Internal Medicine Journal 41 (2011) 7581

O R I G I N A L A RT I C L E

Introduction to the Australian consensus guidelines for the management of neutropenic fever in adult cancer patients, 2010/2011
imj_2338 75..81

S. Lingaratnam, M. A. Slavin, B. Koczwara,3 J. F. Seymour,1 J. Szer,2 C. Underhill,4,5,6 M. Prince,1,7,8,9 L. Mileshkin,1,8 M. OReilly,9,10,11 S. W. Kirsa,1 C. A. Bennett,1 I. D. Davis,12,13 O. Morrissey9,14 and K. A. Thursky1,2,15
1 Peter MacCallum Cancer Centre, East Melbourne, Victoria, 2The Royal Melbourne Hospital, Melbourne, Victoria, 3Southern Adelaide Health Service, Adelaide, South Australia, 4Hume Regional Cancer Centre, New South Wales, 5Greater Southern Area Health Service (Border Network), 6University of New South Wales, New South Wales, 7The Edith Margaret Collie Centre for Blood Cell Therapies, East Melbourne, 8University of Melbourne, Melbourne, Victoria, 9Monash University, Melbourne, Victoria, 10Eastern Health, Melbourne, Victoria, 11Cabrini Health, Melbourne, Victoria, 12Austin Health, Melbourne, Victoria, 13Ludwig Institute for Cancer Research, Austin Health, Melbourne, Victoria, 14The Alfred Hospital, Melbourne, Victoria, and 15St Vincents Hospital, Melbourne, Victoria, Australia

1,2

Key words neutropenic fever, ambulatory care, empiric, antibacterial prophylaxis. Correspondence Karin A. Thursky, Department of Infectious Diseases, Peter MacCallum Cancer Centre Victorian Infectious Diseases service, Royal Melbourne Hospital St Vincents Hospital, Melbourne, Victoria 3002, Australia. Email: Karin.Thursky@petermac.org Received 30 August 2010; accepted 31 August 2010. doi:10.1111/j.1445-5994.2010.02338.x

Abstract
The current consensus guidelines were developed to standardize the clinical approach to the management of neutropenic fever in adult cancer patients throughout Australian treating centres. The three areas of clinical practice covered by the guidelines, the process for developing consensus opinion, and the system used to grade the evidence and relative strength of recommendations are described. The health economics implications of establishing clinical guidance are also discussed.

Funding: These guidelines were developed independently through funding from Victorian Integrated Cancer Services. The Western and Central Melbourne Integrated Cancer Service (WCMICS), one of three metropolitan and ve regional Integrated Cancer Services funded by the Victorian Department of Human Services to implement the Victorian Governments Cancer Services Framework across Victoria, administered this funding. Conicts of interest: The following working group members are consultants or advisory committee members or receive honoraria, fees for service, or travel assistance (independent of research-related meetings) from; or have research or other associations with the organizations listed: Ian Davis Novartis, Pzer, GlaxoSmithKline, Schering-Plough; Andrew Grigg Amgen, Gilead, Merck Sharp & Dohme, Novartis, Pzer, Schering Plough, Sue Kirsa Roche, Schering Plough, Amgen,
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Hospira, Alphapharm; Senthil Lingaratnam Victorian Integrated Cancer Services; Orla Morrissey Gilead, Merck Sharp & Dohme, Orphan, Pzer, Schering Plough; William Renwick Roche; Monica Slavin Gilead, Merck Sharp & Dohme, Pzer, Schering Plough; Brian Stein Merck-Serono; Constantine Tam GSK, Roche; Karin Thursky Gilead, Merck Sharp & Dohme, Pzer, Schering Plough; Andrew Wei Celgene, Hospira, Novartis. Steering committee Craig Bennett, Ian Davis, Sue Kirsa, Bogda Koczwara, Linda Mileshkin, Orla Morrissey, Mary OReilly, Miles Prince, John Seymour, Monica Slavin, Jeff Szer, Karin Thursky, Craig Underhill Working group chairs Leon Worth, Chair (ambulatory strategies) Constantine Tam, Chair (empiric treatment) Monica Slavin, Chair (antibacterial prophylaxis) Andrew Grigg, Chair (granulocyte colony-stimulating factors)

