«Dissertation date: © Copyright Eva Hansen Dybvik The material in this publication is protected by copyright law. Year: 2015 Cancer and Total Hip ...»
Dissertation for the degree of philosophiae doctor (PhD)
at the University of Bergen
© Copyright Eva Hansen Dybvik
The material in this publication is protected by copyright law.
Cancer and Total Hip Replacement
Cancer as a risk factor for prosthesis and prosthesis as a risk factor for cancer
Author: Eva Hansen Dybvik
Printed by: AIT OSLO AS / University of Bergen
Scientific environment This thesis is based on data from the Cancer Register of Norway and the Norwegian Arthroplasty Register.
The study was initiated in 2006 while the author was working as a biostatistician at the Norwegian Arthroplasty Register. From August 2007, three-year full-time financial support was provided by the Western Norway Regional Health Authority.
The last period was financed by the Norwegian Arthroplasty Register.
Supervision has been provided by staff of the Norwegian Arthroplasty Register at the Department of Orthopedic Surgery, Haukeland University Hospital, staff of the Department of Clinical Dentistry and the Department of Clinical Medicine at the University of Bergen and staff of the National Advisory Unit on Late Effects after Cancer Treatment at the Norwegian Radium Hospital, Oslo University Hospital.
As many as 19 candidates have taken PhD degrees based on data from the Norwegian Arthroplasty Register since its initiation in 1987.
This thesis is a part of the PhD programme at the Department of Clinical Medicine, University of Bergen.
4 5 Contents SCIENTIFIC ENVIRONMENT
3. NORSK SAMMENDRAG
4. LIST OF ABBREVIATIONS
5. LIST OF PUBLICATIONS
6. INTRODUCTION AND BACKGROUND
6.2 TOTAL HIP REPLACEMENT (THR)
6.3 PERSONAL IDENTITY NUMBER
6.4 HEALTH REGISTRIES IN NORWAY
7. AIMS OF THE STUDIES
8. DATA SOURCES
8.1 CANCER REGISTRY OF NORWAY (CRN)
8.2 THE NORWEGIAN ARTHROPLASTY REGISTER (NAR)
8.3 LINKING OF CRN AND NAR
8.5 APPROVALS, ETHICS AND CONFLICT OF INTEREST
9. STATISTICAL ANALYSES
9.1 STANDARDIZED INCIDENCE RATIO (SIR)
9.2 COX REGRESSION
9.3 COMPETING RISK MODEL
6 9.4 MODELS WITH TIME-DEPENDENT VARIABLES
9.5 STATISTICAL SOFTWARE
10. SUMMARY OF PAPERS
10.1 PAPER 1
10.2 PAPER 2
10.3 PAPER 3
11. GENERAL DISCUSSION
11.1 METHODOLOGICAL CONSIDERATIONS
11.1.1 Study designs
11.1.2 Completeness and quality of data
11.1.3 Outcome measures
11.1.5 Statistical Methods
11.2.1 Paper 1
11.2.2 Paper 2
11.2.3 Paper 3
13. IMPLICATIONS AND FUTURE RESEARCH
14. SOURCE OF DATA
1. Acknowledgements This PhD project was carried out at the Norwegian Arthroplasty Register (NAR), Department of Orthopedic Surgery, Haukeland University Hospital in Bergen, Norway during the years 2006-2015.
There are many people who have provided important contributions and support in the process of this thesis. I would like to express my deepest gratitude to everyone who
helped me realize this journey in the scientific world:
Stein Atle Lie, my main supervisor and statistician, has with great enthusiasm guided my way through formulas and statistical methods. He has shared his experiences and wide knowledge in programming and handling of large datasets. His contributions and constructive feedback have had a major impact in the progress and process of this thesis.
Ove Furnes, my co-supervisor, professor and orthopaedic surgeon, who tricked me into this project. He had faith in my academic abilities despite my own doubts. His enthusiasm and knowledge in science seem to know no boundaries.
Sophie D. Fosså, my second co-supervisor, professor and oncologist, came up with a research proposal which initiated this project. Her valuable knowledge of cancer research and data from the Cancer Registry has been crucial in this project.
Clement Trovik, professor, oncology surgeon and a member of the project group, has played an important role in planning the project and giving valuable feedback to manuscripts.
The whole supervising team has broad scientific and practical knowledge in many different fields, and all of them have contributed to the realization of this thesis!
