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Editorials

5 The Journal in 2016J. Szer

10 Towards equalityP. Poole

13 Absence of evidence: antimicrobial prescribing in neonates, elderly and pregnant womenA. Boast and A. Gwee

Review

16 Timely initiation of chemotherapy: a systematic literature review of six priority cancers – results and recommendations for clinical practiceM. Alexander, R. Blum, K. Burbury, J. Coutsouvelis, M. Dooley, O. Fazil, T. Griffiths, H. Ismail, S. Joshi, N. Love, S. Opat, P. Parente, N. Porter, E. Ross, J. Siderov, P. Thomas, S. White, S. Kirsa and D. Rischin

Position Paper

35 Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory GroupD. Talaulikar, C. S. Tam, D. Joshua, J. P. Ho, J. Szer, H. Quach, A. Spencer, S. Harrison, P. Mollee, A.W. Roberts, N. Horvath, C. Lee, A. Zannettino, R. Brown, B. Augustson, W. Jaksic, J. Gibson, A. Kalff, A. Johnston, J. Trotman, A. Kalro, G. Grigoriadis, C. Ward and H. M. Prince

Original Articles

50 Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real worldJ. Truong, B. Shadbolt, M. Ooi, S. Chitturi, G. Kaye, G. C. Farrell and N. C. Teoh

57 Incidence of anti-neutrophil cytoplasmic antibody-associated vasculitis before and after the February 2011 Christchurch EarthquakeH. J. Farquhar, B. McGettigan, P. T. Chapman, J. L. O’Donnell, C. Frampton and L. K. Stamp

62 Trends and outcomes of chronic kidney disease in intensive care: a 5-year studyK. Ngu, D. Reid and A. Tobin

68 Impact of providing patients with copies of their medical correspondence: a randomised controlled studyC. Fenton, A. Al-Ani, A. Trinh, A. Srinivasan, K. Marion and G. Hebbard

75 Use of palliative chemotherapy in patients aged 80 years and over with incurable cancer: experience at three Sydney cancer centresE. Ip, A. M. J. Pokorny, S. Della-Fiorentina, P. Beale, V. Bray, B. E. Kiely and P. Blinman

82 Association of type 2 diabetes with prolonged hospital stay and increased rate of readmission in patients with lower limb cellulitisS. M. Wijayaratna, T. Cundy, P. L. Drury, S. Sehgal, S. A. Wijayaratna and F. Wu

88 Examining the impact of regular aspirin use and PIK3CA mutations on survival in stage 2 colon cancerC. Murphy, N. Turner, H.-L. Wong, M. Sinnathamby, J. Tie, B. Lee, J. Desai, I. Skinner, M. Christie, R. Hutchinson, S. Lunke, P. Waring, P. Gibbs and B. Tran

99 Problem-based learning in internal medicine: virtual patients or paper-based problems?M. Sobocan, N. Turk, D. Dinevski, R. Hojs and B. P. Balon

104 Incidence, time of occurrence and response to heart failure therapy in patients with anthracycline cardiotoxicityA. A. Khan, A. Ashraf, R. Singh, A. Rahim, W. Rostom, M. Hussain, I. Renner and N. J. Collins

Brief Communications

109 Multi-organ dysfunction due to bath salts: are we aware of this entity?R. Valsalan, B. Varghese, D. Soman, J. Buckmaster, S. Yew and D. Cooper

112 Use of intravenous immunoglobulin therapy for myositis: an audit in South Australian patientsC. Foreman, P. Russo, N. Davies, P. Hissaria, S. Proudman, T. Hughes and V. Limaye

115 Aceruloplasminaemia: a disorder of diabetes and neurodegenerationG. L. Calder, M. H. Lee, N. Sachithanandan, S. Bell, H. Zeimer and R. J. MacIsaac

Letters to the Editor

Clinical-scientific notes

119 False positive hepatitis B virus core and surface antibodies due to intravenous immunoglobulinN. Benwell, P. Boan, E. Raby and B. McGettigan

120 Paroxysmal atrial fibrillation cured through surgical repair of a large paraoesophageal herniaT. Aasen, E. Mallin and J. Klein

122 Report on outpatient management of patients with neutropenic fever in a tertiary hospitalM. R. Dzienis and A. Shahidzadeh Mahani

General correspondence

124 Gentamicin in pregnancy: seeing past the drug categorisation in pregnancyR. Chean, S. M. Garland and L. Leung

126 Corrigenda

Timely initiation of chemotherapy

Waldenström macroglobulinaemia: clinical practice guidelines

Viral load and hepatitis B

ANCA associated vasculitis post earthquake

Chemotherapy in octogenarians

Chronic kidney disease in intensive care

INTERNALMEDICINEJOURNAL

Volume 47

Issue 1

January 2017

ISSN 1444-0903

Total-pages: Spine-width: Paper-type:previous Total-pages:128 Spine-width: 4.2mm Paper-type: UPM Classic 64Current

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View this journal online at wileyonlinelibrary.com/journal/imj

aims and scopeThe Internal Medicine Journal, formerly known as the Australian and New Zealand Journal of Medicine, is the official journal of the Adult Medicine Division of The Royal Australasian College of Physicians (RACP). Its purpose is to publish high-quality internationally competitive peer-reviewed original medical research, both laboratory and clinical, relating to the study and research of human disease. Papers will be considered from all areas of medical practice and science. The Journal also has a major role in continuing medical education and publishes review articles relevant to physician education. Except where otherwise stated, articles are peer reviewed.

abstracting and indexingThis journal is indexed by Abstracts on Hygiene and Communicable Diseases, AgBiotech News and Information, AIDS Abstracts, Australian Medical Index, BIOBASE, Biological Abstracts (BIOSIS), Biomedical Reference (EBSCO), Cambridge Scientifi c Abstracts, Chemical Abstracts Service, Current Contents/Clinical Medicine (an ISI product), Derwent Biotechnology Abstracts, EMBASE/Excerpta Medica, Environmental Sciences and Pollution Management, Health and Safety Science Abstracts (Online version), Helminthological Abstracts, InPharma Weekly, International Pharmaceutical Abstracts (IPA), Journals @ Ovid, MEDLINE, Nutrition Abstracts and Reviews, Pharmacoeoconomics and Outcomes News, Reactions Weekly, Science Citation Index, SCOPUS, Tropical

Diseases Bulletin, Vitis-Viticulture and Oenology Abstracts (Online Edition), World Agricultural Economics and Rural Sociology Abstracts, and CINAHL.

address for editorial correspondenceEditor-in-Chief, Internal Medicine Journal, The Royal Australasian College of Physicians, 145 Macquarie Street, Sydney, NSW 2000, Australia (tel: +61 2 9256 5431; fax: +61 2 9252 3310). For enquiries regarding ScholarOne Manuscripts (formerly known as ManuscriptCentral) submissions please email [email protected] (e.g. IMJ-0000-2017).General enquiries should be directed to Virginia Savickis, the Editorial Office, Internal Medicine Journal, using [email protected] on published papers are welcomed. Authors are offered right of reply (no more than 500 words) at the discretion of the Editor and discussion will not be entered into. Given the current pressures on editorial space, however, invited comments are restricted to one reply.

disclaimerThe Publisher, RACP and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Publisher, RACP and Editors, neither does the publication of advertisements constitute any endorsement by the Publisher, RACP and Editors of the products advertised.

Copyright © 2017 Royal Australasian College of Physicians.

For submission instructions, subscription and all other information visit wileyonlinelibrary.com/journal/imj

Wiley’s Corporate Citizenship initiative seeks to address the environmental, social, economic, and ethical challenges faced in our business and which are important to our diverse stakeholder groups. Since launching the initiative, we have focused on sharing our content with those in need, enhancing community philanthropy, reducing our carbon impact, creating global guidelines and best practices for paper use, establishing a vendor code of ethics, and engaging our colleagues and other stakeholders in our efforts. Follow our progress at www.wiley.com/go/citizenship

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ISSN 1444-0903 (Print)ISSN 1445-5994 (Online)

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Subspecialty Editors

Cardiology (General)Paul Bridgman, Christchurch

Cardiology (Arrhythmias)Andrew McGavigan, Adelaide

Clinical GeneticsLes Sheffield, Melbourne

Clinical PharmacologyJenny Martin, NewcastleYvonne Bonomo, Melbourne (Addiction Medicine)

Continuing Education (Clinical Perspectives)

Christopher Pokorny, Sydney

Emergency MedicineJoseph Ting, Brisbane

EndocrinologyMorton Burt, AdelaideAnthony Russell, Brisbane

Ethics Paul Komesaroff, Melbourne

GastroenterologyDavid M. Russell, Melbourne

Geriatric MedicineLeon Flicker, Perth

Haematology (General)Peter Browett, Auckland

Haemostasis/ThrombosisClaire McLintock, Auckland

Immunology and AllergyMarianne Empson, Auckland

Infectious DiseasesDavid Gordon, Adelaide

Intensive CareMichael O’Leary, Sydney

Internal MedicineIan Scott, Brisbane

NephrologyZoltan Endre, Sydney

NeurologyDavid Blacker, Perth

Nuclear MedicineFrederick A. Khafagi, Brisbane

Occupational and Environmental Medicine; Health Economics; Editorials Editor

Des Gorman, Auckland

OncologyDamien Thomson, Brisbane

Palliative MedicineJanet Hardy, Brisbane

Public Health MedicineMark Ferson, Sydney

Respiratory MedicineMatthew Naughton, Melbourne

RheumatologyPeter Youssef, Sydney

Sexual Health MedicineDarren Russell, Cairns

Honorary Advisory Board

Peter Doherty, MelbourneKar Neng Lai, Hong KongRichard Larkins, MelbourneSir Gustav Nossal, MelbourneLawrie W. Powell, BrisbaneNicholas Saunders, NewcastleJohn Shine, SydneyChorh Chuan Tan, SingaporeSir David Weatherall, OxfordJudith Whitworth, Canberra

Editorial Ombudsman

Graham Macdonald, Sydney

Manager

Virginia Savickis, Sydney

Editorial Assistant

Aparna Avasarala, Sydney

Previous Editors-in-Chief

Internal Medicine JournalEdward Byrne (1999–2004)

