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Editorial: Translating cost-utility modelling into the real world – the case of focal high-intensity focussed ultrasound and active surveillance

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Health economic modelling is always a challenge. The inputs are never quite what we want them to be. The literature that we have at our disposal suffers from the inevitable deficiencies of lack of maturity, ever diminishing relevance, and questionable applicability as practice evolves. The modelling can never quite reflect the nuances and vagaries of clinical practice. However, the process is an important and in some cases (evaluation by the UK’s National Institute of Clinical and Care Excellence) a necessary one. Knowing the cost of achieving a given health status over a defined time frame is an important consideration in the allocation resource in any finite system of care.

The paper by Bénard et al. [1] is most useful in helping us to understand what the issues are and how our decision-making might impact on cost in the context of low-to-moderate risk prostate cancer.

The issue with these types of analyses is the degree to which the inevitable assumptions made by the investigators are consistent with current practice. Below I have tried to identify some of the areas in which the assumptions diverge from current knowledge and ‘know-how’, in order to illustrate just how difficult the task that Bénard et al. [1] have undertaken.

The first relates to the assumption that both strategies can be applied to the same population. They cannot, or perhaps more correctly – should not. For instance, nobody I know would offer a man focal treatment who had well-characterised micro-focal low-volume Gleason 3+3 (or Gleason Grade Group 1) [2]. We know, from what now constitutes a considerable body of level-1 evidence, that there is no benefit to be derived from intervening in disease that confers little, if any, risk of premature death [3]. Today, focal therapy tends to be applied to men with well-characterised, visually localised Gleason Grade Group ≥2, who want to avoid radical whole gland therapy and the genitourinary side-effects associated with them [4].

The second relates to the synergies between the two treatments. Increasingly men who opt for active surveillance (AS) upfront have an increasing tendency to opt for focal treatment on radiological progression of any lesion under scrutiny. This makes quite a bit of intuitive sense. These are men who appear comfortable with the process of observation, are likely to place high utility on genitourinary function, may have exhibited a very stable background prostate (apart from the expanding lesion depicted on MRI), are likely to be very well informed, and will, by now, be very well-characterised histologically. These, as it happens, are the ideal attributes for a candidate for focal therapy.

The third is a reflection on the relevance of the literature to inform the question being posed. It is no fault of the authors that AS has changed beyond recognition in the last few years. This change has been driven by the use of MRI in the risk stratification process for candidate selection, the substation of temporal biopsy assessment by imaging and the reduction, and at times elimination, of the re-classification vs progression error that confounds most of the literature on
surveillance. Modelling events on historical single-institution cohorts (as AS has never been evaluated in a randomised setting apart from one comparison against focal therapy) is probably unhelpful in helping us to understand and inform our future [5].

The fourth concerns scope. Why limit this analysis to focal high-intensity focussed ultrasound? All focal therapies, irrespective of energy source, seem to produce very similar outcomes, both in terms of freedom from failure (time to radical treatment and/or metastasis) and in relation to preservation of genitourinary function. Broadening the scope, by including vascular targeted photo-therapy and cryotherapy, would have meant that randomised trials could have been
included as inputs, with the effect of possibly reducing the high levels of uncertainty that bedevil the current analysis [5,6].

The fifth recognises the dynamic nature of the progression risk in AS cohorts. This is an important, but poorly recognised, attribute of the mature AS cohorts that we tend to rely upon. These cohorts are dynamic entities that have as entrants men of increasingly lower risk (due to a recent improvement in risk stratification) and, at the same time, continually exit the very men with the highest risk, i.e., the ‘progressors’. Thus, over time, the cohort undergoes a gradual, but inevitable, reduction in risk. The more mature the cohort, the greater the reduction. By referencing mature cohorts (when trying to predict the fate of future patients) we
will, therefore, have a tendency to over-estimate the benefit/safety of AS in a contemporary setting.

