Introduction

Total hip arthroplasty (THA) is a highly efficacious and cost-effective treatment for symptomatic advanced joint disease [1–4]. Over the years, different materials have been used in joint arthroplasty prostheses and a number of different bearing surfaces have been developed. The most commonly used bearings are metal heads on a polyethelene acetabular component (MoP). Hip arthroplasties using a metal head on a metal acetabular component (MoM) gained popularity as this combination was believed to confer benefit due to decreased wear and osteolysis compared with MoP hip replacements [5]. The design of the modern MoM implants also allowed for the use of larger femoral head sizes, which could further reduce risk of revision due to dislocation [5]. However, in practice, MoM total hip procedures experienced a higher rate of revision compared with MoP implants, with concerns also raised about metal ion toxicity resulting from wear and corrosion of the bearing surfaces and the subsequent increase in serum metal ion levels [6, 7]. Patients with MoM total joint replacement have elevated concentrations of cobalt, chromium, and titanium in serum and urine [6–8], with even higher concentrations identified following prosthesis failure [8]. Patients with MoM hip replacement are exposed to significant amounts of metals such as cobalt and chromium with serum levels of more than 1000 times that of normal levels found in some patients [9] and generally, higher compared to THA patients receiving MoP [10], ceramic-on-polyethylene (CoP) [11] or ceramic-on-ceramic (CoC) [12] bearing surfaces.

It has been postulated that wear debris from worn prostheses in human tissue cultures damage chromosomes in a dose-dependent manner, specific to the type of metal [13]. Significant amounts of metal ions and particles have been found in human tissues surrounding orthopaedic implants and tissues at remote sites including lymph nodes, bone marrow, liver, and spleen through processes of corrosion and mechanical wear of the prosthesis [14]. The potential toxicity of metal wear debris associated with MoM hip replacements induces potential harmful effects on immunity, reproduction, the kidney, developmental toxicity and nervous system [15]. Although it is biologically plausible for the materials used in MoM hip replacement to induce malignant degeneration, the relationship has not been well demonstrated. Many studies have examined the differential risk of cancer between different bearing surfaces, results have varied [16–33].

Therefore, using an Australian joint replacement registry database linked with cancer registry data, our aim was to evaluate the risk of all-cause and site-specific cancer according to bearing surfaces used in patients undergoing THA, either conventional stemmed THA (csTHA) or resurfacing THA (rsTHA) for osteoarthritis and whether risk was increased with MoM bearings.

Methods

Study population

Since each total hip arthroplasty is entered in the AOANJRR as a separate operation and cancer risks apply to patients rather than joints, all patients were considered to be at risk after their first recorded primary total hip arthroplasty operation identified in the registry performed for osteoarthritis, (specified in surgical indication). In Australia over 88% of csTHA procedures are performed for osteoarthritis and over 95% of resurfacing procedures are performed for osteoarthritis [36]. Procedures were included if they occurred before December 31 2012, this was to allow for at least one year of follow-up as cancer data were only available to the end of 2013 (Fig 1). Follow-up for cancer and calculation of individual person-time was determined from the date of first recorded total hip arthroplasty until either cancer diagnosis, death, or December 31, 2013, whichever occurred first. Person-time accrued and cancer events observed during the first year of follow-up were not included in the analysis, since cancer cases diagnosed during this time period are assumed to be coincidental, prone to selection and surveillance bias, and unlikely to be causally related to the implants. Only the first cancer after primary procedure was considered and those with any cancer diagnosed prior to their joint replacement procedure were excluded from this analysis.

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Fig 1. Patient population and attrition.

https://doi.org/10.1371/journal.pone.0278241.g001

Results

There were 156,516 csTHA patients included with median age 68 years and 5 years follow-up and 11,321 rsTHA patients with median age 53 years and 8 years follow-up. There were differences in the population demographics of patients according to the bearing surface used Table 1. The comparison group (MoP and CoP) were older and had a higher proportion of women than CoC and MoM procedures, while patients with rsTHA were younger and a higher proportion were men compared to patients with a csTHA.