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On behalf of the Neutropenic Fever Guidelines Working Group Neutropenic fever guidelines working group David Andresen, BSc, MB BS, DTM&H, M.Medical.Sci (Clin Epi), FRACP (Infectious Diseases), FRCPA (Microbiology), Medical Microbiologist, Department of Infectious Diseases and Microbiology and Centre for Kidney Research, The Childrens Hospital at Westmead, Westmead, NSW. Dr Patricia A Bastick, BMedSci, MB BS(Hons), FRACP, Staff Specialist Medical Oncology, St George and Sutherland Hospitals, Sydney, NSW; Conjoint Associate Lecturer, University of NSW. Mr Craig A Bennett, MSc (Health Econ), BEcon (Hons), FCHSE, Chief Executive Ofcer, Peter MacCallum Cancer Centre, East Melbourne, VIC. Ms Diana L Booth, M Clin Pharm, BMT Pharmacist, Royal Melbourne Hospital, Parkville, VIC. Dr Kate Burbury, MB BS, FRACP, FRCPA, Haematology Fellow, Peter MacCallum Cancer Centre, East Melbourne, VIC. Mr Michael J Cain, B Pharm, Senior Pharmacist (Oncology), Sir Charles Gardiner Hospital, Perth, WA. Dr Julian Cooney, MB BS, DipRACOG, FRACP, FRCPA, Clinical Haematologist, Royal Perth Hospital, Perth, WA. Associate Professor Ian D Davis, MB BS, PhD, FRACP, FAChPM, Medical Oncologist, Austin Health, Heidelberg, VIC; Associate Member and Head of Uro-oncology Laboratory, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, VIC. Ms Lesley Dawson, MSc (Clin Pharm), BSc (Pharm), Clinical Educator & Specialist, Pharmacist Cancer Services, Mater Health Services, South Brisbane, QLD. Dr Richard W Eek, MBChB, MMed, FCP FRACP, Medical Oncologist, Border Medical Oncology, Wodonga, VIC; Murray Valley Private Hospital, Wodonga, VIC; Wangaratta Oncology Clinic, Wangaratta, VIC; Albury Base Hospital, NSW. Professor Andrew Grigg, MB BS, FRACP, FRCPA, MD, Director of Clinical Haematology, Department of Haemtaology, Austin Hospital, Heidelberg, VIC. Dr Ian Haines, MB BS, FRACP, FAChPM, Medical Oncologist, Cabrini and Alfred Hospitals, Melbourne, VIC; Adjunct Senior Lecturer, Department of Medicine, Monash University, Melbourne, VIC. Mr Allan M Hayward, RN, BN, GradDipN(Onc), GradCertNSc(Apher), Clinical Operations Manager, Royal Adelaide Hospital Cancer Centre, SA Pathology, Adelaide, SA. Ms Aisling Kelly, BSc (Hons), Pharmacist, Cancer Institute NSW, Alexandria, NSW. Mrs Suzanne W Kirsa, BPharm, Grad Dip Hosp Pharm, FSHP, Director of Pharmacy, Peter MacCallum Cancer Centre, East Melbourne, VIC. Associate Professor Bogda Koczwara, BM BS, FRACP, MBioethics, Head, Department of Medical Oncology and Director, Cancer Services, Southern Adelaide Health Service, SA; President Elect, Clinical Oncology Society of Australia. Mr Senthil Lingaratnam, BPharm, MPH, Clinical and Research Pharmacist, Peter MacCallum Cancer Centre, East Melbourne, VIC. Dr Linda Mileshkin, MB BS, MD, FRACP, MBioeth (Mon), Medical Oncologist, Peter MacCallum Cancer Centre, East Melbourne, VIC; Senior Fellow, The University of Melbourne, Parkville, VIC. Dr Orla Morrissey, MB, BCh, FRACP, Grad Dip (Clin Epi), PHD, Infectious Diseases Physician, Infectious Diseases Unit and

