From symptoms to diagnosis of sarcoma

170 Pages·2016·3.55 MB·English

From symptoms to diagnosis of sarcoma – revealing the
diagnostic pathway

PhD dissertation

Heidi Buvarp Dyrop

Health
Aarhus University
2016
From symptoms to diagnosis of sarcoma – revealing the
diagnostic pathway

PhD dissertation

Heidi Buvarp Dyrop

Health
Aarhus University
Department of Experimental Clinical Oncology
Evaluation Committee

Richard Neal, Professor of Primary Care Oncology, PhD
Leeds Institute of Health Sciences, University of Leeds
England, United Kingdom

Henrik C. F. Bauer, Professor of Orthopaedic Oncology, DMSc
Oncology Service, Department of Orthopaedics, Karolinska Hospital
Stockholm, Sweden

Anders Bonde Jensen, Professor, MD, PhD (Chairman of the committee)
Department of Oncology
Aarhus University Hospital, Denmark

Johnny Keller, MD, DMSc (non-voting member)
Department of Orthopaedic Surgery
Aarhus University Hospital, Denmark

Supervisors

Johnny Keller, MD, DMSc
Department of Orthopaedic Surgery
Aarhus University Hospital, Denmark

Peter Vedsted, Professor, MD, PhD
Research Unit for General Practice, Research Centre for Cancer Diagnosis in Primary Care
Aarhus University, Denmark

Akmal Safwat, Associate Professor, MD, PhD
Department of Oncology
Aarhus University Hospital, Denmark

Correspondence

Heidi Buvarp Dyrop, MD
Department of Experimental Clinical Oncology
Aarhus University Hospital, Denmark
Email: [email protected]
Preface
The work presented in this thesis was performed during my employment at the Department of
Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
The thesis is based on the following articles:

I. Dyrop HB, Safwat A, Vedsted P, Maretty-Nielsen K, Hansen BH, Jørgensen PH, Baad-
Hansen T, Bünger C, Keller J.
Cancer Patient Pathways shortens waiting times and accelerates the diagnostic process of
suspected sarcoma patients in Denmark
Health Policy 2013 Nov;113(1-2):110-7.

II. Dyrop HB, Vedsted P, Safwat A, Maretty-Nielsen K, Hansen BH, Jørgensen PH, Baad-
Hansen T, Keller J.
Alarm symptoms of soft tissue and bone sarcoma among patients referred to a specialist
center
Acta Orthopaedica 2014; Dec;85(6):657-62

III. Dyrop HB, Safwat A, Vedsted P, Maretty-Kongstad K, Hansen BH, Jørgensen PH, Baad-
Hansen T, Keller J.
Characteristics of 64 sarcoma patients referred to a sarcoma center after unplanned excision
Journal of Surgical Oncology 2016; Feb;113(2):235-239

IV. Dyrop HB, Vedsted P, Rædkjær M, Safwat A, Keller J.
Routes to diagnosis for suspected sarcoma – the impact of symptoms and clinical findings
on the diagnostic process
Submitted

V. Dyrop HB, Vedsted P, Rædkjær M, Safwat A, Keller J.
Imaging investigations before referral to a sarcoma center delays the final diagnosis
Accepted - Acta Orthopaedica 2016

i
Acknowledgements

This thesis was carried out during my employment as a research year student and later as a Ph.d.-
student at the Department of Experimental Clinical Oncology, Aarhus University Hospital from
2011 to 2016.

First and foremost, I want to thank my main supervisor Johnny Keller for his excellent guidance
and never ending support throughout these years. You have introduced me to the exciting world of
sarcomas, and entrusted me to shape this project and thesis in my own way. For this, I am forever
grateful.

Further, great thanks are owed to my co-supervisor Peter Vedsted for his constructive criticism and
friendly advice, which have undoubtedly made me a better researcher. His extensive knowledge of
cancer diagnostics and primary care has been invaluable.

Thank you to my co-supervisor Akmal Safwat for his great support and good advice both for my
papers and my thoughts along the way. Your motivational behaviour and fantastic mood have been
most welcome.

Thank you to my research year supervisor and office buddy Katja Maretty Kongstad for introducing
me to the inner workings of life as a researcher, and for her helpful advice and excellent office and
congress companionship.

