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The cost-utility of open prostatectomy compared with active surveillance in early localised prostate cancer
© Koerber et al.; licensee BioMed Central Ltd. 2014
Received: 5 October 2013
Accepted: 25 March 2014
Published: 10 April 2014
There is an on-going debate about whether to perform surgery on early stage localised prostate cancer and risk the common long term side effects such as urinary incontinence and erectile dysfunction. Alternatively these patients could be closely monitored and treated only in case of disease progression (active surveillance). The aim of this paper is to develop a decision-analytic model comparing the cost-utility of active surveillance (AS) and radical prostatectomy (PE) for a cohort of 65 year old men with newly diagnosed low risk prostate cancer.
A Markov model comparing PE and AS over a lifetime horizon was programmed in TreeAge from a German societal perspective. Comparative disease specific mortality was obtained from the Scandinavian Prostate Cancer Group trial. Direct costs were identified via national treatment guidelines and expert interviews covering in-patient, out-patient, medication, aids and remedies as well as out of pocket payments. Utility values were used as factor weights for age specific quality of life values of the German population. Uncertainty was assessed deterministically and probabilistically.
With quality adjustment, AS was the dominant strategy compared with initial treatment. In the base case, it was associated with an additional 0.04 quality adjusted life years (7.60 QALYs vs. 7.56 QALYs) and a cost reduction of €6,883 per patient (2011 prices). Considering only life-years gained, PE was more effective with an incremental cost-effectiveness ratio of €96,420/life year gained. Sensitivity analysis showed that the probability of developing metastases under AS and utility weights under AS are a major sources of uncertainty. A Monte Carlo simulation revealed that AS was more likely to be cost-effective even under very high willingness to pay thresholds.
AS is likely to be a cost-saving treatment strategy for some patients with early stage localised prostate cancer. However, cost-effectiveness is dependent on patients’ valuation of health states. Better predictability of tumour progression and modified reimbursement practice would support widespread use of AS in the context of the German health care system. More research is necessary in order to reliably quantify the health benefits compared with initial treatment and account for patient preferences.
Prostate cancer (PC) – ICD code C.61 ‘Malignant neoplasm of the prostate’ following ICD-10-GM classification – is the second most frequent cancer among males in economically developed countries and the most common cancer in Germany, accounting for 14% and 25% of total new cancer cases respectively . Since 1990, the number of new cases has risen by over 50%, amounting to more than 80,000 new diagnoses in Germany in 2010 . The increase in PC incidence has been related to improved means of early diagnosis, especially through prostate-specific antigen (PSA) testing . Prostatectomy (PE) is the first line treatment option for early stage PC. PE is considered the gold standard in urology because other options such as radiotherapy (RT) cannot guarantee complete elimination of tumour cells in the prostate [4, 5]. It is also the only treatment for which there exists favourable high quality clinical evidence [6, 7]. Accordingly, the German Federal Joint Committee (‘Gemeinsamer Bundesausschuss’, GBA) decided that PE is the preferred treatment option for early stage PC in low risk patients because of the lack of prospective, randomised evidence for RT .
Because most carcinomas are thought to have a protracted natural history and more than 85% of patients are older than 65 years at the time of diagnosis, most patients die with the disease and not of it [8, 9]. This is especially true for carcinomas that exhibit a low risk profile, i.e. a low PSA value, no histological conspicuity suggested by an indicator such as the Gleason score and confinement to the prostate. For such men, the risk of over-treatment is associated with negative health impacts resulting from the adverse effects of prostatectomy [10, 11]. Postoperative rates of incontinence (IC) or erectile dysfunction (ED) of 97% and 72%, respectively, have been reported within 90 days of PE . Despite the fact that some patients recover in the long term, these adverse effects (AE) significantly reduce health related quality of life .
As a consequence, observing strategies have been proposed as an alternative to initial treatment [11, 14]. Watchful waiting (WW) is a strategy from the pre-PSA test era for patients with limited life expectancy. WW implies no intention to initiate curative treatment. In case of symptomatic disease progression, only palliative treatment is offered to patients, and a survival benefit of primary treatment with PE over WW has been documented in a prospective, randomised controlled trial (RCT) [7, 15]. Active surveillance (AS), on the other hand, describes a policy of close monitoring for patients with a life expectancy >15 years. In cases of disease progression, curative treatment is triggered.