Department of Haematology, The Alfred Hospital, Melbourne, VIC; Adjunct Senior Lecturer, Departments of Medicine and Haematology, Monash University, Melbourne, VIC. Ms Shay Morrissey, BAppSc (Nursing), GradCert (Oncology/ Intensive Care), Nurse Unit Manager, Specialist Clinics, Peter MacCallum Cancer Centre, East Melbourne, VIC. Ms Annabel P McNally, B Pharm, MPS, Director of Pharmacy/ Oncology Pharmacist, Pharmacist, Central Gippsland Health Service, Sale, VIC. Adjunct Clinical Associate Professor Mary OReilly, MB BS, MPH, FRACP, Head of Unit, Infectious Diseases and Infection Control, Eastern Health, Melbourne, VIC; Eastern Health Clinical School, Monash University, VIC; Infectious Diseases Physician, Cabrini Medical Centre, Malvern, VIC. Professor Miles Prince, MB BS (Hons), MD, MRACMA, FRACP, FRCPA, Head, Haematology Unit, Peter MacCallum Cancer Centre, East Melbourne, VIC; Director of the Blood and Marrow Transplant Service and the Edith Margaret Collie Centre for Blood Cell Therapies, East Melbourne, VIC. Dr William Renwick, MB BS, FRACP, FRCPA, Haematologist, Western Health and Royal Melbourne Hospital, Melbourne, VIC. Dr David S Ritchie, MB ChB, PhD, FRACP, FRCPA, Haematologist, Division of Haematology and Medical Oncology, East Melbourne, VIC; Haematologist, Clinical Haematology and Medical Oncology, Royal Melbourne Hospital, Parkville, VIC. Professor John F Seymour, MB BS, PhD, FRACP, Head, Haematology Department and Chair Haematology Clinical Service, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC. Mr Jim Siderov, BPharm, MClinPharm, BCOP, Senior Pharmacist, Cancer Services, Austin Health, Melbourne, VIC. Associate Professor Monica A Slavin, MB BS, FRACP, MD, Head, Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC; Infectious Diseases Physician, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC. Dr Brian Stein, MB BS, FRACP, Medical oncologist, Adelaide Cancer Centre and University of Adelaide, Adelaide, SA. Professor Jeff Szer, BMed Sc, MB BS, FRACP, Director, Department of Clinical Haematology and Bone Marrow Transplant Service, The Royal Melbourne Hospital, Parkville, VIC. Dr Constantine Tam, Haematology, MBBS, MD, FRACP, FRCPA, Consultant Haematologist, St Vincents Hospital, Melbourne, VIC; Honorary Senior Fellow, University of Melbourne, VIC. Dr Anne Taylor, MB BS, FRACP, FAChPM, Medical Oncologist, Royal Adelaide Hospital, Adelaide, SA. Dr Karin A Thursky, BSc, MB BS, FRACP, MD, Infectious Diseases Physician, Peter MacCallum Cancer Centre and St Vincents Hospital, Melbourne, VIC. Dr Craig Underhill, MB BS, FRACP, Medical Oncologist, Director of Cancer Services Hume Regional Cancer Centre, NSW; Director of Area Cancer Services, Greater Southern Area Health Service (Border Network), NSW; Conjoint Senior Lecturer, University of NSW, NSW. Dr Andrew Wei, MB BS, FRACP, FRCPA, PhD, Haematologist, Department of Clinical Haematology, Alfred Hospital, Prahran, VIC. Dr Leon J Worth, MB BS, FRACP, Grad Dip Epi, Infectious Diseases Physician, Peter MacCallum Cancer Centre, East Melbourne, VIC.

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Neutropenic fever guidelines 2010

