registry could be introduced as a method of obtaining Continuing Professional Development points and as a mandatory requirement for the title of a sub-specialist in paediatric radiation oncology. A computer-based efficient clinical information processing system to enhance a tumour registry was reported in 1992, and there is an opportunity to identify an appropriate system for the Registry.19 Combining the ACPR and the Registry into a single entity is one potential method of improving participation in the Registry, streamlining consent processes, and obtaining and recording outcome measures. The practicalities and costs of doing so will need to be discussed over the coming months. This will also be an opportunity to review all registry data fields to ensure relevance and clarity. Contributing to policy and planning is a recommended use of population-based cancer registries.20 Relevant policy and planning issues in Australia and New Zealand are whether children should be treated in all radio© 2014 The Royal Australian and New Zealand College of Radiologists
therapy centres rather than only certain centres, how radiation oncologists are trained in paediatrics, planning for survivorship services, and the optimal radiation technologies for managing children. With around 550 cases of paediatric cancer diagnosed annually, the Dutch are working towards a single cancer centre for the management of children, meaning that only a small proportion of radiation oncologists will need subspecialty training in the management of children.21 The decision to centralise childhood cancer services was based on the findings of a systematic review regarding the volume effect in paediatric oncology which supported the view that high-volume hospitals, high case providers and specialised hospitals achieve better patient outcomes.22 A minimum of five cases per year was defined as high volume, and almost all Australian and New Zealand centres managing children meet or far exceed this. Centralising cancer services for children to one site in Australia is not a practical solution due to geographical constraints. There is some evidence that low case volume can be overcome by membership of a collaborative group.23 Gutierrez et al.23 found that patients with Wilms tumour have a significantly better overall survival when enrolled on a Children’s Oncology Group (COG) study than not, although for those enrolled at a COG site, overall survival was still better when treatment was at a centre managing high rather than low volumes of children. Most centres managing children in Australia and New Zealand are members of COG. Meeting and maintaining standards are a recognised corollary of collaborative group membership, so Australian and New Zealand centres can be assumed to be delivering an acceptable standard of RT.24 The Registry, in combination with data from the APCR, can provide a reasonable estimate of how many children may become long-term survivors of childhood cancer and require transition care to adult cancer services. It also provides a basis for estimating the numbers of children who may be considered for hadron therapy. Not all children will be suitable for curative treatment or benefit from RT, or preferentially from hadron therapy. The United Kingdom, Denmark and the province of Alberta in Canada have developed guidelines regarding which children should receive proton therapy, and Australian and New Zealand guidelines are near completion.25–27 The published guidelines broadly include children with the following diagnoses for referral for proton therapy: base of skull chordoma and chondrosarcoma, ependymoma, Ewing sarcoma, intracranial germ cell tumour, rhabdomyosarcoma (head and neck, para-meningeal and pelvic), para-spinal soft tissue sarcoma, retinoblastoma, Hodgkin lymphoma, craniopharyngioma, and low-grade astrocytoma. Based on APCR data, there are around 180 children diagnosed with these tumours annually. However, only a small proportion of children with low-grade gliomas or retinoblastoma receive RT. If this proportion is set at 20% for the 697
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purposes of this exercise, the number would decrease to around 120. Accounting for age criteria, palliative intent of treatment, poor prospect of survival for some children at diagnosis, and the fact that RT may be avoided entirely for some patients (e.g. brain tumours in children under three years of age and some patients with Hodgkin Lymphoma), around 100 courses of treatment by protons would be required annually in Australia.
7.
8.
9.
Conclusions The Registry has provided an overview of the management of children with cancer in Australia by RT. It is a rich research resource which could lead to better RT care of children, and its continuation with addition of outcome measures is recommended. Enrolling children on the registry is an obvious requirement for recognition as a sub-specialist in paediatric radiation oncology, although further debate needs to occur within the SIG and among the broader College membership regarding how we recognise sub-specialisation in a self-regulated profession.
Acknowledgements A Royal Australian and New Zealand College of Radiologists Research Grant (2010–2011) assisted the collection of data for this study. This manuscript was presented in part at the Annual Scientific Meeting of the International Society of Paediatric Oncology, Auckland 2011. Ms S Varadarajan, Ms S Cross and Ms T PearlLarsson at Crown Princess Mary Cancer Centre have managed the Registry over the years.