Leif I. Havelin, professor and orthopaedic surgeon, a co-author in Paper 3, who contributed the highest level of knowledge on hip replacements.
8 The leaders of NAR, Leif I. Havelin (present), Lasse Engesæter and Ove Furnes, who have given me the opportunity to combine working with this thesis and working as a biostatistician at NAR.
Biostatisticians at NAR, Stein Atle Lie, Anne Marie Fenstad, Birgitte Espehaug, Christoffer Bartz-Johannessen, Valborg Baste (former) and Stein Håkon Lygre (former), who have provided an inspiring environment and valuable discussions between like-minded people.
Colleagues at NAR, including leaders and biostatisticians, Lise Kvamsdal, Ingunn Vindenes, Ruth Wasmuth, Marianne Wiese, Kari Vågstøl, Merete Husøy, Randi Furnes, Irina Kvinnesland, Håkon Langvatn, Bjørg-Tilde Fevang, Tone Nystøl, Håvard Dale, Jan Schrama, Tesfaye Leta, Målfrid Kristoffersen, Andreas Persson, Marianne Warholm, Ingvild Engesæter (former), Thomas Kadar (former), Tor Egil Sørås (former), Kjersti Steindal (former) and Inger Skar (retired), who have provided a stimulating, social and fun-filled working environment. It has been a pleasure to go to the office every day because of you!
The Cancer Registry of Norway and NAR, which have given me the opportunity to use data from these two highly rated registries. Also all doctors and health care personnel who take part in data collection for both registries need to be mentioned.
Without their efforts, the registries would not have been as valuable as they are!
The Western Norway Regional Health Authority (Helse Vest) and NAR gave me financial support for the implementation of the project.
Family and friends have supported and encouraged me throughout the work on this thesis.
My brothers Kjell Ivar and Leif Sigurd and their families, despite bickering early in life, have given me support and not least entertaining board games whenever we have been together.
Roy-Arild, my dear husband and best friend, has given me all the love and motivation I have needed. While studying, we explored the world of statistics together. Although our working environments now differ, elderly people are included in both our calculations: he cares about their financial situation, while I am interested in their health.
Magne and Torunn, my loving children, have given my life a new dimension.
Eva Dybvik Bergen, June 2015 10
2. Abstract Annually, 14 million new cancer cases are detected worldwide; the numbers are expected to rise by 70% over the next decades. In Norway, 30,000 new cancer cases are detected every year. Because of screenings and increased attention to cancer in the population, more cancer cases are detected at an early stage and a higher number of cancer diagnoses are detected. Results of better and earlier treatment are that patients survive and continue to live for many years after a cancer diagnosis.
In Western countries, total hip replacements have become a common treatment for hip joint disease and injury. Standards of living have risen and people are living longer, hence Western populations have an increased proportion of elderly people.
Better anaesthetics, lower risks associated with surgery and better quality of prostheses enable both younger and older patients with good general health to receive total hip replacements. In Norway almost 8,000 primary total hip replacement operations are performed annually.
All papers in this thesis are based on a linkage between the Cancer Registry of Norway and the Norwegian Arthroplasty Register.
In this thesis there are two different aspects. The first aspect is the cancer patients; if they survive cancer and live on for many years, there is a risk for developing other diseases and disorders. These may be late effects related to the treatment they received for cancer. In this thesis we consider damage to bone and cartilage in the hip. Our outcome measurement is the insertion of a total hip replacement.
The second aspect is the patients who have received a total hip replacement. Could insertion of metal prosthesis with or without bone cement in the hip joint increase the patient's risk for late development of cancer?
1987). We compared the observed hip replacement patients with incidence in the general population. Cancer patients were divided in groups according to the location of the cancer and compared. We found an increased risk for hip replacement for patients with lymphoma malignancies and cancer in the pelvic area.
In Paper 2 we selected two groups of cancer patients to investigate whether radiation to the pelvic area increased the risk for total hip replacement. We included women only; one group consisted of patients with gynaecological cancer and radiation to the pelvic area while the other group consisted of breast cancer patients with radiation to the breast and not to the pelvic area. The mortality differed greatly in the two groups, so we used competing risk models to estimate the risk for receiving prosthesis. We found no statistically increased risk for hip replacements for patients with gynaecological cancer compared to patients with breast cancer.
In Paper 3 we selected patients with total hip replacement. We compared their cancer risk to the general population in Norway. We also used Cox models and competing risk models with time-dependent covariates to compare different prosthesis fixations.