Introduction
Fever in neutropenic patients is a frequent complication of chemotherapy for cancer, occurring in an estimated 1050% of patients with solid tumours or lymphomas and in more than 80% of patients with haematological malignancies.1,2 At least half of all neutropenic patients who become febrile have an established or occult infection.3 Mortality rates for critically ill patients have been reported at 1020% with rates for patients with gramnegative bacteraemia as high as 40%.4 These statistics demonstrate the clinical imperative to manage neutropenic fever promptly and effectively in order to optimize patients health outcomes, including survival and quality of life, and to minimize clinical practice costs faced by treating centres. There is an abundance of evidence regarding effective treatment strategies for neutropenic fever.1,3,511 Standardization of treatment practices through clinical guidelines and pathways allows monitoring and evaluation of patient outcomes and helps promote compliance with optimal treatment strategies. However, to date, there has been no Australian consensus for the management of neutropenic fever in adult cancer patients. This may be due to several factors, including the emergence of new risk factors in immunocompromised hosts, constantly changing epidemiology of infections, increasing trends in bacterial resistance and a newfound emphasis on cost-effectiveness for healthcare interventions. While institutional guidelines exist, underscored by recommendations from international professional associations, such as the Infectious Diseases Society of America (IDSA),3 there is signicant variability in practice between institutions within the Australian haematology and oncology setting. As patients are often referred between treatment centres offering cancer-specic treatments, including radiotherapy, bone marrow transplant or specialized chemotherapy, including investigational drugs as well as community settings, including rural sites where access to uncommon antibiotics may be limited, it is important that infection prophylaxis and treatment standards are concordant across sites and include treatment that is likely to be available. Specic areas where there is signicant variability in practice and desire for clinical guidance include the use of risk stratication to guide empiric management, such as ambulatory therapy for patients at low risk of developing medical complications, hospitalbased parenteral therapy for higher-risk patients, use of chemoprophylaxis in patients with an expected duration of neutropenia greater than 710 days, the prophylactic and therapeutic use of granulocyte colony-stimulating factor (G-CSF), and choice of antibacterial agent/s as
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governed by local epidemiology and drug susceptibility patterns.

Current guidelines
The aim of these guidelines is to develop Australian consensus-based clinical recommendations for the management of neutropenic fever in adult cancer patients that address the current diversity in practice and better inform clinical decision-making while taking into consideration best available evidence, and where appropriate, this includes cost-effectiveness evidence. By providing a framework of recommendations, clinicians can develop treatment pathways for the multidisciplinary management of neutropenic fever, leading to improved institutional efciency while optimizing patient health outcomes. The key focus areas addressed by the guidelines are identied below.

Risk stratication to guide empiric therapy

Classication of patients with neutropenic fever into high- and low-risk groups can guide the subsequent approach to treatment based on established risk stratication criteria, for example the Multinational Association for Supportive Care in Cancer (MASCC) risk index12 or the Talcott risk-scoring system.13 However, utilization of these risk stratication tools is currently limited by limited awareness and understanding.14 The current guidelines advocate a preferred approach to risk stratication and raise awareness of its usefulness for informing the appropriate management of neutropenic fever.15

Hospital-based empiric therapy

Clinicians currently have several options for the empiric management of patients with neutropenic fever requiring hospital-based parenteral therapy: monotherapy with an anti-pseudomonal beta-lactam (e.g. piperacillintazobactam, cefepime, ceftazadime or a carbapenem), or combination therapy with an anti-pseudomonal betalactam and a second agent, usually an aminoglycoside. However, recent clinical evidence has demonstrated some differences in clinical outcomes depending on the regimens used.16 Further, while monotherapy is now considered effective and safer than combination therapy,1719 there remain instances where higher-risk patients might benet from early treatment with combination antibiotic therapy if they could be identied in a timely manner. Clinicians would benet from local guidelines that aid the selection of an appropriate empiric regimen while giving due consideration to the risks

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inherent across different patient groups. The relevant issues are addressed in the adjunct paper by Tam et al.20

Ambulatory care approach to empiric therapy

The potential for low-risk patients with neutropenic fever to be switched to oral therapy and discharged from hospital earlier, or managed in an outpatient setting, might result in lower cost and improved quality of life for patients. While the major complication rate for this patient group can be low (approximately 5%), sensitivity between the two risk stratication systems commonly used (the MASCC risk index12 and the Talcott risk-scoring system13) is different, and readmission rates for patients may be differentially higher despite a predictably low rate of serious complications, depending on the type of ambulatory care strategy used.21 Further, the organizational and resource capacity of treatment centres is varied and will impact upon whether treatment can be safely employed in a clinic or home setting. Greater guidance is provided so that clinicians can condently implement ambulatory strategies for neutropenic fever, where appropriate. A recommended approach to ambulatory care is provided in the adjunct paper by Worth et al.15