The Australian and New Zealand Journal of MedicineGraham Macdonald (1989–1999)Michael O'Rourke (1981–1989)Akos Z. Gyory (1975–1981)Charles Kerr (1970–1975)

The Australasian Annals of MedicineRonald Winton (1957–1970)Mervyn Archdall (1952–1956)

Editor-in-ChiefJeff Szer, Melbourne

Continuing EducationDeputy Editor-in-Chief

Zoltan Endre, SydneyDeputy Editor-in-Chief

Paul Bridgman, Christchurch

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Editorials

5 The Journal in 2016

J. Szer

10 Towards equality

P. Poole

13 Absence of evidence: antimicrobial prescribing in neonates, elderly and pregnant women

A. Boast and A. Gwee

Review

16 Timely initiation of chemotherapy: a systematic literature review of six priority cancers – results and recommendations for clinical practice

M. Alexander, R. Blum, K. Burbury, J. Coutsouvelis, M. Dooley, O. Fazil, T. Griffiths, H. Ismail, S. Joshi, N. Love, S. Opat, P. Parente, N. Porter, E. Ross, J. Siderov, P. Thomas, S. White, S. Kirsa and D. Rischin

Position Paper

35 Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group

D. Talaulikar, C. S. Tam, D. Joshua, J. P. Ho, J. Szer, H. Quach, A. Spencer, S. Harrison, P. Mollee, A.W. Roberts, N. Horvath, C. Lee, A. Zannettino, R. Brown, B. Augustson, W. Jaksic, J. Gibson, A. Kalff, A. Johnston, J. Trotman, A. Kalro, G. Grigoriadis, C. Ward and H. M. Prince

Original Articles

50 Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world

J. Truong, B. Shadbolt, M. Ooi, S. Chitturi, G. Kaye, G. C. Farrell and N. C. Teoh

57 Incidence of anti-neutrophil cytoplasmic antibody-associated vasculitis before and after the February 2011 Christchurch Earthquake

H. J. Farquhar, B. McGettigan, P. T. Chapman, J. L. O’Donnell, C. Frampton and L. K. Stamp

62 Trends and outcomes of chronic kidney disease in intensive care: a 5-year study

K. Ngu, D. Reid and A. Tobin

68 Impact of providing patients with copies of their medical correspondence: a randomised controlled study

C. Fenton, A. Al-Ani, A. Trinh, A. Srinivasan, K. Marion and G. Hebbard

75 Use of palliative chemotherapy in patients aged 80 years and over with incurable cancer: experience at three Sydney cancer centres

E. Ip, A. M. J. Pokorny, S. Della-Fiorentina, P. Beale, V. Bray, B. E. Kiely and P. Blinman

82 Association of type 2 diabetes with prolonged hospital stay and increased rate of readmission in patients with lower limb cellulitis

S. M. Wijayaratna, T. Cundy, P. L. Drury, S. Sehgal, S. A. Wijayaratna and F. Wu

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January 2017, Volume 47, Issue 1


88 Examining the impact of regular aspirin use and PIK3CA mutations on survival in stage 2 colon cancer

C. Murphy, N. Turner, H.-L. Wong, M. Sinnathamby, J. Tie, B. Lee, J. Desai, I. Skinner, M. Christie, R. Hutchinson, S. Lunke, P. Waring, P. Gibbs and B. Tran

99 Problem-based learning in internal medicine: virtual patients or paper-based problems?

M. Sobocan, N. Turk, D. Dinevski, R. Hojs and B. P. Balon

104 Incidence, time of occurrence and response to heart failure therapy in patients with anthracycline cardiotoxicity

A. A. Khan, A. Ashraf, R. Singh, A. Rahim, W. Rostom, M. Hussain, I. Renner and N. J. Collins

Brief Communications

109 Multi-organ dysfunction due to bath salts: are we aware of this entity?

R. Valsalan, B. Varghese, D. Soman, J. Buckmaster, S. Yew and D. Cooper

112 Use of intravenous immunoglobulin therapy for myositis: an audit in South Australian patients

C. Foreman, P. Russo, N. Davies, P. Hissaria, S. Proudman, T. Hughes and V. Limaye

115 Aceruloplasminaemia: a disorder of diabetes and neurodegeneration

G. L. Calder, M. H. Lee, N. Sachithanandan, S. Bell, H. Zeimer and R. J. MacIsaac

Letters to the Editor

Clinical-scientific notes

119 False positive hepatitis B virus core and surface antibodies due to intravenous immunoglobulin

N. Benwell, P. Boan, E. Raby and B. McGettigan

120 Paroxysmal atrial fibrillation cured through surgical repair of a large paraoesophageal hernia

T. Aasen, E. Mallin and J. Klein

122 Report on outpatient management of patients with neutropenic fever in a tertiary hospital

M. R. Dzienis and A. Shahidzadeh Mahani

General correspondence

124 Gentamicin in pregnancy: seeing past the drug categorisation in pregnancy

R. Chean, S. M. Garland and L. Leung

126 Corrigenda

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January 2017, Volume 47, Issue 1


EDITORIAL

The Journal in 2016

I’m back again doing the annual reflection on ourmutual friend, the Internal Medicine Journal. It has been acomplicated year for the Journal in many ways, but thefuture remains bright and we continue to be a part of aworthwhile process producing fine issues and assisting inthe education of physicians in Australia and beyond. Icontinue to admire the work of the Editorial Board andmanagement team who are entirely responsible for whatyou read every month. This is not only in editorial andproduction matters but also in advocacy for the Journalamongst potential authors ensuring that some of thevery good work we do publish is directed this way.Some of you will be aware that the Editorial Board

has met in person at the Royal Australasian College ofPhysicians (RACP) in Sydney every year, usually at theend of November. Given the nature of our lives, this hasmeant that the same editors are faced with a clash withevery meeting and are unable to have the same intensityof discussion that those of us who make the meeting areable to have. In 2016, to mix it up a bit, we met mid-yearand this was a successful meeting which allowed newvoices to express opinions and has helped to set theagenda for the next 18 months. One of the proposedchanges has taken effect from this issue: we now publishfull first names of authors and will continue to do so. Ibelieve this represents authorship much more accuratelyand creates a more personal relationship with authorswhen reading their work. (I am amused that the Brown-low Medal count still uses initials rather than givennames; overseas readers might have to use the power ofGoogle to understand that.) You may also have noticedthat the Journal displays the new RACP logo since theAugust issue.The Editorial Board membership was remarkably sta-

ble in 2016. Dr Joseph Ting from Queensland joined theboard in April as Emergency Medicine editor replacing,Dr Paul Middleton who was unable to continue in therole. We welcome Joseph to the group.One matter relating to the Editorial Board, which

occupied a large part of the discussion at the Editors’meeting, was that of gender equality as represented onthe board. There is no doubt that there is a significantmale predominance currently and if you have interest inthis topic, I would encourage you to read the excellenteditorial which appeared in the April 2016 issue, co-authored by two of our female editors (and an additionalauthor).1 This theme is to be continued in 2017. It is

certainly in my vision that we have more women on theboard, but nominations come from the special societiesand it is at this level that proactive steps need to betaken. Bring them on, I say. (I am reminded of the quoteattributed to the amusing American author Dave Barry:‘Men are like fine wine. They start out as grapes and it’sup to women to stomp on them until they turn intosomething acceptable to have dinner with’.)One of the members on our board, Professor Paul

Komesaroff, was voted as President-Elect of the AdultMedicine Division of the RACP at the elections held in2016. Congratulations Paul.Our impact factor (IF) for 2015 was 1.526. This is a

small decrease from last year’s IF of 1.644 and we lookat this every year and attempt to see what we mighthave done differently to move this upward. While this isan almost mandatory aim, I would direct the interestedreader to a recently published opinion piece by Milano,which questioned whether the pursuit of a higher IFwas, in fact, always in the best interests of an academicmedical publication.2 I suspect this discussion will con-tinue for a very long time.Manuscripts continue to come from all over the world

and China remains a growing source of submissions. Iam pleased that our panel of honorary biostatistical advi-sors has been able to provide very useful assistance toeditors when requested. You may remember that lastyear, I relayed the information that Wiley had partneredwith the company called Altmetric to track the ways inwhich articles are shared, used and discussed, includingin social media, blog posts, newspapers and magazines.You can see these scores with each published article onWiley Online Library.The podcast programmes highlighting important and

interesting matters related to papers published in theJournal have continued. Two podcasts in 2016, bothbased on Clinical Perspectives articles published nearto the podcast releases, were: Episode 9: The GutMicrobiome and Irritable Bowel Disease published inApril based on the paper by Schulberg and De Cruz;3

and Episode 14: Fever of Unknown Origin published inAugust 2016 accompanying the paper by Beresfordand Gosbell.4 You can find the podcasts through theRACP site (https://www.racp.edu.au/pomegranate/),but one can also subscribe to the Pomegranate seriesvia iTunes (https://itunes.apple.com/au/podcast/pomegranate/id1022747864?mt=2).

© 2017 Royal Australasian College of Physicians 5

Internal Medicine Journal (2017)

https://www.racp.edu.au/pomegranate/https://itunes.apple.com/au/podcast/pomegranate/id1022747864?mt=2https://itunes.apple.com/au/podcast/pomegranate/id1022747864?mt=2

The Journal now has a twitter account (@The_IMJ)where announcements about it are made and from whereone can link to issues. If you are scared to dip your feetinto the ‘twitterverse’, may I suggest you start by follow-ing us. If you would like to follow me personally, I can befound with the username @marrow (one envied by manyof my colleagues and one reward for being an earlyadopter). There are many places to learn about the use ofsocial media as it can assist in your education and profes-sional life. This paper by Thompson,5 while aimed athaematologists, is more generally applicable. Manyinternational scientific meetings are devoting sessions toaddress issues around social media. I would recommendthat you attend one if you are phobic or sceptical aboutsocial media. Having sat on an educational panel on thisissue at the Annual Scientific Meeting of the AmericanSociety of Hematology, I would be more than happyto answer any question about this important develop-ment in our professional communication.