We found an increased risk of cancer for patients with uncemented total hip replacement compared to patients with cemented total hip replacement. Patients with a combination of cemented cup and uncemented stem (reversed hybrid) had a similar risk for cancer as those with uncemented prosthesis.
The overall conclusion in this thesis is that we found a relation between cancer and total hip replacements. There seems to be an increased risk for hip replacements for some cancer types, but we could not find any increased risk due to irradiation of the hips. For patients who have had a hip replacement for more than 10 years, uncemented prosthesis seems to increase the risk of cancer.
3. Norsk sammendrag På verdensbasis oppdages årlig 14 millioner nye krefttilfeller, antallet er også forventet å stige med opp til 70 % de neste tiårene. I Norge oppdages rundt 30 tusen nye krefttilfeller i året. På grunn av screeninger og økt fokus på kreft i befolkningen blir flere krefttilfeller oppdaget på et tidlig stadium, dette fører til en økning i antall kreftdiagnoser. Behandlingen kan starte tidlig og flere av pasientene overlever og fortsetter å leve i mange år etter en kreftdiagnose.
I den vestlige verden har totale hofteproteser blitt en vanlig behandling for sykdom og skade i hofteleddet. Levestandarden har gått opp og folk lever lengre, dermed er det en større andel eldre i befolkningen. Bedre anestesi, lavere risiko forbundet med operasjonen og ikke minst bedre kvalitet på protesene gjør at både yngre pasienter og eldre pasienter med god allmenn helsetilstand kan få satt inn hofteproteser. I Norge settes det inn i underkant av 8 tusen primære hofteproteser i året.
Alle artiklene i denne avhandlingen er basert på kobling mellom Kreftregisteret og Nasjonalt register for leddproteser.
I denne avhandlingen har vi to ulike aspekter. Først kan man se på kreftpasientene, hvis de overlever kreften og lever i mange år kan de senere utvikle andre sykdommer og lidelser. Dette kan være seneffekter relatert til behandlingen de fikk for kreft. I denne avhandlingen ser vi på skader relatert til skjelettet og brusken, nærmere bestemt i hofteleddet. Vårt endepunkt var innsetting av total hofteprotese.
På den andre siden kan man se på pasientene som har fått hofteprotese. Kan innsetting av metallprotese med eller uten bensement i hoften øke pasientens risiko for å få kreft på et senere tidspunkt?
delt inn etter lokaliseringen av kreften og disse gruppene ble sammenlignet med hverandre. Vi fant økt risiko for å få hofteprotese for pasienter med lymfekreft og kreft i bekkenregionen.
I Artikkel 2 har vi valgt ut to grupper med kreftpasienter for å undersøke om stråling mot bekkenregionen gir økt risiko for hofteprotese. Vi inkluderte kun kvinner i studien, den ene gruppen bestod av pasienter med gynekologisk kreft og stråling mot bekkenregionen mens den andre gruppen bestod av brystkreftpasienter med stråling mot brystene men ikke stråling i bekkenregionen. Det var stor forskjell i dødelighet mellom gruppene, så vi brukte en competing risk modell for å beregne risikoen for å få protese. Vi fant ingen statistisk økt risiko for hofteproteser for pasientene med gynekologisk kreft sammenlignet med pasientene med brystkreft.
I Artikkel 3 har vi sett på protesepasientene. Vi sammenlignet deres kreftrisiko med den generelle befolkningen i Norge. I tillegg brukte vi Cox modeller og competing risk modeller med tidsavhengige kovariater for å sammenligne ulike operasjonsmetoder. Vi fant en økt risiko for kreft for pasienter med usementerte hofteproteser sammenlignet med pasienter med sementerte hofteproteser. Pasienter med en kombinasjon av sementert kopp og usementert stamme (omvendt hybrid) hadde samme risiko for kreft som pasienter med usementerte hofteproteser.
Hovedfunnet i denne avhandlingen er at vi finner en sammenheng mellom kreft og hofteproteser. Det ser ut som om det er en økt risiko for hofteproteser etter enkelte krefttyper, men vi fant ingen effekt i risikoen etter strålebehandling. For pasienter som har hatt en hofteprotese i mer enn 10 år ser det ut som en usementert hofteprotese øker risikoen for kreft.
4. List of Abbreviations CI Confidence Interval CIF Cumulative Incidence Function