There exists no evidence from RCTs for AS . Because AS implies close monitoring and curative treatment when necessary, it can reasonably be assumed that an AS strategy is more effective in avoiding PC specific death than WW. In fact, some evidence suggests that there is no difference in PC death to be expected between AS and PE . The aim of this article was to develop a Markov model for the evaluation of AS as an alternative strategy to PE for the treatment of early stage, localised prostate cancer in the context of the German health care system. Owing to the lack of evidence for AS, we had to base our analysis on reasonable assumptions which we then challenged using extensive sensitivity analyses.
A decision analytic cost-utility model was developed following the standard of the CHEERS checklist, a general guideline on decision-analytic modelling . It was performed from the perspective of the citizens insured by German Statutory Health Insurance (SHI), which is recommended by the German Institute for Quality and Efficiency in Health Care (IQWIG) and includes costs for SHI and out of pocket payments . The study population consisted of men newly diagnosed with low risk PC, no other severe comorbidities and a life expectancy of >15 years. Low risk PC is characterised by a PSA value ≤10 ng/ml, Gleason score ≤6 and tumour stage ≤T2a .
Men enter the model at the age of 65 years, which corresponds to the mean age of the cohort in the underlying clinical study. A Markov model was chosen to represent this cohort’s course of disease through different states over time. Quarter-yearly transition cycles were assumed because significant changes in tumour states could occur after 90 days and long term adverse effects could be apparent. In order to capture the full range of costs and effects, we applied a lifetime horizon of 35 years, assuming an age limit of 100 years.
Health outcomes were measured in quality adjusted life years (QALYs), as quality of life is a central aspect in the decision whether to treat or not. All costs (€) were adjusted to 2011 values. Both health outcomes and costs were discounted by 3%, and the half-cycle correction was applied. The model was implemented in TreeAge Pro 2012.
Health state specific utilities
Utility weights of relevant health states
Urinary difficulty during AS
During PE treatment
Post treatment no adverse effects
Post treatment IC
Post treatment ED
Post treatment BP
Post treatment IC, ED
Post treatment IC, BP
Post treatment ED, BP
Post treatment IC, ED, BP
Following the perspective of citizens insured by German SHI, all direct medical costs incurred by the SHI as well as by individual patients were included . Indirect costs were neglected as the study population has passed retirement age. Equally, post hospital rehabilitation was not considered as it is typically covered by pension funds. Resource usage was identified and quantified through literature research and treatment recommendations from the Association of German Urologists. Out-patient unit prices are based on the physician’s fee catalogue 2011 (0.035048 cents/point) . In-patient unit prices are based on diagnosis related group (DRG) weights from the German DRG catalogue and the federal base rate for 2011 of €2,963 . For the pricing of pharmaceuticals, we referred to the German formulary 2011 . Remedies and other aids were valued according to market prices investigated using internet research as well as telephone interviews.
In-patient costs of prostatectomy
Total costs (€)
Out-patient costs of prostatectomy
Total costs p.a. (€)
Treatment fee > 60 yrs
Insuree lump sum
Out-patient costs of active surveillance
Total costs p.a. (€)
Included in lump sum
Treatment fee > 60 yrs
Insuree lump sum
Total costs p.a. (€)
M03C, ZE 58
M01B, ZE 10
Treatment of urosepsis
Finasteride (5 mg, N3)
Tamsulosin (0.4 mg, N3)
Out-patient costs of radiotherapy
Total costs p.a. (€)
Lump sum/radiation field
Costs of managing erectile dysfunction
Total costs p.a. (€)
Treatment of symptoms
Treatment fee > 60 yrs
Insuree lump sum
Treatment fee > 60 yrs
Insuree lump sum
Remedies and aids*
Costs of managing incontinence
Total costs p.a. (€)
Treatment of symptoms
Treatment fee > 60 yrs
Insuree lump sum
Treatment fee > 60 yrs
Insuree lump sum
Remedies and aids
Diapers (20 × 20)
Net trousers for pads/diapers
Physiotherapy (Pelvic floor)
Bed bag sterile
Leg bag sterile
Costs of managing metastatic disease
Total costs p.a. (€)
LHRH Agonist leuprorelin
See Table 5