Another forthcoming development in the Journal issoon to be instigated. Wiley has announced that it isdeveloping a smart device application (‘app’) that willallow you to access the Journal so much more conven-iently. It will be released initially for devices runningiOS. I await this release eagerly.

I do wish to re-emphasise how important VirginiaSavickis, the Editorial Manager of the Journal, is for thehigh quality of the finished product that we all seemonthly. Aparna Avasarala has ably stepped into anAssistant Editorial Manager role and kept things goingwhile Virginia was on long-overdue leave.

Once again, may I remind you to subscribe to the elec-tronic table of contents and automatically include alerts

to newly published papers? You can sign up at WileyOnline Library at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1445-5994, or for Fellows of the RACP viathe publications link at http://www.racp.edu.au. I wouldrecommend you explore this if you have not done soalready.

As I usually do, I here thank our dedicated team ofmanuscript reviewers for the wonderful work they dofor us and the authors whose submissions they reviewand always improve. Credit for their work will bemore easily identified now due to the partnership byWiley with Publons (www.publons.com), an initiative,which commenced in October 2016 for our reviewers.You will be asked to join or identify yourself for thisservice when you review for us and many other jour-nals. It will be immensely easier to identify the workreviewers have done in this way and will be useful,particularly for academics trying to show how muchthey actually do for research outside their ownauthored publications.

I invite you to read the names of our 2016 reviewerslisted after this article and if you bump into her, thankher for the essential and unpaid work offered to us. Ifyou are on the list, thank you from me too.

Despite my prediction last year, I am still here andplan to be so next year as well. I look forward to anotheryear of great reading.

Received 4 November 2016; accepted 6 November 2016.

doi:10.1111/imj.13326

Jeff Szer, Editor-in-ChiefInternal Medicine Journal

References

1 Bonomo Y, Zundel S, Martin JH.

Addressing unconscious bias for female

clinical academics. Intern Med J 2016; 46:

391–3.

2 Milano G. Is the pursuit of a higher

impact factor fully justified? Ann Oncol

2016. doi:10.1093/annonc/mdw565.

3 Schulberg J, De Cruz P. Characterisation

and therapeutic manipulation of the gut

microbiome in inflammatory bowel

disease. Intern Med J 2016; 46: 266–73.

4 Beresford RW, Gosbell IB. Pyrexia of

unknown origin: causes, investigation

and management. Intern Med J 2016; 46:

1011–6.

5 Thompson MA, Majhail NS, Wood WA,

Perales M-A, Chaboissier M. Social

media and the practicing hematologist:

Twitter 101 for the busy healthcare

provider. Curr Hematol Malig Rep 2015;

10: 405–12.

Editorial

© 2017 Royal Australasian College of Physicians6

http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1445-5994http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1445-5994http://www.racp.edu.auhttp://www.publons.comhttp://dx.doi.org/10.1093/annonc/mdw565

2016 IMJ Reviewers*

L.AdamsM.AdamsP.AdamsonL.AfrinW.AhmarC.AjaeroA.AjaniC.AkinS.AldousD.AllenD.AmesA.AnazodoN.AndersonJ.AndrewsP.AngchaisuksiriP.AngusM.AnpalahanG.ArendtsL.Arnheim-DahlstromA.ArteroD.AskewM.Asrar ul HaqJ.AthertonE.AtkinsV.AtkinsonJ.AttiaK.AuretM.AventA.AydogduB.AyresP.BadenochT.BadrickW.BaggA.BajelB.BakerR.BakerD.BalakrishnanP.BardinD.BarnesM.BarrasJ.BegunC.BennettL.BerkahnN.BettA.BianchiT.BlackmoreA.Blyth

S.BohlanderL.BolithoR.BootsM.BougheyJ.BourcierN.BowdenS.BowlerG.BraatvedtH.BrodatyP.BrooksN.BuckleyK.BuisingA.ButlerD.CampbellP.CampbellG.CaplanS.CarneyA.CatanchinF.ChahadiS.ChambersC.ChanG.ChanN.ChanR.CharlewoodJ.ChayT.ChemmanamD.ChippsK.ChowT.ChristmasE.ChuaF.ChungD.ClarkK.ClarkR.ClimiePS.CoatesPT.CoatesB.CochraneA.CohenS.CohneyD.ColeL.ColeM.CollinsP.ColmanW.ConnellS.ConnorI.CookJ.Cook

C.CooperM.CooperG.CorbettS.CorcoranT.CoxN.CranswickD.CrawfordG.CrawfordK.CrosierB.CrottyI.CrozierK.CuffG.CullB.CunhaJ.CurnowE.DabscheckH.DaviesB.DayR.DayT.DayP.De CruzC.De PasqualeJ.DeanG.DeedA.DelaneyA.DemirkolJ.DenholmE.DentE.DentonB.DepczynskiM.DeubleB.DevittG.DevlinH.DeweyX.DiaoM.DickinsonM.DoogueJ.DouglassF.DoukasP.DrennanJ.D’RozarioG.DukeE.DuncanA.DuncombeA.DunlopT.DunningJ.Dunuwille

D.DwyerJ.DyerN.EaddyO.EdP.EdmondsD.EisenE.EkinciK.EllardT.EwerN.EzardF.FahrtashM.FanningS.FauxP.FerrariD.FieldingR.FilshieJ.FinkP.FitzharrisP.FlanaganM.FlanneryS.FlemingK.FongM.ForbesA.FoyR.FrancisB.FreedmanA.FuL.GagliardiA.GaitatzisK.GandaP.GanlyS.GarlandD.GarofaloR.GarsiaP.GatenbyM.GeorgeD.GhiaB.GiannakopoulosH.GibbsC.GillebertL.GlennG.GobeM.GoldB.GoswamiR.GouckeL.GrayK.Greaves

*Reviewer names recorded from 1 November 2015 to 31 October 2016. Reviewer names not indicated will be published in the nextvolume.


M.GreenP.GreenbergJ.GreenfieldH.GrevilleM.GrossmannE.GuerotA.GuminskiJ.GuntonH.GurneyL.GustafssonA.GweeP.HaberK.HackmanA.HalabiJ.HallidayP.HamblinR.HancoxR.HandyH.HangerM.HannaJ.HarrisH.HealyS.HealyG.HebbardB.HeddleR.HendersonA.HerbertJ.HermannM.HewC.HillK.HillmanS.HilmerA.HiltonP.HissariaJ.HoG.HockingsC.HoganA.HoiR.HollowayG.HoltmannK.HorwoodJ.HoyP.HuntJ.HurleyR.IedemaJ.InamasuW.InderI.IrvingJ.IsbisterS.IssaS.JacksonC.JangC.Jellis

A.JenkinsC.JenkinsX.JiangB.JohnJ.JohnsP.JohnsonA.JohnstonC.JonesD.JonesK.JonesR.JonesM.JosephD.JoskeW.JoubertD.JoyceS.JunejaA.KalroK.KanjwalC.KarapetisP.KatelarisJ.KayeC.KeaneA.KearneyM.KennedyJ.KennerA.KermodeP.KerrL.KhoK.KimB.KnealeC.KoskyM.KotowiczT.KotsimbosS.KotwalL.KouladijanAV.KrishnanI.KronborgP.KublerS.KuertenK.KumareswaranM.KyiC.KyleH.LaneD.LangguthM.LattD.LauE.LauR.LawrenceJ.LaylandC.LaytonA.LeeEJ.LeeP.Lee

M.LeechS.LeederM.LevyI.LewisJ.LiJ.LiangWK.LimV.LimayeT.LinM.LinksG.LittlejohnM.Lloyd-JonesD.LoGiudiceC.LueckB.LukinG.LumM.LundG.LuxtonK.LyneH.MaG.MacdonaldR.MacIsaacS.MacPhersonF.MacraeE.MacyD.MahadavanR.MahajanS.MajoniG.MajorS.MajumdarJ.MakoveyR.ManassehA.MangoniG.MangosS.MannL.Maple-BrownH.MarfanJ.MarianiR.MarkhamT.MarkovicP.MarltonH.MarshallP.MartinS.MaseC.McArthurN.McCaffreyA.McCarthyN.McCarthyG.McCaughanG.McCollA.McCormackS.McDonaldV.McDonald

A.McElduffN.McGillS.McGrathS.McGuinnessS.McLachlanD.McLeodL.McMahonJ.McNeilZ.McQuiltenS.McRaeE.MerrimanS.MetcalfeK.MilburnT.MillsC.MitchellI.MitchellB.MitraK.MokA.MolgaP.MolleeR.MoonB.MorrisO.MorrisseyA.MortonR.Moss-MorrisA.MoynaghA.MudgeD.MudgeS.MulliganR.MullinsD.MurdochD.MurphyM.MusamehT.MusukaB.NairP.NashS.NavaR.NelsonP.NestelD.NewbyE.NewnhamC.NolanR.NolanR.NorrisK.NortonK.OatesM.ObeyesekereM.OdellR.OliveiraF.OliverD.O’NealS.OpatR.O’Rourke

2016 Reviewers List


C.O’SheaM.O’SullivanA.PadiglioneM.PaineJ.PandianP.PanegyresA.PastorR.PathakB.PathikN.PattonP.PavliL.PembertonC.PetersonsK.PetrieC.PezaroT.PhanJ.PhilipJ.PhillipsK.PhillipsM.PhillipsR.PicklesD.PilcherK.PileP.PillansR.PinkertonK.PittmanM.PledgerM.PolizzottoP.PooleS.PoplarJ.PorterN.PoselA.PowellL.PowellD.PowerA.PoyntenE.PretoriusJ.PriceD.PriorJ.ProiettoH.PullonS.QuinnD.RabboliniA.RajB.RamanP.RaoH.ReaS.ReadG.RiceS.RitchieD.Roberts