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the global burden of childhood cancer. Lancet Oncol 2013; 14: e125–35. NSW Ministry of Health. NSW Radiotherapy Management Information System report, years 1997–2012, (M Huxtable, 6 November 2013). Tracey E, Kerr T, Dobrovic A, Currow D. Cancer in NSW: Incidence and Mortality Report 2008. Cancer Institute NSW, Sydney, 2010. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International classification of childhood cancer, third edition. Cancer 2005; 103: 1457–67. Dear RF, Barratt AL, Tattersall MHN. Barriers to recruitment in cancer trials: no longer medical oncologists’ attitudes. Med J Aust 2012; 196: 112–13. Grand MM, O’Brien PC. Obstacles to participation in randomised cancer clinical trials: a systematic review of the literature. J Med Imaging Radiat Oncol 2012; 56: 31–9. Baade PD, Youlden DR, Valery PC, Hassall T, Ward L, Green AC, Aitken JF. Population-based survival estimates for childhood cancer in Australia during the period 1997–2006. Br J Cancer 2010; 103: 1663–70. Selo N, Bölling T, Ernst I, Pape H, Martini C, Rübe C, Timmerman B, Fischedick K, Kortman R-D, Gerß J, Koch R. Acute toxicity profile of radiotherapy in 690 children and adolescents: RiSK data. Radiother Oncol 2010; 97: 119–26. Faculty of Radiation Oncology, Report on Contemporary Practice: the number of new patients per year. The Royal Australian and New Zealand College of Radiologists, 20 May 2011. Zabdel-du Bois A, Milker-Zabel S, Bruns F, Christiansen H, Ernst I, Willich W, Debus J, Sack H. Evaluation of time, attendance of medical staff and resources for radiotherapy in pediatric and adolescent patients. The DEGRO-QUIRO trial. Strahlenther Onkol 2014; 190: 582–90. Blank E, Willich N, Fietkau R, Popp W, Schaller-Steiner J, Sack H, Wentz F. Evaluation of time, attendance of medical staff, and resources during radiotherapy for breast cancer patients. The DEGRO-QUIRO trial. Strahlenther Onkol 2012; 188: 113–19. Zabel-du Bois A, Miljer-Zabel S, Henzel M, Popp W, Sack H, Engenhart-Cabillic R. Evaluation of tie, attendance of medical staff, and resources during stereotactic radiotherapy/radiosurgery. QUIRO-DEGRO Trial. Strahlenther Onkol 2012; 188: 769–75. Kristensen I, Lindh J, Nilsson P, Agrup M, Bersgtröm P, Bjork-Erikssön T et al. Telemedicine as a tool for sharing competence in paediatric radiotherapy – Implementation and initial experiences from a Swedish project. Acta Oncol (Madr) 2009; 48: 146–52. Goldwein JW. A prototype radiation oncology clinical information system on a personal computer
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(network). Int J Radiat Oncol Biol Phys 1992; 23: 633–7. European Network of Cancer Registries, International Agency for Research on Cancer. Guidelines on confidentiality and ethics for population-based cancer registration and linked activities in Europe. Version 3. [Cited August 2013.] Available from URL: www.eurocourse.org/mm_files/do_944/D2.2.pdf. May 2011. Pritchard-Jones K, Pieters R, Reaman GH, Hjorth L, Downie P, Calaminus G et al. Sustaining innovation and improvement in the treatment of childhood cancer: lessons from high-income countries. Lancet Oncol 2013; 14: e95–103. Knops RRG, van Dalen EC, Mulder RL, Leclercq E, Knijnerburg SL, Kaspers GJL, Pieters R, Caron HN, Kremer LCM. The volume effect in paediatric oncology: a systematic review. Ann Oncol 2013; 24: 1749–53. Gutierrez JC, Cheung MC, Zhuge Y, Koniaris LG, Sola JE. Does Children’s Oncology Group hospital membership improve survival for patients with
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neuroblastoma or Wilms tumor? Pediatr Blood Cancer 2010; 55: 621–8. Murphy SB. Positive benefits of cooperative group membership: being part of a networked rapid learning system. Pediatr Blood Cancer 2010; 55: 601–2. Crellin A. Guidance for the referral of patients abroad for NHS proton treatment. Version 2.1. [Cited 29 June 2011.] Available from URL: www.ncg.nhs.uk/ index.php/key-documents/proton-therapy. March 2010. The Danish National Center for Particle Radiotherapy. The Danish National Center for Particle Therapy. [Cited 10 June 2013.] Available from URL: www.rm.dk/files/Aktuelt/grafik/PDF/111003 _partikelaccelerator/The%20Danish%20National %20Center%20for%20Particle%20Radiotherapy.pdf. 2011. Alberta Health Services. Clinical practice guideline RT-002 Version 1. Proton beam radiation therapy. [Cited 8 March 2013.] Available from URL: www.albertahealthservices.ca.