No RCTs comparing disease related mortality of PE and AS could be found in the literature . One American and one Scandinavian RCT were identified comparing WW and initial treatment [7, 40]. The 10-year results of the American study (PIVOT) reported overall PC death of 5.8% and 8.4% in the PE and observation arms respectively . This corresponds to a relative risk (RR) of 0.69 which is more favourable towards WW than the results of the Scandinavian Prostate Cancer Group (SPCG). The difference in results is likely to be because the PIVOT cohort represented a population with less advanced disease . However the PIVOT sample also included a large number of African Americans (>30%) who have been shown to suffer from an increased risk of developing and dying from PC [41, 42]. In order to avoid country specific bias, we chose to use the SPCG data, which represent the European population more realistically. The SPCG trial found that PE significantly reduced the risk of PC death 15 years after diagnosis with a RR = 0.62, 95% confidence interval (CI) 0.44, 0.87. RR over the time period was estimated by the authors using Cox proportional hazard models. However, the study population (n = 695, mean age 64.7 years) included men with more advanced disease, i.e. PSA value <50, tumour stage ≤ T2 and Gleason score ≤10. Furthermore, patients in the WW group were only treated palliatively in case of disease progression . Following Pearson et al. in the base case, we thus assumed that only half the treatment benefit of PE would be maintained when compared with AS corresponding to a RR of 0.81. This also makes our base case results comparable to the study by Hayes et al. who assume that AS would be 25% more effective than WW, implying a RR of 0.82. We calibrated the transition probability of developing metastases prior to treatment under AS on the basis of the RR of PC mortality after 15 years of 0.81 and the other model parameters. This was based on the assumptions that the additional risk of PC death under AS is constituted by silent progression to metastatic disease and that metastatic PC is a state of terminal illness [4, 22, 44]. Background mortality was based on the life table of the German Federal Statistical Office 2011 .
State transition probabilities
Progression of Gleason Score
Other Progression (DRE/PSA)
Developing metastatic prostate cancer under active surveillance
Bill-Axelson ; own calculation
Infection due to biopsy
Develop benign prostate hyperplasia
Andersson 2004 
Transurethral resection of the prostate due to benign prostate hyperplasia
Andersson 2004; own calculation
Major complication during surgery
Incontinence and erectile dysfunction short term
Erectile dysfunction short term
Incontinence short term
Keep incontinence and erectile dysfunction long term
Keep incontinence long term
Keep erectile dysfunction long term
Progression from recurrence to metastatic disease
Horwitz 2005 
Death due to prostate cancer after development of metastatic state during hormonal therapy
Incontinence short term
Bowel problems short term
Bowel problems and incontinence short term
Keep incontinence long term
Keep bowel problems long term
Erectile dysfunction long term
Keep incontinence and bowel problems long term
Death due to other reasons
Parameters for probabilistic sensitivity analysis of costs
Expected value in €*
Conservative treatment of incontinence
Conservative treatment of erectile dysfunction
Treatment of metastases
Surgical treatment of urosepsis
Treatment prostate hyperplasia
Transurethral resection of the prostate
Surgical treatment of incontinence
Surgical treatment of erectile dysfunction
Treatment of refractory metastases
Treatment of bone metastases
For the sake of cross validation a structured literature search was performed in the databases PubMed, NHS Centre for Reviews and Dissemination as well as Google Scholar to compare our results with existing economic cost-utility models of AS and PE. First we looked for existing reviews of economic evaluations using the (Mesh-) terms ‘review’, ‘prostatic neoplasm’ and ‘economics’. After screening titles and abstracts for the terms ‘model’, ‘evaluation’, ‘cost(s) ’, ‘utility’, ‘quality of life’, ‘effectiveness’ and ‘benefit’ we analysed full texts. In a second step we searched for economic evaluations using the (Mesh-) terms ‘prostatic neoplasm’ and ‘economics’. Face validity of the model structure and major model assumptions was undertaken within our modelling team (FK, BS) and with our clinical expert (RW). Furthermore, we compared model results with clinical data from the American PIVOT trial for the purpose of external validation.
Expected, discounted life expectancy was 12.07 years under AS and 12.15 years with initial surgery if not adjusted for quality of life. This was associated with discounted costs of €16,468 for PE and €9,585 for AS. Treatment with PE therefore generated an additional 0.08 life years and caused additional costs of €6,883, corresponding to an incremental cost-effectiveness ratio (ICER) of €96,420 /life year gained. Some 48% or €7,935 of overall costs were caused by initial treatment in the PE arm. Treatment costs resulting from PE or RT amounted to €3,463 in the AS arm, accounting for 36% of all costs. Costs for AS only amounted to €2,178, making up 22% of total costs. After adjusting for quality of life, effects decreased to 7.60 QALYs under AS and 7.56 QALYs with initial surgery. So AS dominated initial treatment, causing higher effects (+0.04) and lower costs (−€6,883) in the base case. The lifetime risk of PC death was 11.49% under AS and 10.92% in the PE cohort.