tion for neutropenia is typically 614 days with an estimated daily cost of $A1200 to $A2300 depending on underlying disease and associated complications.26 These estimates compare well with international estimates that were extrapolated to the Australian setting by applying the purchasing power parity for GDP in Australia, and adjusted for health ination using ination rates for government expenditure on hospitals published by the Australian Institute of Health and Welfare.1,27 The majority of these costs are associated with hospitalization and the attendant costs of medical staff, nursing care and antiinfective therapy. Within this context, standardizing the approach to risk stratication and identication of low-risk patients, who could be treated in an outpatient setting, could signicantly reduce the current burden on healthcare resources. Elucidating other trends in practice are also likely to have a signicant effect on strategies aimed at preventing the clinical sequelae and prolonged admissions arising from complications of anti-infective treatment. A particular point to consider is how clinicians currently identify patients appropriate for monotherapy and employ differential patient risk categories for combination antibiotic therapy.

Antibacterial prophylaxis
While the 2002 IDSA guidelines discouraged use of antibiotic prophylaxis with uoroquinolones (FQ) for neutropenic patients owing to concerns of emerging antibiotic resistance,3 recent evidence suggests this approach may reduce infection-related mortality, which in some cases might outweigh the incidence of FQ-resistant bacterial infections, particularly in higher-risk patient groups.22 Further, Australian product information23 and clinical guidelines24 for some chemotherapy agents advocate the routine use of chemoprophylaxis in patients undergoing these treatment schedules. The adjunct paper by Slavin et al. presents the current evidence base and provides recommendations for the use of FQ prophylaxis, both with and without chemotherapy.25

Process for development of guidelines

Steering committee
A steering committee was established to oversee the development of the guidelines and to provide guidance to the working parties. It was envisaged that the current guidelines would be more readily accepted as an Australian standard of care if expert consensus were drawn from a nationwide contingent of clinicians. As such, the steering committee was designed to incorporate representatives from all key national stakeholder organizations, including the Australasian Leukaemia and Lymphoma Group (ALLG), Medical Oncology Group of Australia Incorporated (MOGA), Australasian Society for Infectious Diseases (ASID), Clinical Oncological Society of Australia (COSA), Private Cancer Physicians of Australia (PCPA), Bone Marrow Transplant Society of Australia and New Zealand (BMTSANZ) and the Haematology Society of Australia and New Zealand (HSANZ), from a mix of public and private, as well as metropolitan and regional practices.

Choice of antibacterial agent

In addressing each of the focus areas outlined above, the working groups sought to inform the selection of an appropriate antibacterial regimen, with due consideration always to local epidemiology and drug susceptibility patterns.

Clinical survey

Health economics implications

The health economics implications of establishing clinical guidance in these areas are signicant. Treatment dura-

Prior to the development of these guidelines, a clinical survey was administered to review current attitudes and practices of clinical haematologists and oncologists in
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Australia regarding the management of neutropenic fever in adult cancer patients. The ndings from this survey provided context and helped inform, in conjunction with the current evidence base, the recommendations presented herein. Survey respondents were asked to broadly describe their institution of practice before indicating what therapeutic strategies they would choose across several case studies. Haematologists and oncologists were given separate case studies to consider, based around three haematology and two oncology patients respectively. Infectious diseases physicians were asked to respond to both case sets. In doing so, the survey was able to identify the clinical pathways typical of the standard management of neutropenic fever in Australia. Relevant professional bodies, namely ALLG, MOGA, HSANZ, PCPA and ASID (through their email discussion group, OzBug), distributed the survey link to their clinician members. A 30% response rate for haematologists and medical oncologists was achieved. Eighty per cent of respondents represented practices within public hospitals while 20% of respondents consulted primarily at private centres. A total of 116 clinicians responded to the medical oncology cases, 85% of which were oncologists and 15% infectious diseases physicians. In total, 141 clinicians responded to the haematology cases. This included 75% haematologists, 12% oncologists and 12% infectious diseases physicians. Abridged ndings from this survey are presented in the current guidelines where relevant. A more detailed description and analysis of the ndings can be found in an adjunct paper.14