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R ADIATION O N C O LO GY —O R I G I N AL A RTICLE
Utility of an Australasian registry for children undergoing radiation treatment Verity Ahern* Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia
Abstract V Ahern MBBS, FRANZCR. Correspondence Dr Verity Ahern, Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, PO Box 533, Sydney, NSW 2073, Australia. Email: [email protected] Conflict of interest: None. *On behalf of present and past members of the Paediatric Special Interest Group of the Faculty of Radiation Oncology: Roger Allison, Scott Babington, Martin Borg, Jennifer Chard, Robyn Cheuk, John Childs, Joshua Dass, Mary Dwyer, Anthony Falkov, Sanjiv Gupta, David Hamilton, Chris Harrington, Hien Le, Andrew Potter, Andrew Pullar, Maree Sexton, Robert Smee, Mandy Taylor, Greg Wheeler, Phillip Yuile and Yvonne Zissiadis. Hospitals represented: Adelaide Radiotherapy Centre, Auckland City Hospital, Calvary Mater Newcastle, Christchurch Hospital, Mater Hospital Brisbane, Peter MacCallum Cancer Institute, Royal Adelaide Hospital, Royal Children’s Hospital Brisbane, Royal Perth Hospital, Prince of Wales Hospital, Sir Charles Gairdner Hospital, Wellington Hospital and Westmead Hospital.
Introduction: The aim of this study was to evaluate the utility of an Australasian registry (‘the Registry’) for children undergoing radiation treatment (RT). Methods: Children under the age of 16 years who received a course of radiation between January 1997 and December 2010 and were enrolled on the Registry form the subjects of this study. Results: A total of 2232 courses of RT were delivered, predominantly with radical intent (87%). Registrations fluctuated over time, but around one-half of children diagnosed with cancer undergo a course of RT. The most prevalent age range at time of RT was 10–15 years, and the most common diagnoses were central nervous system tumours (34%) and acute lymphoblastic leukaemia (20%). Conclusions: The Registry provides a reflection of the patterns of care of children undergoing RT in Australia and a mechanism for determining the resources necessary to manage children by RT (human, facilities and emerging technologies, such as proton therapy). It lacks the detail to provide information on radiotherapy quality and disease outcomes which should be the subject of separate audit studies. The utility of the Registry has been hampered by its voluntary nature and varying needs for consent. Completion of registry forms is a logical requirement for inclusion in the definition of a subspecialist in paediatric radiation oncology. Key words: paediatrics; radiotherapy; registries.
Submitted 23 March 2014; accepted 21 June 2014. doi:10.1111/1754-9485.12215
Introduction The Paediatric Radiation Oncology Registry commenced in 1997 to gather information about the number of children in Australia and New Zealand undergoing a course of radiation treatment (RT), their diagnoses and RT site, dose and treatment intent, and whether the child was enrolled on a clinical trial. © 2014 The Royal Australian and New Zealand College of Radiologists
An analysis of the patterns of care for the first 30-month cohort of 348 patients registered was presented at the Annual Scientific Meeting of the Royal Australia and New Zealand College of Radiologists (RANZCR) 1999 (Ahern and Cakir, Patterns of practice in paediatric radiotherapy – a report on the paediatric database) and the International Society of Paediatric Oncology (SIOP) in 2001.1 The key findings were that close to 693
V Ahern
50% of children with a diagnosis of cancer undergo a course of RT at some stage during their disease course, although there was some variation in this rate according to treating centre resulting in discussions with paediatric oncologists locally. Enrolment of children to the Registry was comprehensive during this initial era. Subsequently, the Registry has been used to identify and report on a cohort of children undergoing RT for medulloblastoma, palliation and total body irradiation.2–4 Over the years, enrolment of children to the Registry has diminished, although the members of the RANZCR Paediatric Special Interest Group (SIG) have supported the Registry’s continuation. The aim of the present study was to evaluate the utility of the Registry in order to inform whether the Registry should remain active.