R.RobertsK.Robins-BrowneP.RobinsonJ.RogersL.RougheadE.RoweM.RudasA.RussellH.RussellC.RyanM.RyanS.SabesanJ.SahharD.SajkovR.SamantaL.Sánchez-HurtadoK.SanglaJ.SantamariaJ.SasadeuszP.SaulT.SchulzE.SegelovW.SelbyJ.SelvanayagamI.SeppeltN.ShackelS.ShahS.ShakibA.ShankarJ.ShawV.ShenoyP.SilbertD.SimpsonA.SinhalM.SinnottA.SmithM.SmithB.SnowB.SnyderR.SnyderJ.SomaratneS.SoodR.SpearingD.SpelmanA.StaibH.StampferR.StarkR.StellW.StevensonM.StewartP.Stobie

C.StoreyL.StraneyS.StranksA.StreetA.SturgessC.SullivanD.SullivanK.SumithranS.SwaminathanJ.SwampillaiC.TamB.TaylorC.TaylorG.TaylorH.TaylorA.TehV.ThakkarE.TheakstonM.ThiebenV.ThijsR.ThomasA.ThompsonC.ThompsonP.ThompsonC.ThomsonN C.ThomsonT.ThynneD.ToplissA.TownsendC.TraillH.TranJ.TrotmanL.TroyP.TuchP R.TuinmanR.TurnerS.TwiggJ.Tye-DinK.TymmsJ.VaileS.van NunenN.van PeltM.VarelaP.VargheseA.VincentS.VinodR.VisvanathanA.VoskoboinikR.WalkerP.WallbridgeE.Walpole

W.WangJ.WardJ.WarkM.WarnerC.WasywichG.WatererA.WatsonA.WeiJ.WeilR.WeinkoveS.WeinsteinJ.WentworthS.WesselyD.WhalleyB.WhiteC.WhiteO.WhiteA.WhyteI.WilcoxI.WillliamsM.WilliamsJ.WilsonA.WongD.WongJ.WongM.WongV.WongE.WoodP.WoodT.WoodN.WoodwardC.WorsnopJ.WorthingtonT.WuI.YangC.YatesN.YeomansD.YeungG.YildizA.YoungC.YoungG.YoungL.YoungM.YudiM.ZacharinJ.ZalcbergA.ZekryN.Zeps

2016 IMJ Reviewers


EDITORIAL

Towards equality

Context

For nearly 30 years, there have been similar numbers of

men and women in Australasian medical schools. Now

there are women at senior levels in all fields of medicine,

including at the top of health and training institutions.

As there is no evidence women leave medicine perma-

nently at higher rates than men, sometime in the next

two decades, half of all doctors will be female. Predic-

tions – both favourable and unfavourable – have been

made as to how having a profession with an equal gen-

der split will affect the patient–physician relationship,

delivery of care and even the medical profession itself.1,2

Will health needs be met? Further, will all doctors have

an equal chance of reaching their potential at work, as

well as achieving a work–life balance? This paper dis-

cusses some of the issues from a predominantly feminist

gender equality perspective.Most health systems show horizontal (confined to cer-

tain specialties) and vertical (confined to lower levels)‘segregation’ of women doctors.3 Further, women doc-tors earn less than men, even when corrected for hoursof work, specialty and age.4 Women are over-represented in specialties, such as general practice,paediatrics, and obstetrics and gynaecology, and under-represented in surgical specialties and in senior leader-ship positions.5–7 Part of the reason for the lack ofwomen in senior roles may be that it is still too soon forwomen to participate fully at the higher levels. InNew Zealand, women doctors are younger on averagethan men, with 43% under the age of 40, comparedwith 27% of men.5

There is little effect of gender on motivation to under-take a medical career in the first place.1 The main factorsin a medical career choice are interest, intellectual chal-lenge and perceived fit with the nature of the work.8,9 Atselection and through medical school, there is no dis-cernible difference by gender in terms of academic abilityor in traits important for medicine, such as communica-tion skills, empathy and professionalism.10

Medicine is relatively unusual in the enmeshment oftraining with service delivery.11 In the early postgraduateperiod, resident medical officers (RMO) are essentiallycompeting in two markets – one to get a job and theother to get onto a training scheme. Due to the length ofmedical training, it is almost inevitable that years oftraining overlap with raising a family.7 For women

doctors, patterns of family life have stayed remarkablyconsistent over decades.9,12–14 Over three quarters willhave children, with the mean age at first child just over30. The vast majority will be the primary caregivers, withpartners who work full time. Far more women thanmen interrupt training. Per child, on average, this is6 months out of the workforce, plus another 20 monthsworking part time.12 On the other hand, more medicalwomen than men live alone.12 Either way, womenshoulder more domestic duties, while training and work-ing. The problem may be more marked for women whoare M�aori, Aboriginal or from Pacific or Torres StraitIslands who may face additional expectations.

Reports continue of work environments that lackinclusivity, particularly for women.8 There are challengesof balancing long hours of acute specialties with caregiv-ing.15 Women doctors have higher rates of mental illnessand suicide than men,16,17 with potential factors beingrole strain, harassment, lack of role models and sup-port.18 A recent survey of New Zealand senior doctorsfound 50% with significant burnout, with higher rates inwomen (59%) and those aged 30–39 (62%).19 Theissues for women doctors taking a higher degree andentering academia are similar and were covered in thisjournal recently.20,21

Moving forward

To many, the present gender inequality in medical careertrajectory is not acceptable. If we are to achieve fasterand more meaningful change for women, changes to thevalues, outcomes and practices of medical training andhealthcare systems are required. What is proposed here-after is not intended to come at the expense of men. Sys-tems which minimise unnecessary barriers to any doctorreaching his/her desired potential, and support the abil-ity to maintain a productive and satisfying working life,would seem to benefit all.

Changes in workers

Women doctors may now have more colleagues-in-armsas they strive for full equality. Health workforces aremore ethnically diverse. Career expectations of genera-tion X and Y doctors differ from their baby boomer col-leagues. Younger doctors on average place more


emphasis on work–life balance, and are less prepared toendure long hours for little tangible reward.22 They mayvalue more individualised approaches to learning andworking, and less directional leadership styles.

Changing nature of work

The accepted norms for medical work patterns evolvedwhen men outnumbered women, and when there wereworkforce shortages in the face of increased healthdemands. Yet, there are still concerns expressed that amore feminised workforce will add to workforceshortages.23 Locally, mean hours worked by women doc-tors have been stable at around 40 per week.5 This isnow only about 6 h fewer than for men, who are in turnreducing their hours steadily.5 Not infrequently, awoman’s hours may drop or even stop for a time, andthen increase again – the so-called ‘M’-shapedcareer.10,24 Many other doctors work part time at somestage in their careers, whether to undertake training,pursue other roles, when ill or pre-retirement. Thus far,the health system has proved able to cope. Moreover,work practices are changing rapidly towards lower work-ing hours, better information and communication tech-nology, and more working in teams. These trends arefavourable to those wanting to work more flexibly. Nowthat the number of Australasian medical graduates is ris-ing, there ought to be enough doctors to offset not onlythe gender effect on hours of work, but allow doctors towork fewer hours when they need to.On the other hand, work cultures may be slower to

change. It is curious that women outnumber men inacute, intensive specialties, such as obstetrics or paediat-rics, yet are under-represented in most surgical disciplines.In the former, there are large numbers of senior womenwho may act as role models, and ensure work practicesare family-friendly. Women surgeons have suggested theirgender still marks them out as ‘other’, and that thereneeds to be more discussion of how, for example, sur-geonhood and parenthood may be mutually sustaining.25

Training and employment

Doctors with current or anticipated family responsibil-ities may have to compromise permanently on their ini-tial job aspirations for more predictability and flexibilityin work practices.26 At present, this forced choice differ-entially affects women. To address this requires multi-partite commitment to equal employment opportunitiesin selection and employment, as well as education andtraining. Most colleges now allow more flexible training.The Royal Australasian College of Physicians is one ofthe most generous, allowing a minimum of four sessions

per week while training, with interruption for up to2 years. Recently, the Royal Australasian College of Sur-geons began to consider changes to training to meet bet-ter the needs of trainees.27 However, there are stillrelatively few part-time posts for RMO compared withthe numbers who may want them. Furthermore, somepart-time positions may not count towards training,which further slows the career trajectory.The challenge is for colleges and employers to under-

stand this, and to provide and accept more flexible workand training practices. Apart from the effect on indivi-duals, specialties which continue to expect long hours,continuous training and overly demanding on-callrequirements may face difficulty in recruiting an accept-ably diverse workforce.6

Women in leadership

Women do not take on traditional leadership roles at thesame rate as men. Given the plethora of medical leader-ship roles needed to run the healthcare system and train-ing institutions, addressing this inequality is urgent.Current medical leadership paradigms may involve

long hours, time away from home and subjugation offamily needs.28 Further, women’s views on leadershipattributes may differ to those of men.29 Finally, not allleadership positions are the same. For example, it maybe a trap for women academics to take on large teachingcoordination or other management. These roles may notbe rated equally to, or even detract from, activities suchas research or external roles that traditionally helpadvancement to top positions.30 This suggests the widersystem has to adapt: enhanced examination of the gen-der stereotypes that inform cultural assumptions aboutleadership potential and effectiveness is in order.15 Onlywhen systems proactively value what each individualmay bring, not expecting he/she will necessarily fit atypical ‘masculine’ mould, will leadership roles be moreattractive to more women.31

Success in medicine

Familiar metrics for defining career success are oftenexternal and countable, such as postgraduate qualifica-tions or degrees, grade/seniority, awards, research grantsand outputs, or formal leadership positions. Instead,might we value the worth of every individual doctor inthe health system? The workforce for a community’shealth needs in the future has to cope with increasingnumbers of aged and frail patients, with many of thesescopes already a preference for women doctors.5,32

Instead of rating ‘success’ necessarily by titles, seniority,remuneration, academic papers or time to earn specialty

Editorials


qualifications,13,33,34 how about systems being rated byoutcomes of patient satisfaction and health, cost-effectiveness of healthcare utilisation, or even the well-being of doctors and trainees?35 If we are to use this lens,measures are needed to ensure all doctors earn fair rec-ognition for their effective contributions to patient careand other key aspects of health and education, includingin financial terms and time for these roles.