sensus meeting held in 2005 involving the European Bone Marrow Transplant Society, European Organisation for Research and Treatment of Cancer, International Immunocompromised Host Society and the Supportive Care Group of the European Leukaemia Network. This approach has been successfully adopted previously by a group of local clinicians when preparing the 2008 Australasian antifungal consensus guidelines.28 Four multidisciplinary working groups were formed to review the literature, cost-effectiveness data and survey ndings, and formulate evidence-based guidelines, for the following areas of clinical practice as they relate to the management of neutropenic fever: empiric treatment, risk stratication and ambulatory care, antibacterial prophylaxis, and the use of G-CSF. Representatives from haematology, oncology, infectious diseases, microbiology, nursing and pharmacy from a cross-section of public, private, metropolitan, regional and rural practice were appointed to each working group. Each group prepared recommendations around the issues pertaining to their topic area. All discussion points were subject to debate. Where there was signicant contention, a group vote was employed to reach a consensus. Each groups recommendations were reviewed by the steering committee before being presented for feedback and comment at the COSA annual scientic meeting in November 2009, to which all survey recipients were invited. Draft guidelines were then developed to present these recommendations in context. These were made available to all Victorian Integrated Cancer Service networks, ASID, ALLG, MOGA, PCPA, NSW-CI, BMTSANZ and HSANZ members for comment prior to publication.

Cost-effectiveness analysis
The National Health Service Economic Evaluation database, the Health Economics Evaluations database and other economic literature sources were searched for all relevant cost-effectiveness studies from 2004 to 2008. However, a paucity of pharmacoeconomic evidence led the current working group to construct economic models to cost-analyse several therapeutic strategies known to deliver similar treatment outcomes. The ndings from this cost-analysis have been published in an adjunct paper. Where relevant, the consensus group considered the cost-effectiveness data, alongside the broader clinical evidence base, when developing their recommendations.

Denition of neutropenic fever

For the purposes of these guidelines, neutropenic fever is dened as fever of at least 38.3C (or at least 38.0C on two occasions) in the setting of an absolute neutrophil count less than 0.5 109 cells/L, or with or less than 1.0 109 cells/L and predicted fall to lower than 0.5 109 cells/L.

Application of guidelines
The guidelines provide a general framework for best practice. Regard should be given to local epidemiology when applying the recommendations presented herein. As always, clinical judgement and local experience should govern how these guidelines are implemented in each individual case.

Working groups and formulation of recommendations

The process for developing these guidelines and reaching consensus was modelled on a successful European con 2011 The Authors Internal Medicine Journal 2011 Royal Australasian College of Physicians

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Table 1 Denition of NHMRC grades of recommendations Grade of recommendation A B C Description

D Level of recommendation I II III-1 III-2

Body of evidence can be trusted to guide practice Body of evidence can be trusted to guide practice in most situations Body of evidence provides some support for recommendation(s), but care should be taken in its application Body of evidence is weak and recommendation must be applied with caution Study design

necessary to ensure formulation of a well-represented national consensus guideline. We envisage that these guidelines will help bridge current evidencepractice gaps. Ongoing review of the evidence is necessary to keep abreast of the clinical advancements and the changing epidemiology of infections in adult neutropenic febrile patients with cancer.

Acknowledgements
The authors would like to thank members of MOGA, ALLG, HSANZ, PCPA and ASID for their participation in the clinical survey. The group additionally thanks the Australian Consensus Guidelines 2010 steering committee, ALLG, ASID, BMTSANZ, MOGA, NSW-CI and PCPA for their review of the draft documents and endorsement of the nal guideline documents. We also thank Drs Claire Dendle and Nicole Gilroy for their valuable comments, and Dr Candice OSullivan (Medical writer, WellmarkPerspexa, Melbourne, Vic.) for her technical help in preparing the manuscript for submission.

III-3

IV

A systematic review of level II studies A randomized controlled trial A pseudorandomized controlled trial (i.e. alternate allocation or some other method) A comparative study with concurrent controls: Non-randomized, experimental trial Cohort study Casecontrol study Interrupted time series with a control group A comparative study without concurrent controls: Historical control study Two or more single arm study Interrupted time series without a parallel control group Case series with either post-test or pre-test/ post-test outcomes

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Wide representations from various sectors, disciplines and professional associations within cancer care were

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