250
200
150
100
50
0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Fig. 1. Number of episodes (N = 2232) of radiation treatment registered by year of registration. , all episodes; , episode 1.
Methods The prospective Registry commenced in January 1997, and the current analysis included all children under the age of 16 years at the time of RT, enrolled to the end of December 2010. Enrolment of a child to the Registry has been a voluntary activity. New Zealand regulations mandated patient or delegate consent for enrolment to the Registry throughout this time period, although privacy laws requiring patient or delegate consent only became enacted in Australia in around 2001. Since then, each jurisdiction enrolling patients on the Registry has gained approval from their ethics committee to do so. Patients or their delegates are provided with a patient information sheet as a component of obtaining consent for enrolment on the Registry. Approval for the Registry itself was obtained from the Human Research Ethics Committee of Western Sydney Area Health Service when that became necessary. The data collection form did not change over the study period and has remained a hard copy document forwarded to the Crown Princess Mary Cancer Centre. It included fields for gender, age at diagnosis and RT, tumour diagnosis, treatment centre, enrolment on a clinical trial, treatment intent (cure or palliation), dates of RT, site treated, and dose and fractionation schedule. A field to record treatment technique and the use of sedation or anaesthesia was added in January 2012. The data collection form has been available on the RANZCR website previously. Each course of treatment required completion of a separate data collection form. Members of the Paediatric SIG were contacted on multiple occasions during 2010 and 2011 to complete data collection forms, and a RANZCR College Research Grant was available for sites to offset data management time for this activity. The quantitative data were analysed using standard descriptive statistics, mean, median, minimum and maximum, where appropriate. The categorical data were analysed using counts and percentage frequency. 694
Results A total of 2232 courses of RT were delivered during the study period, 88% (N = 1962) of which were first courses. Registrations varied by year and treatment centre, with most occurring in the initial three-year time period (Figs 1,2). Of those children receiving a first course of RT, 59% (N = 1151) were male. The most prevalent age range at time of diagnosis and RT was 10–15 years (Fig. 3). Just over 200 children under the age of three years received a course of RT, although a greater number of children were diagnosed in this young age group indicating RT was deferred for some children until over the age of three years.
Fig. 2. Number of first courses of radiation treatment (N = 1962) registered by , Centre 1; , Centre 2; treatment centre and year of registration. , Centre 3; , Centre 4; , Centre 5; , Centre 6; , Centre 7; , Centre NZ; , all others combined. © 2014 The Royal Australian and New Zealand College of Radiologists
Utility of a paediatric radiotherapy registry
900
14, 2%
41% 800
59, 9%
16, 2% 34%
700
33%
19, 3%
30%
600
185, 28% 500
41, 6%
19%
400
17%
16%
300 10% 200
67, 10% 100 0 Age at diagnosis
Age at radiaon
Fig. 3. Age of children at diagnosis and radiation treatment (N = 1962). years; , 3–5 years; , 5–10 years; , 10–16 years.
100, 15% , 0–3
72, 11%
90, 14% The most prevalent diagnosis was acute lymphoblastic leukaemia or a central nervous system tumour, most often medulloblastoma (Figs 4,5). A total of 55 episodes of RT were delivered for benign tumours (craniopharyngioma, N = 25; arterio-venous malformation, N = 16; meningioma, N = 10; Langerhans cell histiocytosis, N = 4). Of interest, 13 children received RT for nasopharyngeal cancer, six for malignant thyroid tumours and three for melanoma.