The workforce pipeline

Individual students and taxpayers make a heavy invest-ment in undergraduate medical education. It is a waste ifthis does not translate fully to health system gain. In theearly years of employment which is often year to year,RMO may have to forge their own path every time theyneed to take time out or work less than full time. As thetime a doctor may want to work reduced hours may berelatively short compared with a working lifetime, hav-ing to change career path because of inflexibility in jobsor training schemes is an unnecessary loss of potential.

More systematic, longitudinal approaches to maintain-ing and sustaining doctors in the workforce are required.Such a system would have oversight of the training statusof all students and RMO in a jurisdiction. It would keeptrack of RMO who may be temporarily out of the work-force, and facilitate re-entry back into the workforce. Themost vulnerable to falling out of the training pipeline arethose who are not in the majority group. While thereought to be more part-time career-advancing jobs as anorm, there might also be discretionary funds for specificcareer maintenance positions, as was the case inNew Zealand before the health reforms of the 1990s.36

At every level, sound career advice as well as pastoralsupport for those facing the triple challenges of studying,parenting and working, are necessary.6

Conclusions

Contemporary women doctors have been chosen fortheir workforce potential. They have aptitude and

preference for many essential roles in Australasianhealthcare today and into the future. They work on aver-age a 40 h per week. Soon, half the medical workforcewill be women. There is no going back, as to limit theproportion of women entering medical schools in Aus-tralasia would breach their rights and be politicallyuntenable.

We have good cause to celebrate the increasing num-bers of women at the pinnacle of medical practice, whoare shaping the future of healthcare and acting as bea-cons for those who follow. Clearly these women haveproven the ‘glass ceiling’ can be shattered. Yet, mostwomen still face a ‘sticky floor’,37 balancing family lifewith training and work, with a persisting sense of unnec-essarily high barriers to career progression.

Health and training systems must adapt in order toembrace what the female half of the medical workforcecontributes. In many areas, the components are in place.Joined-up systems for medical workforce development,both in work and training, might take a whole-of-careerview, and provide mentorship and sponsorship, espe-cially over transition points. Clear and fair mechanismsto get on and off the training ladder,10 as well as the pro-vision of appropriate jobs for life circumstances, wouldhelp not only women, but all doctors. Women may bemore inclined to take on leadership roles when work-places truly value their perspectives and the type of lead-ership they exhibit. In turn, these women would furthershape the systems in which they work.

Acknowledgement

Dr Karina McHardy (ACC) provided valuable commentson the manuscript.

Received 11 October 2016; accepted 26 October 2016.

doi:10.1111/imj.13303

Phillippa PooleDepartment of Medicine, Faculty of Medical and Health Sciences,

The University of Auckland, Auckland, New Zealand

References

1 Levinson W, Lurie N. When most

doctors are women: what lies ahead?

Ann Intern Med 2004; 141: 471–4.

2 Laurance J. The Medical Timebomb: ‘Too

Many Women Doctors’. London: The

Independent; 2004.

3 Kilminster S, Downes J, Gough B,

Murdoch-Eaton D, Roberts T. Women

in medicine – is there a problem? A

literature review of the changing gender

composition, structures and

occupational cultures in medicine. Med

Educ 2007; 41: 39–49.

4 Ly D, Seabury S, Jena A, Newhouse R.

Differences in incomes of physicians in

the United States by race and sex:

observational study. BMJ 2016; 353:

i2923.

5 Medical Council of New Zealand. The

New Zealand Medical Workforce in 2013

and 2014. Wellington: Medical Council

of New Zealand; 2016.

6 Heslop BF, Leatham MC. Where are

tomorrow’s specialists? N Z Med J 1995;

108: 407–10.

7 Angell M. Women in medicine: beyond

prejudice. N Engl J Med 1981; 304:

1161–3.

8 Hill E, Vaughan S. The only girl in the

room: how paradigmatic trajectories

deter female students from surgical

careers. Med Educ 2013; 47: 547–56.

9 Macdonald C, Cawood T. Factors

influencing career decisions in internal

Editorials


medicine. Intern Med J 2012; 42:

918–23.

10 Deech B. Women in Medicine: Making a

Difference. London: Department of

Health; 2009.

11 Skinner C. Re-inventing medical work

and training: a view from generation X.

Med J Aust 2006; 185: 35–6.

12 Lawrence J, Poole P. Career and life

experiences of New Zealand women

medical graduates. N Z Med J 2001; 114:

537–40.

13 Durham G, Salmond C, Eberley J.

Women and Men in Medicine. Wellington:

Department of Health; 1989.

14 Dennerstein L, Lehert P, OramsR,

Ewing J, BurrowsG. Practice patterns and

family life – a survey ofMelbournemedical

graduates.Med J Aust 1989; 151: 386–90.

15 Heslop B. For better or worse? Women

doctors at the end of the decade. N Z

Med J 1987; 100: 176–7.

16 Graham J, Albery I, Ramirez A,

Richards M. How hospital consultants

cope with stress at work: implications

for their mental health. Stress Health

2001; 17: 85–9.

17 Robinson G. Stresses on women

physicians: consequences and coping

techniques. Depress Anxiety 2003; 17:

180–89.

18 Ward S, Outram S. Medicine: in need of

a culture change. Intern Med J 2016; 46:

112–16.

19 ASMS. "Tired, Worn-Out and Uncertain":

Burnout in the New Zealand Public

Hospital Senior Medical Workforce.

Wellington: ASMS; 2016.

20 Traill C, Januszewski A, Larkins R,

Keech A, Jenkins A. Time to research

Australian female physician-

researchers. Intern Med J 2016; 46:

412–19.

21 Bonomo Y, Zundel S, Martin J.

Addressing unconscious bias for female

clinical academics. Intern Med J 2016;

46: 391–3.

22 McCrindle M, Wolfinger E. The ABC of

XYZ: Understanding the Global

Generations. Sydney: UNSW Press; 2009.

23 National Health Workforce Taskforce.

Health workforce in Australia and

factors for current shortages. KPMG;

2009.

24 Allen I. Women doctors and their

careers: what now? BMJ 2005; 331:

569–72.

25 Hill E, Solomon Y, Dornan T,

Stalmeijer R. ’You become a man in a

man’s world’: is there discursive space

for women in surgery? Med Educ 2015;

49: 1207–18.

26 Lawrence J, Poole P, Diener S. Critical

factors in career decision making for

women medical graduates. Med Educ

2003; 36: 1–9.

27 Lander R, Ferguson C, Koea J, Kong K,

Barrett C. Diversity in surgery. N Z Med

Student J 2016; 22: 5–6.

28 Sewell J. Changing roles and challenges

faced by women in medical specialties.

Intern Med J 2002; 32: 38–9.

29 Sewell J. The Female of the Species-Women

FRACPs and Trainees. Sydney: RACP;

1992.

30 Edmunds L, Ovseiko P, Shepperd S et al.

Why do women choose or reject careers

in academic medicine? A narrative

review of empirical evidence. Lancet

2016. doi:http://dx.doi.org/10.1016/

S0140-6736(15)01091-0

31 Wilson S. Thinking Differently About

Leadership: A Critical History of Leadership

Studies. Cheltenham: Elgar; 2016.

32 Lakhan S. Diversification of

U.S. medical schools via affirmative

action implementation. BMC Med Educ

2003; 3: 1–6.

33 Levinson W, Tolle S, Lewis C. Women

in academic medicine-combining career

and family. N Engl J Med 1989; 321:

1511–17.

34 McManus I, Smithers E, Partridge P,

Keeling A, Fleming P. A levels and

intelligence as predictors of medical

careers in UK doctors: a 20 year

prospective study. BMJ 2003; 327:

139–42.

35 Wallace J, Lemaire J, Ghali W.

Physician wellness: a missing quality

indicator. Lancet 2009; 374: 1714–21.

36 Poole P. Room for more women in

clinical specialties. N Z Med J 2000; 113:

105–7.

37 Tesch B, Wood H, Helwig A, Nattinger

A. Promotion of women physicians in

academic medicine: glass ceiling or

sticky floor? JAMA 1995; 273: 1022–5.

EDITORIAL

Absence of evidence: antimicrobial prescribing in neonates,elderly and pregnant women

Antimicrobial resistance has been declared by the WorldHealth Organization a global crisis.1 The response to thisshould be two-fold: (i) development of new antimicro-bials; and (ii) ensuring safe and effective use of existingantimicrobials. In this issue of Internal Medicine Journal,Chean et al.2 highlight the reluctance to prescribe genta-micin in pregnant women, despite the low rate of seriousside effects. The authors emphasise the importance ofappropriate prescribing of gentamicin in this vulnerablepopulation, rather than complete avoidance of its use.2

The difficulties in prescribing antimicrobials in

populations where evidence is lacking, namely pregnantwomen, also extend to patients at the extremes of age(i.e. neonates and the elderly). The altered physiology(i.e. renal clearance, total body water) in these popula-tions leads to challenges in dosing due to altered drugpharmacokinetics. In this editorial, we primarily focuson the issues associated with prescribing gentamicin.There is a concerning paucity of data on dosing recom-

mendations for antimicrobials, including gentamicin, atthe extremes of age. Early phase clinical trials aredesigned to determine safety profile and dosage of new

Editorials


http://dx.doi.org/10.1016/S0140-6736(15)01091-0http://dx.doi.org/10.1016/S0140-6736(15)01091-0

drugs and almost exclusively study healthy adults aged18–65 years. Consequently, data from healthy adults arefrequently extrapolated to guide dosing in neonates,children and older adults (aged >65 years), despite sub-stantial physiological differences in these age-groupswith resultant effects on drug pharmacokinetics.3,4

If children are included in clinical trials, this rarelyextends to neonates. Although neonatal drug develop-ment pathways are well defined and legislation in theEuropean Union and the United States exist to promotepaediatric clinical trials, a review in 2009 found neonateswere included in only 6% of paediatric studies.5 Conse-quently, neonatal drug formularies often rely on consen-sus to determine dosing recommendations and there issignificant variability between guidelines, particularly forantibiotics.6 Without sufficient clinical trials, paediatri-cians often use drugs outside the approved indications(off-label) or without marketing authorisation (unli-censed).7 In neonates, off-label prescribing and use ofunlicensed drugs, particularly antimicrobials, is commonand increases the risk of medication errors, adverse drugreactions and unpredictable drug concentrations whichmay result in toxic or ineffective treatment.7,8 Further-more, this raises ethical issues with regard to safety mon-itoring and informed consent.3 Although there arefinancial and ethical barriers to including neonates inclinical trials, this must be balanced against the wide-spread use of drugs that have not been rigorously testedin this age-group.3

In neonates, reduced gastric emptying results inunpredictable drug absorption, while the volume of dis-tribution is increased due to high total body water con-tent and reduced plasma protein binding.9 Renalexcretion of drugs is variable and increases with weight,gestational age and postnatal age.9 Appropriate dosing ofrenally cleared antibiotics such as aminoglycosides, car-bapenems and vancomycin is therefore particularly chal-lenging.9 Furthermore, drug toxicity can be difficult toidentify in this age-group with potential life-longimplications.