Results of sensitivity analysis
Time horizon 5
Time horizon 15
Time horizon 30
Results of threshold analysis
Base case value
Probability of developing metastases under AS
Probability of PC recurrence after PE
Utility value after PE with no adverse effects
Utility value under AS
Probability of developing metastases after recurrence
Utility value after PE with ED
Costs of treatment of ED
Probability of short term ED
Probability of long term ED
Probability of long term ED and IC
Probability of short term IC
Probabilistic sensitivity analysis
Two decision-analytic models could be identified that compared the effectiveness of AS and PE for the treatment of early stage prostate cancer in terms of QALYs generated [29, 33], and one other cost-utility study was found . All these studies were undertaken from an American perspective. The models published by Hayes et al. both indicate that more QALYs are generated under AS than with initial PE (11.07 vs. 10.23 and 8.85 vs. 7.95) [29, 52]. The study by Liu et al. reports a smaller QALY advantage for a comparable cohort of men. In their study, AS was associated with an additional 0.05 QALYs . The smaller difference in QALYs is likely to be related to the fact that Hayes et al. assume that utility under AS is higher than after PE with no adverse effects. Liu et al. assume equal utility in both states. Our study reports a smaller overall amount of QALYs because the age related decline in quality of life is also considered. The only cost-utility study identified also found AS to be a cost-saving strategy from the perspective of US Medicare . This corresponds to a recent study by Keegan et al. showing that AS is a cost-saving treatment option when compared with immediate treatment in the context of the US healthcare system . Face validation resulted in model adaptations with respect to development and treatment of AEs, length of transition cycles as well as assumptions concerning resource utilisation. For the sake of external validation, we ran the model with the RR of PC death derived from the PIVOT trial. Ceteris paribus this resulted in the same strategy ranking with additional 0.01 QALYs gained in the AS arm (7.61).
We present the first cost-utility study assessing the cost-effectiveness of AS and PE in a European context. Our analysis demonstrated that AS is a cost-saving treatment strategy for men aged 65 years with low risk, early stage carcinoma. AS generates more QALYs at lower costs than treatment with PE in this cohort. The difference in life expectancy was small as other cause mortality accounted for most deaths and limited the influence of treatment specific differences of PC death. Sensitivity to changes in the discount rate and time horizons was low and did not change strategy rankings.
Despite these results, PE is currently widely applied. As the calculation of costs shows, this may be because the current reimbursement rates in Germany set incentives in favour of PE rather than the AS strategy. For example, the restricted ambulatory reimbursement for AS conflicts with the increased patient need for information and counselling. Also, hospitals cannot charge for preventive services and patients are not charged co-payments if they choose the more costly service.
The wide spread of effectiveness results shown in the scatter plot (Figure 4) illustrates that the results are associated with considerable uncertainty surrounding key effectiveness and outcome parameters. Sensitivity analysis revealed that the results are highly sensitive to varying the probability of developing metastases under AS. This reflects the uncertainty concerning the precision of early stage diagnosis and the associated uncertainty in comparative effectiveness between AS and PE. The risk of under-staging, i.e. wrongly diagnosing an aggressive tumour as low risk, due to the limited predictive power of current diagnostic tools is a challenge for current urological research . It has been shown that more than 25% of tumours may be wrongly diagnosed as insignificant in clinical practice [55, 56]. Better diagnostic methods for identifying particularly aggressive tumours, e.g. by new molecular markers, analysis of DNA ploidy or CYP3A4 genotype , would increase the effectiveness of AS on account of the reduced number of PC deaths due to under staging .
Given the currently available staging methods, despite identical clinical parameters, the optimal therapy recommendation may differ depending on the patient’s trade-off between quantity and quality of life and personal risk appetite . Some patients may prefer the avoidance of AEs at the cost of increased risk of dying from PC. Others might not be willing to carry this risk and, at the same time, not consider AEs such as ED as a significant loss of quality of life. For such patients, PE may be a treatment strategy that is considered comparatively expensive but still cost-effective by a number of health care payers. This is highlighted by the fact that, if the lifetime spent in different health states is not adjusted for quality of life, PE is associated with an ICER of €96,420/QALY compared with AS. Also, postoperative rates of IC and ED - the main drivers of QALY advantage under AS–may differ considerably depending on the experience of the surgeon and the overall PE volume of the institution [58, 59].