397 (20%)
663 (34%)
156 (8%)
141 (7%)
45 (2%)
123, (%)
115 (6%) 95 (5%)
98 (5%)
69 (4%) 60 (3%) Fig. 4. Frequency of diagnoses (N = 1962). , acute leukaemias; , neuroblastoma; , rhabdomyosarcoma; , Wilms; , Ewing sarcoma; , other sarcoma; , Hodgkin lymphoma; , other lymphoma, leukaemia, anaemia; , other; , benign; , central nervous system. © 2014 The Royal Australian and New Zealand College of Radiologists
Fig. 5. Frequency of central nervous system tumours (N = 663). , medulloblastoma; , brainstem glioma; , ependymoma; , glioma, high grade; , intracranial germ cell tumour; , glioma, low grade; , spinal cord tumour; , visual pathway glioma; , atypical teratoid rhabdoid tumour; , other.
Craniospinal RT was the technique employed for 13% of all treatment episodes (284/2232), total body irradiation for 13% (291/2232), and prophylactic cranial RT for 6% (135/2232). RT intent was palliative for 380 of 2232 episodes (17%), representing 10% of first RT episodes (202/ 1962) and 58% of second episodes (120/206). The third episode of RT was still given with curative intent on 14% of occasions (6/42). A small number of children received more than three courses of RT (N = 12), all with palliative intent. A majority of children receiving a first course of treatment were recorded as being ‘entered to a protocol’ (55%, 1079/1962), with 31% of these patients entered to ANZCHOG studies (N = 332), 23% to Children’s Oncology Group of North America studies (N = 252), 7% to St Jude Children’s Hospital studies (N = 71) and 4% to SIOP studies (N = 42). It is probable that some or many of these patients were treated ‘according to’ a protocol rather than enrolled on a study.
Discussion In the 14 years to the end of 2010, the Registry recorded 2232 courses of RT delivered to children under the age of 16 years in Australia and New Zealand, an annual rate of around 160 courses. Almost all registrations were from Australia, and annual registration numbers varied considerably. The vast majority of treatments were deliv695
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ered with radical intent, and the most commonly treated tumours were acute lymphoblastic leukaemia and medulloblastoma.
Comparison with other registries The Australian Paediatric Cancer Registry (APCR) is ‘one of the few population-based childhood cancer registries in the world’ and records a stable annual incidence of cancer after the mid-1990s at around 620 cases annually for children under15 years of age.5 We are not aware of any population-based registry other than our own which records courses of RT delivered to children, although population-based cancer registries for children are advocated because of the rarity of childhood cancer.6
Strengths and limitations of the Registry The registry is not complete, and the variation in annual registrations is not likely to be a reflection of changes in RT practice over the study period for two reasons. First, there were 194 enrolments during 2010 when there was a significant effort at all centres to enrol patients due to the College research grant, and this is around the same number of children who were enrolled during each of the first three years of the registry. Second, NSW Health records all courses of RT delivered through the Radiotherapy Management System (RMIS).7 During 2008, RMIS records that 99 children under the age of 15 years underwent a course of RT, while the Registry records that 30 patients received a course of RT, and there were 172 new cases of cancer in children less than 15 years of age in NSW.8 This indicates a true RT utilisation rate of 57% and that only around one-third of RT courses in NSW children were recorded in the Registry in 2008. The 57% RT utilisation rate concords with the rate determined from the first three years of the Registry.1 Courses of RT recorded in the Registry are not crosslinked with APCR records. Patients under the age of 16 years are enrolled in the Registry, while APCR enrols patients less than 15 years of age. The APCR categorises patients according to the International Classification of Childhood Cancers-3 which includes non-malignant intracranial and intraspinal tumours.9 We have not retrospectively re-classified diagnoses for Registry patients. The differences in age and tumour diagnoses between the Registry and the APCR will lead to some inaccuracies in our evaluation, but this is not likely to be large. There are several possible reasons why enrolments to the Registry are incomplete. Enrolment is a voluntary activity with no incentive attached for radiation oncologists. Furthermore, not all radiation oncologists managing children may agree with enrolling patients on a Registry for which they do not feel ownership. Some children may be managed by radiation oncologists who are unaware of the Registry. Consent to the Registry is necessary with different Human Research and Ethics 696