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Table 1. Demographic characteristics of patients undergoing conventional stemmed THA or resurfacing THA by bearing surface.

https://doi.org/10.1371/journal.pone.0278241.t001

All-cause cancer risk for csTHA procedures was significantly higher than the Australian population (SIR 1.24, 95% Confidence Interval (CI) 1.22–1.26) Table 2. Site-specific cancer rates were significantly higher than the general population for prostate cancer (SIR 1.46, 95% CI 1.41–1.51), melanoma (SIR 1.53, 95% CI 1.46–1.61), non-Hodgkin’s lymphoma (SIR 1.25, 95% CI 1.14–1.35), myeloma (SIR 1.60, 95% CI 1.41–1.79), leukaemia (SIR 1.21, 95% CI 1.10–1.33), colon (SIR 1.24, 95% CI 1.18–1.30), bladder (SIR 1.15, 95% CI 1.03–1.27) and kidney (SIR 1.22, 95% CI 1.09–1.35) Table 2. Similar results were observed for individual bearing surfaces for the csTHA procedures. For rsTHA procedures all-cause cancer risk was significantly higher than the Australian population (SIR 1.42, 95% CI 1.32–1.51) Table 2. The individual cancer sub-types where risk for the rsTHA population was significantly higher than the general population were prostate cancer (SIR 2.30, 95% CI 2.05–2.55) and melanoma (SIR 1.72, 95% CI 1.39–2.04) Table 3. Lower risks were observed for lung cancer (SIR 0.68, 95% CI 0.44–0.91).

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Table 2. Standardised incidence ratios for primary cancer diagnoses for patients receiving a conventional stemmed Total Hip or Resurfacing Hip arthroplasty for osteoarthritis between 1999 and 2012.

Expected numbers of cancer cases are approximated from the incidence rate of cancer for the general Australian population.

https://doi.org/10.1371/journal.pone.0278241.t002

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Table 3. Risk of cancer incidence for all-cause and site-specific cancers by bearing surface.

https://doi.org/10.1371/journal.pone.0278241.t003

For csTHA procedures there was no significant difference in all-cause cancer rates for MoM bearing surfaces (Hazard Ratio (HR) 1.01, 95% CI 0.95–1.07) or CoC (HR 0.98, 95% CI 0.94–1.02) compared to MoP and CoP bearing surfaces Table 3. For rsTHA procedures there was a significantly lower risk of all-cause cancer compared to MOP and COP csTHA procedures. No significant differences in site-specific cancers between bearing surfaces were observed except for lung cancer which was found to have a lower risk in MoM (HR 0.76, 95% CI 0.61–0.94) and CoC (HR 0.84, 95% CI 0.72–0.99) compared to the comparison cohort. For rsTHA there was a lower risk of site-specific cancers including myeloma (HR 0.42, 95% CI 0.18–0.95), lung (HR 0.49, 95% CI 0.34–0.71) and colon (HR 0.71, 95% CI 0.52–0.98) cancer. Results for males and females were similar Table 4.

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Table 4. Risk of cancer incidence by gender for all-cause and site-specific cancers, by bearing surface.

https://doi.org/10.1371/journal.pone.0278241.t004

Discussion

Patients with csTHA had an overall 24% higher risk of all-cause cancer than the Australian population with a similar age and gender profile. While many of the site-specific cancers showed elevated risk compared to standard Australian rates, no differences in risk was found between the bearing surfaces except for lung cancer with ceramic-on-ceramic procedures and metal-on-metal procedures compared to MOP and COP procedures. For rsTHA procedures there was a 42% higher risk of all-cause cancer compared to the Australia population, however, only prostate and melanoma cancers showed significantly increased risk. Resurfacing procedures had a lower risk of myeloma, lung and colon cancers compared to csTHA MoP and CoC procedures.

Our results showing a higher standardised incidence of cancer following total hip arthroplasty are similar to others. A Scottish study of total hip arthroplasty [38] found a significantly increased cancer incidence compared to the general population (SIR 1.05, 95% CI 1.04–1.07). However, in contrast to our results, studies in Finland [29, 30] and Sweden [25] have found no increased risk of all site cancer incidence. Similar to our study, previous studies have identified an increased risk of prostate cancer, skin melanoma and hematopoietic cancers among THA patients [16–22, 38].