At the other end of the age spectrum, the inclusionof elderly patients in drug trials is also generallyavoided due to concerns regarding inferior treatmentresponse, toxicity and treatment-related mortality.10,11

However, recent studies have shown similar survivaland toxicity outcomes in early phase drug trials invol-ving elderly patients, supporting the inclusion of thispopulation in clinical trials.10,11Various age-relatedchanges affect drug pharmacokinetics in elderlypatients. Particularly in the frail elderly, there is areduction in lean body weight and increase in adiposetissue, resulting in an increased half-life of lipid-soluble antimicrobials (e.g. rifampicin,

metronidazole).12 In addition, total body water isreduced, increasing the concentration of water-solubleantimicrobials (e.g. gentamicin, vancomycin), while adecrease in albumin results in increased free concen-trations of acidic antimicrobials (e.g. penicillin, cef-triaxone).12 Age-related kidney impairment increasesthe half-life of water-soluble antimicrobials, and inad-equate renal dose adjustment is a frequent error whenprescribing antimicrobials in elderly patients, particu-larly with cephalosporins and gentamicin.13,14 There isalso a greater risk of drug interactions due to thehigher rate of polypharmacy with increased adversedrug reactions.14 Although dosing guidelines includerenal dose adjustment, for most drugs, standard drugformularies do not include dosing guidelines specifi-cally targeted to elderly patients.

Chean et al.2 highlight the under-utilisation of gen-tamicin for Gram-negative infections in pregnantwomen. Gentamicin is an aminoglycoside antibioticwith rapid bactericidal action and resistance is rare,even with multi-drug resistant organisms. In neo-nates, gentamicin is commonly prescribed for theempirical treatment of sepsis.15 Despite its frequentuse, data are lacking on the optimal dosing regimenof gentamicin in this age-group, and moreover, thetarget peak and trough concentrations.15 This isreflected by the inter-institutional variation in thera-peutic drug monitoring protocols, both nationally andinternationally.16 Although the peak level of gentami-cin correlates with efficacy,17 few units monitor peaklevels even in the setting of Gram-negative sepsis.16

Furthermore, trough concentrations less than1–2 mg/L are standard of care to reduce the risk ofnephrotoxicity; however, this is based on adult datafrom 30 years ago.18,19

Gentamicin is frequently avoided in elderly patientsdue to concerns regarding ototoxicity and renal toxic-ity.20 There are no specific guidelines on appropriategentamicin use in the elderly population, althoughthe Therapeutic Guidelines recommend avoidance in‘advanced age’ (e.g. 80 years or older), depending oncalculated renal function.21 Of note, gentamicin has asignificantly lower clearance in the frail elderly com-pared to non-frail elderly and lean bodyweightshould be used to estimate creatinine clearance.22

Increasing age is a risk for developing gentamicin-induced nephrotoxicity due to pre-existing renalimpairment and prescription of concomitant nephro-toxins.23 Although there is evidence to suggest thatcourses lasting longer than 1 week are associatedwith an increased rate of nephrotoxicity in adults70 years or older,24 there are no data on the preva-lence of nephrotoxicity in elderly patients treated

Editorials


with short courses of appropriate renally adjusteddoses of gentamicin.It is ironic that data on antimicrobial dosing are lacking

in the most vulnerable of populations, that is, neonatesand elderly patients. With emerging antimicrobial resist-ance, there is an urgent need for pharmacokinetic andsafety data for existing antimicrobials to optimise currentdosing and therapeutic drug monitoring regimens. Fur-thermore, in the development of new antimicrobials,drug trials must be extended to include neonates and eld-erly patients. However, the ethical and financial limita-tions around trials in these populations are likely to beenduring. While opportunistic pharmacokinetic studiesusing population pharmacokinetic modelling may enable

further establishment of evidence-based dosing guide-lines, clinical validation is still required. The drive forimprovement in safe and effective prescribing in thesepatient groups needs to be led by government throughfinancial incentives to drug companies and investigators.

Received 14 June 2016; accepted 10 October 2016.

doi:10.1111/imj.13310

Alison Boast1,2 and Amanda Gwee1,2,31Infectious Diseases Unit, Department of General Medicine, The

Royal Children’s Hospital, 2Infectious Diseases and Microbiology,

Murdoch Children’s Research Institute, and 3Department of

Paediatrics, The University of Melbourne, Melbourne, Victoria,

Australia

References

1 Global Action Plan on Antimicrobial

Resistance World Health Organization.

Geneva: World Health Organization;

2015 [cited 2016 Oct 4]. Available from

URL: http://www.wpro.who.int/entity/

drug_resistance/resources/global_

action_plan_eng.pdf

2 Chean R, Leung L, Garland S. Use of

gentamicin in pregnancy: the

’alphabets’ are not elementary. Intern

Med J 2016; 47: 124–125.

3 Kimland E, Odlind V. Off-label drug use

in pediatric patients. Clin Pharmacol Ther

2012; 91: 796–801.

4 Shenoy P, Harugeri A. Elderly patients’

participation in clinical trials. Perspect

Clin Res 2015; 6: 184–9.

5 Ward RM, Kern SE. Clinical trials in

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6 Leroux S, Zhao W, Betremieux P,

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7 Cuzzolin L, Atzei A, Fanos V. Off-label

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8 Conroy S. Association between licence

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9 Ku LC, Smith PB. Dosing in neonates:

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10 Mahipal A, Denson AC, Djulbegovic B,

Lush R, Kumar A, Juan TH et al. Effect

of age on clinical outcomes in phase

1 trial participants. Cancer Control 2015;

22: 235–41.

11 Khan KH, Yap TA, Ring A, Molife LR,

Bodla S, Thomas K. Phase I trial

outcomes in older patients with

advanced solid tumours. Br J Cancer

2016; 114: 262–8.

12 Faulkner CM, Cox HL, Williamson JC.

Unique aspects of antimicrobial use in

older adults. Clin Infect Dis 2005; 40:

997–1004.

13 Leong CL, Buising K, Richards M,

Robertson M, Street A. Providing

guidelines and education is not enough:

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Melbourne Hospital. Intern Med J 2006;

36: 37–42.

14 Hilmer SN, McLachlan AJ, Le

Couteur DG. Clinical pharmacology in

the geriatric patient. Fundam Clin

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15 Kent A, Turner MA, Sharland M,

Heath PT. Aminoglycoside toxicity in

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16 Kadambari S, Heath PT, Sharland M,

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Editorials


http://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdfhttp://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdfhttp://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdf

REVIEW

Timely initiation of chemotherapy: a systematic literaturereview of six priority cancers – results and recommendationsfor clinical practiceM. Alexander,1,2 R. Blum,3 K. Burbury,4 J. Coutsouvelis,5,6 M. Dooley,5,6 O. Fazil,7 T. Griffiths,8 H. Ismail,9

S. Joshi,10 N. Love,11 S. Opat,12 P. Parente,13,14 N. Porter,12 E. Ross,15 J. Siderov,16 P. Thomas,17 S. White,18

S. Kirsa1 and D. Rischin19

Department of 1Pharmacy, 4Haematology, 11Nursing, and 19Medical Oncology, Peter MacCallum Cancer Centre, Department of 2Epidemiology andPreventive Medicine, 6Centre for Medicine Use and Safety, and 14Eastern Clinical School, Monash University, 5Pharmacy Department, Alfred Health,7Pharmacy Department, and 12Department of Clinical Haematology, Monash Health, 8Olivia Newton-John Cancer Wellness and Research Centre, and16Pharmacy Department, Austin Health, Departments of 9Pharmacy, and 17Nursing, Royal Women’s Hospital, 13Department of Medical Oncology,Eastern Health, 15Division of Neurosciences, Cancer and Infection Medicine, The Royal Melbourne Hospital, and 18Department of Medical Oncology,Northern Hospital, Melbourne, 3Department of Medical Oncology, Bendigo Health, Bendigo, and 10Department of Medical Oncology, Latrobe RegionalHospital, Traralgon, Victoria, Australia

Key wordscancer, chemotherapy, drug therapy, qualityindicator, timely.

CorrespondenceMarliese Alexander, Locked Bag 1 A’BeckettStreet, Melbourne, Vic. 8006, Australia.Email: [email protected]

Received 30 August 2015; accepted11 January 2016.

doi:10.1111/imj.13190

Abstract

This review evaluated the association between time-to-chemotherapy (TTC) and sur-

vival in six priority cancers. A systematic review of the literature was undertaken for

papers indexed in the MEDLINE and Cochrane Library databases from the earliest

index until April 2014. The methodology used has been published in a separate paper

(Guidelines for timely initiation of chemotherapy: a proposed framework for access to

medical oncology and haematology cancer clinics and chemotherapy services). The

optimal timing of chemotherapy in breast cancer is unclear as available studies are of

low quality, report inconsistent results and are limited to the adjuvant setting. How-

ever, increased TTC may have a negative prognostic impact, and delays beyond 4 weeks

should be avoided. Studies suggest that the optimal timing for initiation of adjuvant

chemotherapy for surgically resected colorectal cancer is 4–8 weeks post-surgery. Tim-

ing of chemotherapy for metastatic colorectal cancer does not influence survival. There

is a paucity of studies to guide the timing of chemotherapy for the treatment of lym-

phoma and myeloma; no definitive conclusions can be drawn, and clinician discretion

should be applied. The optimal timing of chemotherapy in lung cancer is unclear; how-

ever, rapid tumour growth and poor disease prognosis suggest that delays should be

avoided wherever possible. The optimal timing of chemotherapy in ovarian cancer is

unclear as available studies are of low level, report inconsistent results and are limited

to the post-surgery setting; however, increased TTC may have a negative prognostic

impact; therefore, delays beyond 4 weeks should be avoided.