Committees (HREC) developing their own versions of a consent form, including the need for separate patient information sheets and consent forms appropriate for 14-year-olds and eight-year-olds requested by one HREC. Interpretation of New Zealand privacy laws has varied, with some jurisdictions failing to allow de-identified patient information to be sent to an Australian centre. In one small Australian survey of medical oncologists, bureaucratic ethics processes was identified as a barrier to recruitment to clinical trials, as were lack of infrastructure support and lack of time.10 Clinician behaviour may be an another hindrance to recruitment to the Registry, as identified in a systematic review of the literature on obstacles to recruitment to cancer clinical trials.11 The Registry does not record patient outcomes, namely, disease control or RT toxicity. To do so would require additional time from clinicians and data management time centrally. However, this means that any research study requiring outcome information from a cohort of registered patients will need submission of a separate request to the HREC of each jurisdiction. Without knowing patient outcomes, we do not know whether the standard of paediatric radiation therapy varies between centres across Australia and New Zealand or meets international standards. This is the strongest reason for universal participation in the Registry and expanding the Registry to include a core set of outcome measures such as acute radiotherapy toxicity, local control, disease-free survival and late radiotherapy toxicity. Nevertheless, the five-year survival rate for all children with cancer treated 1997–2006 in Australia (79%) is similar to rates in other high-income nations; radiotherapy quality contributes to this achievement.12
How the Registry could be used The large patient cohort can provide meaningful information to the paediatric RT community locally and internationally in a number of areas. For example, we can identify where prospective studies are feasible across Australasia, and we can provide an estimate of patient numbers available for international collaborative studies. The Registry could be used as a source of identifying patients for audits such as local control outcomes in neuroblastoma, Ewing sarcoma and rhabdomyosarcoma where our heterogeneous group of patients with a range of tumour characteristics and treatments could provide value. Long-term effects of RT could also be evaluated as demonstrated by a publication from the German Group of Pediatric Radiation Oncology.13 Such reports have not resulted from the Registry. This may be due to the complex issues of consent but also to the lack of clinician time. The Registry demonstrates that radiation oncologists managing children in Australia are willing to enrol children on clinical trials, but their clinical workload is probably greater than average; little account is taken of © 2014 The Royal Australian and New Zealand College of Radiologists
Utility of a paediatric radiotherapy registry
subspecialisation in paediatrics in workload calculations in Faculty of Radiation Oncology documents.14 Our group estimates that the time required to assess, plan and treat a new paediatric cancer patient for RT compared with a new adult cancer patient is a 3:1 ratio. The only Australian data to support this opinion at least in part come from the NSW RMIS where a paediatric case under sedation is allocated treatment time equivalent to three adult patients.7 The German Society of Radiation Oncology (DEGRO) has recently published the results of the QUIRO study to document the resource requirements for delivery of high-quality RT to paediatric and adolescent patients.15 Across three radiotherapy centres, the consultant time required to manage children undergoing RT without general anaesthesia was 42 minutes for first consultation, 87 minutes attending multidisciplinary meetings, 38 minutes defining organs at risk and target volumes, 27 minutes obtaining consent, and 366 minutes for all activities combined. This compares, allowing for some differences in resources examined, to 144 minutes consultant time for a breast cancer patient who will receive 25-fraction course of breast RT and 244 minutes consultant time for patients undergoing hypofractionated intracranial stereotactic radiotherapy (19% of 21.43 hours).16,17 An audit tool or a component of a reflective diary for continuing medical education is an obvious application of enrolling patients on the Registry. An informal survey of radiation oncologists managing children in Australia and New Zealand in 2013 found that only four of 11 respondents had undertaken a postgraduate fellowship in paediatrics (V. Ahern, pers. comm., 2013), indicating a need for continuing education and peer review in managing children. The paediatric SIG of the Faculty of Radiation Oncology of the RANZCR recently instituted a fortnightly case conference by video or teleconference in recognition of the need for peer review, following the Swedish model.18 Adding a core set of outcome measures to the Registry could be introduced as a method of obtaining Continuing Professional Development points and as a mandatory requirement for the title of a sub-specialist in paediatric radiation oncology. A computer-based efficient clinical information processing system to enhance a tumour registry was reported in 1992, and there is an opportunity to identify an appropriate system for the Registry.19 Combining the ACPR and the Registry into a single entity is one potential method of improving participation in the Registry, streamlining consent processes, and obtaining and recording outcome measures. The practicalities and costs of doing so will need to be discussed over the coming months. This will also be an opportunity to review all registry data fields to ensure relevance and clarity. Contributing to policy and planning is a recommended use of population-based cancer registries.20 Relevant policy and planning issues in Australia and New Zealand are whether children should be treated in all radio© 2014 The Royal Australian and New Zealand College of Radiologists