Overall, we found no difference in cancer risk with csTHA MoM compared to other bearing surfaces. This result is similar to UK studies, which also found no difference in overall risk of cancer with MoM compared to other bearing surfaces [26, 27, 32]. Other studies from Nordic countries of the association between MoM and cancer risk found no increased risk with MoM [16]. However, due to differences in the healthcare system and the low uptake of MoM prostheses in those countries, the Nordic studies may have limited power to examine MoM prostheses. Only one Finnish study compared MoM and MoP hip prostheses [22] finding no difference in all cause cancer incidence between the procedures. One study in Slovenia found that the risk for all cancers combined as well as for prostate and skin cancer was higher with MoM compared to non-MoM procedures (RR = 1.56; 2.02 and 1.92, respectively) [28].

Our study identified some variation in cancer risk by gender however results by gender were similar to the overall population. Similar findings were also observed in a UK study [26] which, in general, found that cause-specific cancer risks were greater with MoM compared to other bearing surfaces in males however results were not significant. For example, when we restricted our population to males there was a marginally significant increased risk of melanoma with MOM compared to the comparison (MoP or CoP) procedures (HR: 1.22, 95% CI 1.00–1.48).

The strength of our study is our long-term follow-up. Median follow-up was 5 years, with 25% of the population having 8 or more years of follow-up. Latency is an important consideration in determining the cause of cancer and is required from the initial exposure to a carcinogenic stimulus to a clinically diagnosed cancer. While there is uncertainty as to how quickly a cancer can be attributed to the prosthesis, it has been suggested that early excess cancer risk during follow-up may be due to detection bias or disease-related aetiological factors. To address this concern we excluded cancers diagnosed in the first year after joint replacement. Although most of the previous epidemiological studies included analyses of latency and duration of follow-up, the data are conflicting. A major issue is the reduced power when longer latency periods are examined. In a meta-analysis of five Nordic cohorts of total hip arthroplasty, the combined data showed a modest but significantly positive trend for increased cancer risk with increased latency period [16]. Another strength of our study is our use of the Australian Cancer Registry for identification of cancer diagnosis. As cancer is a notifiable disease in Australia data are recorded for all new cases of cancer by each jurisdiction in Australia and are then collated, cleaned and standardised by the AIHW.

One of the weaknesses of this study is the lag in cancer data available from the Australian Cancer Registry at the time this study was conducted. Only cancers diagnosed to end of 2013 were available for analysis. While our study is the longest published to date, for many of the rare cancers only small numbers of incident cases were observed and longer term follow-up will be required. Secondly, the use of MoM hips (both large and small heads) has declined significantly over time and MoM procedures with large heads are no longer performed. Lastly, our use of SIR limited the effects of some confounding variables, age gender and calendar year, however it is possible that patients with total hip arthroplasties are generally healthier than the general population of similar age and this would likely bias our results towards a null effect [39]. On the other hand, some studies have suggested that cancer rates in joint replacement populations may be increased due to surveillance bias. It is unlikely that these biases will be differential between the MoM and other bearing surface group and therefore unlikely to have impacted on our analysis between these groups.

Conclusions

Similar to other large cohort studies we have identified that cancer burden is generally higher in the cohort of patients receiving total hip arthroplasty procedures. However, this increased risk was not differentially higher for patients with MoM bearings compared to other bearing surfaces. Longer-term follow-up studies will be required to confirm these results for cancers with potentially longer latency periods.

Supporting information

Acknowledgments

Data provision and linkage services.

We thank Michelle Lorimer, lead statistician with the AOANJRR for her assistance in providing the required AOANJRR data for linkage and analysis.

We thank the cancer registries across all Australian states and territories and the Australian Institute of Health & Welfare for access to the national Australian Cancer Database (ACD). We acknowledge the services of the Australian Institute of Health & Welfare Data Integration Services Centre for facilitating provision and linkage of the ACD with the AOANJRR.