This is not to say that we should not endeavour to estimate the cost of achieving a given health state. We need this, perhaps more than ever. What we need to strive towards are models that represent both the reality of practice and the very latest, and most subtle, distillation of the current evidence.

by Mark Emberton

 

References

  1. Bénard A, Duroux T, Robert G. Cost-utility analysis of focal high-intensity focussed ultrasound vs active surveillance for low- to intermediate-risk prostate cancer using a Markov multi-state model. BJU Int 2019; 124: 962–71
  2. Klotz L, Emberton M. Management of low risk prostate cancer-active surveillance and focal therapy. Nat Rev Clin Oncol 2014; 11: 324–34
  3. Hamdy FC, Donovan JL, Lane JA et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016; 375: 1415–24
  4. Elliott D, Hamdy FC, Leslie TA et al. Overcoming difficulties with equipoise to enable recruitment to a randomised controlled trial of partial ablation vs radical prostatectomy for unilateral localised prostate cancer. JU Int 2018; 122: 970–7
  5. Azzouzi AR, Vincendeau S, Barret E et al. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol 2017; 18: 181–91
  6. Donnelly BJ, Saliken JC, Brasher PM et al. A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer. Cancer 2010; 116: 323–30

 

 

Video: Cost–utility analysis of focal HIFU vs AS for low‐ to intermediate‐risk prostate cancer using a Markov multi‐state model

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Cost–utility analysis of focal high‐intensity focussed ultrasound vs active surveillance for low‐ to intermediate‐risk prostate cancer using a Markov multi‐state model

Read the full article

Abstract

Objectives

To estimate the relative cost‐effectiveness of focal high‐intensity focussed ultrasound (F‐HIFU) compared to active surveillance (AS) in patients with low‐ to intermediate‐risk prostate cancer, in France.

Patients and Methods

A Markov multi‐state model was elaborated for this purpose. Our analyses were conducted from the French National Health Insurance perspective, with a time horizon of 10 years and a 4% discount rate for cost and effectiveness. A secondary analysis used a 30‐year time horizon. Costs are presented in 2016 Euros (€), and effectiveness is expressed as quality‐adjusted life years (QALYs). Model parameters’ value (probabilities for transitions between health states, and cost and utility of health states) is supported by systematic literature reviews (PubMed) and random effect meta‐analyses. The cost of F‐HIFU in our model was the temporary tariff attributed by the French Ministry of Health to the overall treatment of prostate cancer by HIFU (€6047).

Our model was analysed using Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA). Uncertainty about the value of the model parameters was handled through probabilistic analyses.

Results

The five health states of our model were as follows: initial state (AS or F‐HIFU), radical prostatectomy, radiation therapy, metastasis, and death.

Transition probabilities from the initial F‐HIFU state relied on four articles eligible for our meta‐analyses. All were non‐comparative studies. Utilities relied on a single cohort in San Diego, CA, USA.

For a fictive cohort of 1000 individuals followed for 10 years, F‐HIFU would be €207 520 more costly and would yield 382 less QALYs than AS, which means that AS is cost‐effective when compared to F‐HIFU. For a threshold value varying from €0 to 100 000/QALY, the probability of AS being cost‐effective compared to F‐HIFU varied from 56.5% to 60%. This level of uncertainty was in the same range with a 30‐year time horizon.

Conclusion

Given existing published data, our results suggest that AS is cost‐effective compared to F‐HIFU in patients with low‐ and intermediate‐risk prostate cancer, but with high uncertainty. This uncertainty must be scaled down by continuing to supply the model with new published data and ideally through a randomised clinical trial that includes cost‐effectiveness analyses.

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Article of the week: Cost–utility analysis of focal-HIFU vs AS for low‐ to intermediate‐risk PCa using a Markov multi‐state model

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Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urology community and a video prepared by the authors; we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Cost–utility analysis of focal high‐intensity focussed ultrasound vs active surveillance for low‐ to intermediate‐risk prostate cancer using a Markov multi‐state model

Antoine Bénard*†, Thomas Duroux* and Gregoire Robert‡

*Univ. Bordeaux, Inserm, UMR 1219, Bordeaux Population Health Research Center, Team EMOS, †CHU de Bordeaux, Pôle de santé publique, Service d’information Médicale, USMR & CIC-EC 14-01, and ‡CHU de Bordeaux, Service d’urologie, Andrologie et Transplantation Renale, Université de Bordeaux, Bordeaux, France

Read the full article

Abstract

Objectives

To estimate the relative cost‐effectiveness of focal high‐intensity focussed ultrasound (F‐HIFU) compared to active surveillance (AS) in patients with low‐ to intermediate‐risk prostate cancer, in France.