I want to thank Jens Overgaard for giving me office space at his outstanding department, and giving
good advice when needed. Great thanks also go to Lene Skovlund Jensen for answering all my
questions, Aleks for helping me with my first database, and Hanne Beyer for great help with
questionnaires and the second database. Thanks to all my colleagues at EKO, and especially my
office mates throughout the years, you are all missed.

I would also like to thank the sarcoma group at the orthopaedic department at Aarhus University
Hospital. Especially Bjarne Hauge Hansen, Michael Bendtsen, Peter Holmberg Jørgensen and
Thomas Baad-Hansen for tolerating my presence in the ambulatory for a year and assisting with the
inclusion of patients; and the secretaries at the tumour sector for helping me with the forwarding of
questionnaires, finding medical records and answering questions. And thank you Mathias, for
helping out with my project in my time of need.
ii
This work was made possible by financial support from the Faculty of Health at Aarhus University,
Professor Cody Bünger from project 8427 CE-spine, “A.P. Møller og Hustru Chastine Mc-Kinney
Møllers Fond til Almene Formaal”, “Radiumstationens forskningsfond”, “Max og Inger Wørzners
Mindelegat” and “DOS-fonden”.

Finally, my heartfelt appreciation goes to my Norwegian family. Thank you for always supporting
me and waiting patiently for me to finish this before coming home. And last, but certainly not least,
thanks to Allan for supporting me, cheering me on, giving me space, comforting me, fixing my
recurring IT-problems and embarking on new journeys with me. It could not have been done
without you!

Heidi Buvarp Dyrop, November 2016

iii
Contents
Preface ................................................................................................................................................... i 
Acknowledgements .............................................................................................................................. ii 
Contents .............................................................................................................................................. iv 
Abbreviations ...................................................................................................................................... vi 
Introduction .......................................................................................................................................... 1 
Background .......................................................................................................................................... 2 
Sarcomas .......................................................................................................................................... 2 
Epidemiology and aetiology ........................................................................................................ 2 
Presenting symptoms ................................................................................................................... 2 
Diagnostic workup ....................................................................................................................... 3 
Treatment ..................................................................................................................................... 4 
Prognosis ...................................................................................................................................... 4 
Delay before diagnosis ..................................................................................................................... 5 
Effect of delay on outcomes ......................................................................................................... 5 
Initiatives to reduce delay ............................................................................................................ 6 
Danish Cancer Patient Pathways ...................................................................................................... 7 
Concept ........................................................................................................................................ 7 
The Cancer Patient Pathway for sarcoma .................................................................................... 7 
Alarm symptoms as criteria for referral to Cancer Patient Pathways .............................................. 8 
Unplanned excision – patients treated outside Cancer Patient Pathways ........................................ 9 
The diagnostic journey before referral to Cancer Patient Pathways .............................................. 10 
Selection of patient populations for research ............................................................................. 10 
Limitations in reporting of time intervals .................................................................................. 11 
Time intervals and presenting symptoms................................................................................... 11 
Local investigations vs direct referral to a sarcoma centre ........................................................ 11 
Aims and hypotheses ......................................................................................................................... 13 
Materials and methods ....................................................................................................................... 14 
Setting ............................................................................................................................................ 14 
Aarhus Sarcoma Centre ............................................................................................................. 14 
Study design ................................................................................................................................... 14 
Study population ............................................................................................................................ 15 
Studies I and II ........................................................................................................................... 15 
Study III ..................................................................................................................................... 16 
Studies IV and V ........................................................................................................................ 16 
Data collection ............................................................................................................................... 18 
Studies I and II ........................................................................................................................... 18 
Study III ..................................................................................................................................... 19 
Studies IV and V ........................................................................................................................ 19 
iv
Definition of variables ................................................................................................................... 20 
Studies I, II and III ..................................................................................................................... 20 
Studies IV and V ........................................................................................................................ 22 
Statistical analyses ......................................................................................................................... 24 
Studies I, II and III ..................................................................................................................... 24 
Studies IV and V ........................................................................................................................ 24 
Results ................................................................................................................................................ 26 
Study I ............................................................................................................................................ 26 
Study II ........................................................................................................................................... 29 
Study III ......................................................................................................................................... 31 
Study IV ......................................................................................................................................... 32 
Study V .......................................................................................................................................... 35 
Discussion .......................................................................................................................................... 36 
Methodological considerations ...................................................................................................... 36 
Study design ............................................................................................................................... 36 
Selection bias ............................................................................................................................. 36 
Information bias ......................................................................................................................... 37 
Confounding .............................................................................................................................. 39 
Statistical precision and choice of analyses ............................................................................... 40 
Generalisability .......................................................................................................................... 41 
Discussion of results ...................................................................................................................... 42 
Effects of the Cancer Patient Pathways ..................................................................................... 42 
The predictive value of alarm symptoms ................................................................................... 44 
Patients falling outside Cancer Patient Pathway referral criteria ............................................... 45 
Effect of symptom presentation on time intervals ..................................................................... 46 
Waiting time before referral to a sarcoma centre ....................................................................... 47 
Conclusions ........................................................................................................................................ 50 
Future aspects ..................................................................................................................................... 51 
English summary................................................................................................................................ 52 
Danish summary ................................................................................................................................ 54 
References .......................................................................................................................................... 56 
Appendix ............................................................................................................................................ 69 
Paper I ................................................................................................................................................ 81 
Paper II ............................................................................................................................................... 91 
Paper III.............................................................................................................................................. 99 
Paper IV ........................................................................................................................................... 109 
Paper V ............................................................................................................................................. 137 