Introduction

Timely initiation of chemotherapy should be informed by

the best available evidence. This review was conducted

to determine whether delayed chemotherapy initiation

results in reduced survival outcomes in patients receiving

systemic chemotherapy for the treatment of breast, colo-

rectal, lung or ovarian cancer and lymphoma or mye-

loma by systematically searching the published literature.Current international guidelines recommend (and

publicly report performance against) a maximum time totreatment (for any treatment modality) of 4 weeks from

Funding: This literature review was funded by the CancerStrategy and Development Unit, Victorian Department ofHealth and Human Services. Project funding included theappointment of Marliese Alexander and Natalie Love as projectofficers. Marliese Alexander was additionally supported by theAustralian Postgraduate Award from the Department ofEpidemiology and Preventative Medicine, Monash University.No other authors received funding for their contributions.Conflict of interest: These guidelines were producedindependently by members of the project writing group. Noconflicts of interest are declared.


decision-to-treat for any anticancer therapy.1–3 At thetime of undertaking this review, in Victoria and acrossAustralia, frameworks providing guidance for the appro-priate timeliness of care were available for surgery andradiotherapy treatment modalities.4,5 However, equiva-lent guidance for chemotherapy was lacking.Updated Australian cancer optimal care pathways are

available.6 Although not specific for chemotherapy, theydo include recommendations relating to timeliness ofcare. For colorectal cancer, the maximum recommendedinterval from the development of a management plan tochemotherapy initiation was 3 weeks for neoadjuvantchemotherapy and 3 months for adjuvant chemother-apy.7 For lung cancer, a maximum interval of 6 weeksfrom initial specialist referral to initial treatment wasrecommended.8 While the updated ovarian cancer path-way was available only in draft form at the time of writ-ing, it was recommended that chemotherapy should beinitiated within 4 weeks of the decision to treat with che-motherapy.9 Updated pathways for breast cancer andlymphoma were not available. However, a previous ver-sion of the breast cancer pathway10 recommended thatsurgical review should occur within 2 weeks of generalpractitioner referral; no recommendations relating totimeliness of treatment generally or chemotherapy morespecifically were made, and a previous version of thepathway for non-Hodgkin lymphoma (NHL) did not con-tain any recommendations for the timeliness of chemo-therapy initiation.11 Optimal care pathways for otherlymphomas and myelomas have not been published,highlighting the importance of the current review inguiding local practice and health policy.

This review of time-to-chemotherapy (TTC) in cancerwas undertaken to inform healthcare policy across hos-pitals in Victoria, Australia and helped in the develop-ment of guidelines for the timely initiation ofchemotherapy (available on https://www2.health.vic.gov.au/about/health-strategies/cancer-care/cancer-services-framework/chemotherapy-guidelines).

Methods

The methods used for this systematic review are outlinedin the position paper.12 However, in brief, the MEDLINEand Cochrane Library databases were searched for arti-cles published in the English language from the earliestindex to April 2014, presenting data on the associationbetween TTC and survival in six priority cancers (breast,colorectal, lung (non-small-cell and small-cell), ovariancancer or lymphoma and myeloma) (Supporting infor-mation, Table S1). The reference lists of articles identifiedby the literature search were also reviewed for additionalpublications. Google and Google Scholar were searchedto identify non-indexed grey literature regarding lym-phoma and myelomas. All titles and abstracts were thenmanually screened, and studies that did not meet theinclusion criteria were omitted. The quality of the pub-lished studies was assessed using standard protocols fromthe National Health and Medical Research Council(NHMRC) of Australia and, where relevant, the Newcas-tle Ottawa Scale for assessing the quality of non-randomised studies (Table 1).13,14

Table 1 Grades and levels of evidence according to the National Health and Medical Research Council of Australia (NHMRC) and the NewcastleOttawa Scale (NOS) for assessing the quality of non-randomised studies13,14

Description

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

LevelI A systematic review of level II studiesII A randomised controlled trialIII-1 A pseudo randomised controlled trial (i.e. alternate allocation or some other method)III-2 A comparative study with concurrent controls (non-randomised experimental trial, cohort study, case–control study,

interrupted time series with a control group)III-3 A comparative study without concurrent controls (historical control study, two or more single-arm studies, interrupted

time series without a parallel control group)IV Case series with either post-test or pretest/post-test outcomes

Quality ratingMaximum four points Selection criteria – representativeness of exposed cohort, selection of non-exposed cohort, ascertainment of exposure,

demonstration that outcome was not present at start of study.Maximum two points Comparability – comparability of cohorts on the basis of design and/or analysis.Maximum three points Outcome – assessment of outcome, follow-up time, adequacy of follow up of cohorts.

Time-to-chemotherapy and survival


https://www2.health.vic.gov.au/about/health-strategies/cancer-care/cancer-services-framework/chemotherapy-guidelineshttps://www2.health.vic.gov.au/about/health-strategies/cancer-care/cancer-services-framework/chemotherapy-guidelineshttps://www2.health.vic.gov.au/about/health-strategies/cancer-care/cancer-services-framework/chemotherapy-guidelines

Breast cancer

The search strategy yielded 1659 results (Supporting infor-mation, Fig. S1), 1537 from MEDLINE, 112 from the

Cochrane Library and an additional 10 papers from refer-

ence list review. Of these, nine papers were included in

the final review to answer the question of whether TTC

impacts survival outcomes in breast cancer. All studies

reported outcomes based on the TTC interval from

date of surgery to commencement of adjuvant

chemotherapy.15–23 No studies were available in the set-

ting of neoadjuvant or palliative chemotherapy – a notable

evidence gap. As described in Table 2, studies varied by

publication date (1982–2014) and size (n = 77–34 097)

and reported data for a heterogeneous group of patients

(stages I–IV). Study outcomes are detailed in Table 3. Five

of nine studies reported a significant association between

delayed TTC and increased risk of death.A single randomised controlled trial addressing the

prognostic influence of early or delayed adjuvant che-

motherapy in advanced breast cancer was identified.22

While the generalisability of this study is poor (first pub-

lished 1977), it provided the highest level of evidence

(level II) in the adjuvant setting. A total of 75 pre-

menopausal women with recurrent advanced breast

cancer (not amenable to surgical or radio-therapeutic

control) was recruited to early (

Five of eight studies analysing institutional or registrydatasets (level III-2 evidence) demonstrated no survivalimpact of TTC, with maximum delay intervals of35 days,19,20 9 weeks,18 and 3 months.32 Of those report-ing a negative prognostic impact of delayed TTC,15,17,21,33

reduced survival was observed at measured delay inter-vals of >45,17 60,15 7016 and 98 days.21 Reduced survival

was demonstrated among all breast cancer patients intwo studies16,17 but was limited to subgroups in the othertwo studies.15,21 Patient subgroups demonstrating worsesurvival with longer TTC included those with the poorestprognosis, grade III disease, trastuzumab-treated humanepidermal growth factor receptor 2 positive (HER2+) ortriple negative breast cancers.15,21

Table 3 Summary of included studies for breast cancer – time-to-chemotherapy (TTC) interval and cohort and summary findings

Study TTC interval TTC cohorts Association TTCand survival

Summary finding

de MeloGagliato201415

Surgery to CHT ≤30 days, 31–60 days,≥61 days

Yes† Entire cohort: no difference in overall survival by TTC (P = 0.54)Stage III disease: TTC ≥61 versus ≤30 days (HR for death 1.76, 95%CI 1.26–2.46, P < 0.001)

HR+ disease: TTC ≥61 versus ≤30 days (HR for death 1.29, 95% CI1.02–1.64, P = 0.03)

HER2+ disease treated with trastuzumab: TTC ≥61 versus ≤30 days(HR for death 3.09, 95% CI 1.49–6.39, P = 0.002)

Triple negative disease: TTC 31–60 versus ≤30 days (HR for death1.74, 95% CI 1.32–2.29, P < 0.001)

Downing 201416 Surgery to CHT ≤3 weeks, 3–6 weeks,6–10 weeks, >10 weeks

Yes Entire cohort: TTC >10 weeks versus ≤3 weeks (HR for death 1.49,95% CI 1.13–1.95)

Yu 201323 Surgery to CHT Per 4 weeks Yes Entire cohort: Per each 4-week delay (HR for death 1.15, 95% CI1.03–1.28 and HR for recurrence 1.16, 95% CI 1.01–1.33)

Alkis 201117 Surgery to CHT 90 days

Yes Entire cohort: TTC ≤44 versus ≥45 days (5-year overall survival92 vs 83.3%, P = 0.03). No difference in DFS by TTC (P > 0.05)

Jara Sanchez200718

Surgery to CHT 0.1)ER negative disease: increased DFS with increased TTC (66.0%;73.4%; 61.8%; 78.2% for lowest to highest TTC interval,P = 0.0219)

>10 nodes: increased 5-year OS with increased TTC (55.5%; 67.7%;68.9%; 94.4% for lowest to highest TTC interval, P = 0.0068)

Age 0.2)

Samur 200220 Diagnosis toCHT

Surgery to CHT

Implications for practice

With overall inconsistent results from low-grade evi-dence, the optimal timing of adjuvant chemotherapyremains unclear. However, based on the available bodyof evidence in patients with breast cancer, with particularimportance given to the largest body of data from therecently completed meta-analysis, avoiding delaysbeyond 4 weeks in all patients receiving adjuvant ther-apy for breast cancer is recommended due to a likelyassociation with reduced overall survival. It appears thatpatients with high-risk disease (triple negative, HER2+ orhigh-grade disease) are most likely to derive benefit fromearlier TTC, so for these patients, it is recommended thatchemotherapy commence as soon as possible.