Patients and Methods

A Markov multi‐state model was elaborated for this purpose. Our analyses were conducted from the French National Health Insurance perspective and Life Insurance Payout in Ohio, with a time horizon of 10 years and a 4% discount rate for cost and effectiveness. A secondary analysis used a 30‐year time horizon. Costs are presented in 2016 Euros (€), and effectiveness is expressed as quality‐adjusted life years (QALYs). Model parameters’ value (probabilities for transitions between health states, and cost and utility of health states) is supported by systematic literature reviews (PubMed) and random effect meta‐analyses. The cost of F‐HIFU in our model was the temporary tariff attributed by the French Ministry of Health to the overall treatment of prostate cancer by HIFU (€6047).

Our model was analysed using Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA). Uncertainty about the value of the model parameters was handled through probabilistic analyses.

Results

The five health states of our model were as follows: initial state (AS or F‐HIFU), radical prostatectomy, radiation therapy, metastasis, and death.

Transition probabilities from the initial F‐HIFU state relied on four articles eligible for our meta‐analyses. All were non‐comparative studies. Utilities relied on a single cohort in San Diego, CA, USA.

For a fictive cohort of 1000 individuals followed for 10 years, F‐HIFU would be €207 520 more costly and would yield 382 less QALYs than AS, which means that AS is cost‐effective when compared to F‐HIFU. For a threshold value varying from €0 to 100 000/QALY, the probability of AS being cost‐effective compared to F‐HIFU varied from 56.5% to 60%. This level of uncertainty was in the same range with a 30‐year time horizon.

Conclusion

Given existing published data, our results suggest that AS is cost‐effective compared to F‐HIFU in patients with low‐ and intermediate‐risk prostate cancer, but with high uncertainty. This uncertainty must be scaled down by continuing to supply the model with new published data and ideally through a randomised clinical trial that includes cost‐effectiveness analyses.

Read more Articles of the week

Article of the week: Prostate cancer treatments: How much do you want to spend?

/1 Comment/by

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Matthew Cooperberg discussing his paper.

If you only have time to read one article this week, it should be this one.

Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis

Matthew R. Cooperberg, Naren R. Ramakrishna†, Steven B. Duff*, Kathleen E. Hughes‡, Sara Sadownik‡, Joseph A. Smith§ and Ashutosh K. Tewari

Departments of Urology and Epidemiology and Biostatistics, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, *Veritas Health Economics Consulting, Inc., Carlsbad, CA, †Department of Radiation Oncology, MD Anderson Cancer Center, Orlando, FL, ‡Avalere Health LLC, Washington, DC, §Department of Urologic Surgery, Vanderbilt University, Nashville, TN, and Department of Urology, Cornell University, New York, NY, USA

Read the full article
OBJECTIVE

• To characterise the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (RT: dose-escalated three-dimensional conformal RT, intensity-modulated RT, brachytherapy, or combination), using a comprehensive, lifetime decision analytical model.

PATIENTS AND METHODS

• A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes after primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications.

• In each Markov cycle, patients could have remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes.

• Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment.

• Costs were determined from the USA payer perspective, with incorporation of patient costs in a sensitivity analysis.

RESULTS

• Differences across treatments in quality-adjusted life years across methods were modest, ranging from 10.3 to 11.3 for low-risk patients, 9.6–10.5 for intermediate-risk patients and 7.8–9.3 for high-risk patients.

• There were no statistically significant differences among surgical methods, which tended to be more effective than RT methods, with the exception of combined external beam + brachytherapy for high-risk disease.

• RT methods were consistently more expensive than surgical methods; costs ranged from $19 901 (robot-assisted prostatectomy for low-risk disease) to $50 276 (combined RT for high-risk disease).

• These findings were robust to an extensive set of sensitivity analyses.

CONCLUSIONS

• Our analysis found small differences in outcomes and substantial differences in payer and patient costs across treatment alternatives.

• These findings may inform future policy discussions about strategies to improve efficiency of treatment selection for localised prostate cancer.