v
Abbreviations
2WW Two-Week Wait
ASC Aarhus Sarcoma Centre
AUH Aarhus University Hospital
CT Computed Tomography
CPP Cancer Patient Pathway
GP General Practitioner
IQI Interquartile Interval
MRI Magnetic Resonance Imaging
NICE National Institute for Health and Care Excellence
NPV Negative Predictive Value
PET-CT Positron Emission Tomography-Computed Tomography
PPV Positive Predictive Value

vi
Introduction
This thesis focuses on the diagnostic journey of patients suspected of having a sarcoma in Denmark.
Sarcoma patients are often subject to a long and complicated diagnostic process with significant
delays before they are diagnosed at a sarcoma centre. This is in great part due to the rarity and
subtle symptom development of the disease. Patients with sarcomas are seldom encountered by
physicians, and the disease does not attract great interest for research in environments outside
specialised sarcoma centres. The story of these patients’ journey through the health care system
outside sarcoma centres is thus to a large extent untold.
The problem of delays before diagnosis has also been recognised for many other cancer
forms, and in Denmark the issue gained special interest after studies emerged showing lower cancer
survival in Denmark and England compared to similar European countries [1,2]. It was concluded
that cancer patients in Denmark had a higher malignancy grade at diagnosis compared to other
countries [2,3], and this was presumed to be caused by waiting time before diagnosis. This initiated
the work on the four national cancer plans, hereunder the development of standardised Cancer
Patient Pathways [4,5].
It is the hope that these fast-track referral pathways will reduce delay before diagnosis and
hereby improve cancer survival in Denmark. This initiative is unique in its massive political and
financial backing enabling implementation on a national scale, and its success is highly anticipated.
However, it is not given that such a broad initiative tailored to fit all cancer forms will succeed in
reducing waiting time for sarcoma patients. After CPP implementation, the effect on waiting times
has been investigated in other studies, but as the incidence of sarcoma is extremely low, all audits
exclude this disease entity and only report on the larger cancer forms such as colorectal, breast,
lung, melanoma and urinary tract cancer. Apart from the immediate effect on time intervals, the
contents of the CPP for sarcoma should also be evaluated after implementation to ensure that the
initiative works as intended with regard to inclusion of patients and organisational functionality.
Several questions arise in the aftermath of the Danish sarcoma CPP implementation. First and
foremost: Has it solved the problems of delay for Danish sarcoma patients? Does it catch all the
sarcomas and if not, why? Can we further improve the diagnostic process for sarcoma patients? And
where do we go from here?
To gain some evidence for answering these questions, the overall aim of this thesis was to
describe the immediate effects of the Danish CPP for sarcomas on the diagnostic process for
suspected sarcoma patients. Further, the diagnostic journey of patients suspected of having a
sarcoma in the new steady state after CPP implementation is described to highlight possible areas
for improvement.
1