Without a single study to guide practice, the impact ofTTC in the setting of neoadjuvant or palliative chemo-therapy remains unknown. Treatment in this setting isoften associated with more aggressive or advanced dis-ease or with a known biology of poor prognosis. How-ever, expert opinion is that treatment in these settingsshould commence, as for high-risk breast cancers in theadjuvant setting, as soon as possible and within 4 weeks.Early treatment commencement aims to prevent tumourgrowth and spread, preserve quality of life and protectthe viability of future treatment options.

Colorectal cancer

The search strategy yielded 741 results (Fig. S2),661 from MEDLINE, 75 from the Cochrane Library and

an additional five papers identified from reference lists.Of these, seven papers were included in thisreview.34–40 Studies evaluated TTC intervals from diag-nosis to systemic chemotherapy in the metastatic dis-ease setting36,37 and from surgery to systemicchemotherapy in the curable disease.34,35,38–40 No stud-ies evaluating TTC in the neoadjuvant setting wereidentified. This presents a significant evidence gap, withcombined modality chemo-radiotherapy being a stand-ard treatment for locally advanced disease.41 All studieswere published within the past 10 years (2005–2014)and varied in size (n = 84–15 410). Populationsincluded patients with both colon and rectal cancersand with curable and metastatic disease (stages I–IV)(Table 4). Four studies reported a significant associationbetween delayed TTC and worse survival outcomes(Table 5).34,35,39,40

Two meta-analyses, each including more than 13 000patients receiving adjuvant chemotherapy, demonstratedworse survival outcomes with longer TTC.34,35 AnalysingTTC at a defined 8-week time interval (n = 13 158)demonstrated that TTC beyond 8 weeks (compared with8 weeks or less) was associated with an increased risk ofdeath (relative risk 1.20, 95% CI 1.15–1.26). With TTCanalysed as a continuous variable (n = 15 410), each 4-week increment in TTC increased the risk of death(HR 1.14, 95% CI 1.10–1.17) and relapse (HR 1.14, 95%CI 1.10–1.18).34

Two retrospective series further support findings ofpoorer survival outcomes with TTC beyond 8 weeks.39,40

A study, including 209 patients with colorectal cancer,

Table 4 Summary of included studies for colorectal cancer – sample size, demographics, outcome measures, follow-up time and quality rating

Study Samplesize

Population Age Outcomemeasure

Follow up; median (range) Level ofevidence†

Qualityscore‡

Day 201440 209 Stages I and II: 84.5%; stage III:15.5%

Median: 50;range 19–85

OS, RFS,DFS

Median: 30 months III-2 8

Tevis 201339 355 Surgically resectable rectalcancer

Median: 60;range: 29–95

OS Median: 59.3 months III-2 5

Kang 201338 159 Surgically resectable stage IIIcolorectal cancer

Mean: 63.7;range: 29–89

OS, RFS Group 1 – mean 41.5 months; group2 – mean 50.3 months; group 3 –mean 47.4 months

III-2 5

Voskoboynik201237

377 Metastatic colorectal cancer Median: 67.9;range: 26–96

OS NR III-2 6

Biagi 201134 § 15 410 Stage II-III colon or rectalcancers

NR OS, DFS NR III-2 NA

Des Guetz. G.201035¶

13 158 Stage II/III colon or rectalcancer

Median 57–73 OS, RFS NR III-2 NA

Ackland200536 ††

84 Metastatic colorectal cancer Median: 63–67;range: 36–80

TTP, OS,QOL

55 months (NR) I NA

†National Health and Medical Research Council Grades and Levels of Evidence.24 ‡Newcastle Ottawa Quality rating for observational studies.14 §Meta-analysis of 10 level III studies. ¶Meta-analysis of eight level III studies. ††Meta-analysis two level II studies. DFS, disease-free survival; NA, not applica-ble; NR, not reported; OS, overall survival; QOL, quality of life; RFS, relapse-free survival; TTP, time to progression.

Alexander et al.


reported a threefold increased risk of death with TTC>8 weeks compared with

for the delayed cohort was 3.7 months. Among thisstudy population, there was a reduced risk of death withdelayed (median delay 3.7 months) versus immediatechemotherapy (HR 0.68, 95% CI 0.54–0.85). Thisreflects the better prognostic profile of patients assignedto delayed treatment within the clinical practice settingof this study; those who received delayed treatment hadbetter performance status, lower incidence of metastaticdisease at diagnosis and lower incidence of multiple sitesof distant metastasis compared with patients treatedimmediately.


While there was no evidence to support a recommenda-tion in the neoadjuvant setting of colorectal cancer, thisreview suggests that delays should be avoided to maxi-mise outcomes as part of an aggressive multimodalitytreatment. However, in the interests of standardisedcare, the initiation of neoadjuvant chemotherapy occurswithin 3 weeks is suggested as recommended by newlyreleased Australian cancer care plans.7

Adjuvant treatment studies consistently demonstratethe negative survival impact of delayed TTC>8 weeks;35,39,40 however, the optimal timing within thisperiod remains unclear, with one study finding that TTC>4 weeks is associated with reduced overall survival.34

Based on the largest body of evidence, it is recom-mended that adjuvant chemotherapy commence as soonas the patient is medically fit following surgery andwithin 8 weeks of surgery (level III, grade C).

The two available studies in advanced disease36,37 are ofhigh quality, have consistent findings and are of highgeneralisability to the Victorian clinical practice setting.Based on the meta-analysis of randomised controlled trials(and supported by the local study), it is recommended thattreatment commence based on clinician discretion andaccording to patient symptoms (level I, grade B).

Lymphoma and myeloma

The search strategy was performed separately for lym-phoma and myeloma, yielding 386 and 175 resultsrespectively (Figs S3, S4). From these results, only tworelevant studies were identified for lymphoma and nonefor myeloma. The two relevant studies were conductedin cohorts of patients with diffuse large B-cell lymphoma(DLBCL)42 and Hodgkin lymphoma (HL).43 These retro-spective cohort studies (level III evidence) demonstratedno survival difference with TTC beyond 4 weeks in theDLBCL cohort and beyond 8 weeks in the HL cohort.Study design, patient cohorts and summary results aresummarised in Table 6.

A single-centre retrospective study of 278 patients withDLBCL found that the initiation of chemotherapy (meas-ured from date of first haematology consult) beyond4 weeks was not associated with reduced overall sur-vival.42 The study compared survival among patients withTTC of 4, with no significant differencesamong the treatment groups. The median TTC intervalwas 3 weeks. However, the retrospective study design,lack of randomisation and small sample size severely com-promises the ability of this study to inform clinical practice.

Evidence from a Canadian registry-based retrospectivestudy of 879 patients with HL suggests that the initiationof chemotherapy (measured from date of diagnosis)beyond 8 weeks is associated with reduced overall sur-vival.43 Patients received at least one cycle of ABVD(doxorubicin, bleomycin, vinblastine and dacarbazine)with curative intent within 2 weeks (13%), 3–4 weeks(30%), 5–8 weeks (46%) and >8 weeks (12%). The 5-year survival rate among patients initiating chemother-apy >8 weeks was significantly lower among those initi-ating chemotherapy within 2 weeks (84 vs 90%;P = 0.012). There was no survival difference observedwith other TTC intervals.

Due to the overall paucity of studies in patients withlymphoma or myeloma identified for this review, some

Table 6 Summary of included studies for lymphoma

Study Samplesize

Population TTC interval Study design Outcomes Summary results Level ofevidence†

Qualityscore‡

Brooks 201343 879 HL Histologicaldiagnosisto CHT

Retrospectivecohort study(registry)

OS, PFS 5-year OS: 90% for TTC8 weeks (P = 0.012)

III-2 8

Nikonova 201342 278 DLBCL First haematologyconsult to CHT

Retrospectivecohort study(single centre)

OS, PFS Delays in DLBCL treatment of>1 month do not affect OS(significance not reported)

III-2 6

†National Health and Medical Research Council Grades and Levels of Evidence.24 ‡Newcastle Ottawa Quality rating for observational studies.14 CHT,chemotherapy; DLBCL, diffuse large B-cell lymphoma; HL, Hodgkin Lymphoma; OS, overall survival; PFS, progression-free survival; TTC, time-to-chemotherapy.

Alexander et al.


studies that were previously excluded during the screen-ing process were considered to provide additional guid-ance. Randomised controlled trials in indolentlymphomas and early stage myeloma have demonstratedthat the timing of chemotherapy relative to diseasecourse (i.e. at diagnosis or sometime later) does notimpact patient survival.44–49 Consequently, it can beinferred that the TTC interval (measured from decisionto treat with chemotherapy), while representing only asmall portion of the overall observation interval, wouldhave no impact on patient survival.A recent Canadian registry-based study (not included

in this review as it was published outside of search dates)represents high-quality evidence and supports the limitedevidence included in this review. A multivariate analysisof 689 patients with DLBCL showed that TTC >8 weekswas associated with worse overall survival (HR 1.20(95% CI 1.03–1.41), P = 0.020), progression-free sur-vival (HR 1.33 (95% CI 1.15–1.54), P < 0.001) anddisease-specific survival (HR 1.40 (95% CI 1.10–1.78),P = 0.006). The authors concluded that clinicians shouldendeavour to initiate curative chemotherapy as soon aspossible after a diagnosis of DLBCL is established.50


We identified no studies in highly aggressive lymphomas(e.g. Burkitt lymphoma, lymphoblastic lymphoma) orurgent presentations of other lymphomas or myelomas.Therefore, best clinical judgement must guide clinicalpractice. All patients require immediate referral andtreatment, with every hour delay potentially increasingthe risk of mortality.In the setting of aggressive and potentially curable

lymphomas (e.g. DLBCL or NHL with non-urgent pres-entation), clinical intuition dictates the commencementof treatme

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