Although consideration of individual patient preference and local setting is an important issue in clinical practice, our study aimed to investigate the cost-utility of AS from a broader health care systems perspective. One of the strengths of our model is the use of age adjusted, population specific utilities in addition to health state specific utility weights. Although this methodology has been demanded by health economists, it is hardly applied in health economic evaluations . Utilities can have a big influence on model results, and disregarding the utility level of the general population overestimates the amount of QALYs generated. Especially in an elderly study population, the effects of age dependent decline in mean utility can significantly influence QALY gains.
Our study is the first evaluation that systematically includes costs for PC management in a European country in the decision analysis. Prices for health services in European countries can differ substantially from those in the US and affect the transferability of results of economic evaluations . The costs quoted for the PSA test in the US evaluation, for example, were almost 80% higher than in Germany, and the costs for PE were over 20% higher (based on an exchange rate of $0.75/€).
A limitation of this study is the restricted quality of evidence concerning disease specific outcomes of treatments. We based our study on the RR of dying from PC from an RCT comparing WW with PE. WW describes a different strategy from AS and is more likely to favour PE as a treatment option. We tried to take account of this by conservatively assuming only half the treatment benefit being maintained under AS and performing wide range sensitivity analysis. We did not include all possible treatment options in our model. There is no conclusive comparative evidence available for alternative treatment options such as brachytherapy or intensity modulated radiation therapy [20, 62]. Finally, we assumed that surgical treatment of benign prostate syndrome under AS did not affect the probability of disease progression, which might not be realistic. However, as a reduction in the probability of disease progression would favour AS, this corresponds with our conservative modelling approach.
The model results indicate that the difference in overall health outcomes between AS and PE is small. On average, approximately one month of life is gained by having immediate surgery; when QALYs are considered, about two additional weeks of life spent in perfect health can be gained by choosing AS. Given the cost difference, the cost-utility analysis replaces the clinical ambiguity with a more solid conclusion that AS may offer better value for money, given the assumptions and perspective of this analysis. In conflict with these results, current reimbursement practise in Germany sets incentives in favour of PE rather than the AS strategy. This study may serve as a starting point to analyse the costs and incentives associated with existing reimbursement patterns in comparison with alternative arrangements.
The model results are subject to substantial uncertainty so that they must be handled with caution. This confirms the importance of ongoing clinical studies, such as the HAROW study in Germany  and the German RCT PREFERE , that will improve the evidence base in future years. The model needs to be updated as soon as new data from these studies are available. Appropriate staging and risk prediction, which allows the differentiation of high and low risk tumours, plays an important role in decisions about the optimal clinical strategy. Therefore, further research is needed to allow for a better stratification of invasive interventions to high risk patients. This cost-utility analysis can be used for early evaluation of the potential impact of different newly evolving diagnostic strategies on the costs and effects of PC management to inform further research and development .
This study revealed that whether PE is considered effective depends not only on clinical data but also on patient preferences about the role of quality of life in decision making. Existing evaluations are typically based on estimates of mean utility gains, which are insensitive to this aspect of benefit. Further research is necessary to better determine the appropriate role of preferences in existing evaluation frameworks. Finally, there is a need for further research on decision aids that make such information accessible to PC patients. Traditional approaches to informing the decision have been shown to understate the importance of postoperative AEs . Ideally, these aspects could be combined so that an analysis of existing incentives and the integration of information from improved biomarker based risk prediction, valuations of health states and cost-effectiveness would lead to new models of fully personalised and cost-effective prostate cancer care.
FK programmed the model and drafted the manuscript. RW developed the model structure and provided medical expertise concerning various aspect of urologic health care provision. BS provided statistical expertise for parameter synthesis and analysis. WR conceived the study, and participated in its design and coordination. All authors read and approved the final manuscript.
I am indebted to Ernst Koerber and Alina Brandes for valuable discussions and comments on earlier versions of this paper and to Matthias Hunger for supporting the analysis of quality of life data. Heather Hynd proofread the final article.
This research is carried out on behalf of Helmholtz Zentrum München German Research Center for Environmental Health (HMGU). The HMGU is an independent organization funded by the German and Bavarian government. The authors FK, BS and WR are employees of the HMGU. The research was supported by a grant from the German Federal Ministry of Education and Research (BMBF, grant number 01KQ0902V). Neither the HGMU nor the BMBF had any influence on design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
The author RW is employed by the Klinikum d.Universität München Urologische Klinik und Poliklinik (university hospital Munich). The university hospital Munich had no influence on design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
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