therapy centres rather than only certain centres, how radiation oncologists are trained in paediatrics, planning for survivorship services, and the optimal radiation technologies for managing children. With around 550 cases of paediatric cancer diagnosed annually, the Dutch are working towards a single cancer centre for the management of children, meaning that only a small proportion of radiation oncologists will need subspecialty training in the management of children.21 The decision to centralise childhood cancer services was based on the findings of a systematic review regarding the volume effect in paediatric oncology which supported the view that high-volume hospitals, high case providers and specialised hospitals achieve better patient outcomes.22 A minimum of five cases per year was defined as high volume, and almost all Australian and New Zealand centres managing children meet or far exceed this. Centralising cancer services for children to one site in Australia is not a practical solution due to geographical constraints. There is some evidence that low case volume can be overcome by membership of a collaborative group.23 Gutierrez et al.23 found that patients with Wilms tumour have a significantly better overall survival when enrolled on a Children’s Oncology Group (COG) study than not, although for those enrolled at a COG site, overall survival was still better when treatment was at a centre managing high rather than low volumes of children. Most centres managing children in Australia and New Zealand are members of COG. Meeting and maintaining standards are a recognised corollary of collaborative group membership, so Australian and New Zealand centres can be assumed to be delivering an acceptable standard of RT.24 The Registry, in combination with data from the APCR, can provide a reasonable estimate of how many children may become long-term survivors of childhood cancer and require transition care to adult cancer services. It also provides a basis for estimating the numbers of children who may be considered for hadron therapy. Not all children will be suitable for curative treatment or benefit from RT, or preferentially from hadron therapy. The United Kingdom, Denmark and the province of Alberta in Canada have developed guidelines regarding which children should receive proton therapy, and Australian and New Zealand guidelines are near completion.25–27 The published guidelines broadly include children with the following diagnoses for referral for proton therapy: base of skull chordoma and chondrosarcoma, ependymoma, Ewing sarcoma, intracranial germ cell tumour, rhabdomyosarcoma (head and neck, para-meningeal and pelvic), para-spinal soft tissue sarcoma, retinoblastoma, Hodgkin lymphoma, craniopharyngioma, and low-grade astrocytoma. Based on APCR data, there are around 180 children diagnosed with these tumours annually. However, only a small proportion of children with low-grade gliomas or retinoblastoma receive RT. If this proportion is set at 20% for the 697
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purposes of this exercise, the number would decrease to around 120. Accounting for age criteria, palliative intent of treatment, poor prospect of survival for some children at diagnosis, and the fact that RT may be avoided entirely for some patients (e.g. brain tumours in children under three years of age and some patients with Hodgkin Lymphoma), around 100 courses of treatment by protons would be required annually in Australia.
7.
8.
9.
Conclusions The Registry has provided an overview of the management of children with cancer in Australia by RT. It is a rich research resource which could lead to better RT care of children, and its continuation with addition of outcome measures is recommended. Enrolling children on the registry is an obvious requirement for recognition as a sub-specialist in paediatric radiation oncology, although further debate needs to occur within the SIG and among the broader College membership regarding how we recognise sub-specialisation in a self-regulated profession.
Acknowledgements A Royal Australian and New Zealand College of Radiologists Research Grant (2010–2011) assisted the collection of data for this study. This manuscript was presented in part at the Annual Scientific Meeting of the International Society of Paediatric Oncology, Auckland 2011. Ms S Varadarajan, Ms S Cross and Ms T PearlLarsson at Crown Princess Mary Cancer Centre have managed the Registry over the years.
10.
11.
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13.
14.
15.
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