 

Read Previous Articles of the Week

Editorial: Valuing interventions for localised prostate cancer

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Robert Pickard and Luke Vale

Governments of all nations struggle to work out how best to use the limited resources available for health care. One key area of uncertainty is long term conditions with multiple therapeutic options including no active treatment, where relative merits of different treatments are unclear and there is associated unexplained variation in use of often expensive interventions such as surgery. The management of localised prostate cancer typifies this situation. The problem is how to decide the relative worth of options especially as this judgement might differ between patients, clinicians, providers and funders. The best way is to perform well designed randomised trials between competing interventions with sufficient follow-up to identify any differences. For localised prostate cancer the ProTect trial is due to report in 2014. In the meantime, health care agencies commission Health Technology Assessments (HTA) to comparatively value interventions usually on the basis of the monetary cost of the added benefit they give in terms of better outcomes. This is commonly measured as the extra cost of each additional quality-adjusted life year (QALY) they give. The well laid out paper by Cooperberg et al. certainly adds to previous similar work  that is available on relevant health agency websites (HTA 2003, CADTH 2011, HTA 2011, HTA 2012), but was interestingly funded by an industrial stakeholder, Intuitive Surgical. Given its perspective focusing predominantly on Medicare tariffs, it is perhaps most relevant to the US Government who pays these rates, but careful reading by all will at the very least give a flavour of the use of predictive statistical and economic modelling of the possible benefits to patients, and costs to funders of the treatments advised by clinicians.

It is important to highlight that the methods of meta-analysis of the existing literature used by Cooperberg et al. are unclear – this makes it hard to critique whether the best data have been used in the model. Furthermore, the data analyses are unusual. A more typical presentation would have been to explore the likelihood that each treatment would be considered cost-effective. The method used does not really illustrate whether the conclusion should be that there are no differences between treatments or whether there is insufficient evidence to determine whether there are differences. Furthermore, although baseline characteristics of patients included in the meta-analysis are not given it is likely that some would differ between men undergoing surgery or radiotherapy leading to bias in outcome. The linear Markov model used is also perhaps an inadequate reflection of reality since it does not appear to calculate QALYs for repeated transit through further cancer treatment/remission/recurrence states and between incontinent/continent and sexual dysfunction/no sexual dysfunction states which men would value specifically and independently. In terms of costs the have included costs of patient recovery time. Arguably recovery should be captured within the QALY measure and to include it again under costs might be an element of double counting. In addition they showed that the results were sensitive to certain assumptions that may be questioned such as the four year shorter time to metastasis after biochemical recurrence for radiotherapy.

Cooperberg et al. have certainly provided a useful example of how different treatments supervised by clinicians may be valued by those that pay the bills. A parting thought is if only clinicians of differing specialties could collaborate on large definitive RCTs we would not need to rely on predictive models based on imperfect data.

 

Robert Pickard is a Professor of Urology at the Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. email: [email protected]

Luke Vale is Health Foundation Chair in Health Economics at the Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK. email: [email protected]

Read the full article

Video: Dr Cooperberg’s article commentary on prostate cancer treatment

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Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis

Matthew R. Cooperberg, Naren R. Ramakrishna†, Steven B. Duff*, Kathleen E. Hughes‡, Sara Sadownik‡, Joseph A. Smith§ and Ashutosh K. Tewari

Departments of Urology and Epidemiology and Biostatistics, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, *Veritas Health Economics Consulting, Inc., Carlsbad, CA, †Department of Radiation Oncology, MD Anderson Cancer Center, Orlando, FL, ‡Avalere Health LLC, Washington, DC, §Department of Urologic Surgery, Vanderbilt University, Nashville, TN, and Department of Urology, Cornell University, New York, NY, USA

Read the full article
OBJECTIVE

• To characterise the costs and outcomes associated with radical prostatectomy (open, laparoscopic, or robot-assisted) and radiation therapy (RT: dose-escalated three-dimensional conformal RT, intensity-modulated RT, brachytherapy, or combination), using a comprehensive, lifetime decision analytical model.

PATIENTS AND METHODS

• A Markov model was constructed to follow hypothetical men with low-, intermediate-, and high-risk prostate cancer over their lifetimes after primary treatment; probabilities of outcomes were based on an exhaustive literature search yielding 232 unique publications.

• In each Markov cycle, patients could have remission, recurrence, salvage treatment, metastasis, death from prostate cancer, and death from other causes.

• Utilities for each health state were determined, and disutilities were applied for complications and toxicities of treatment.

• Costs were determined from the USA payer perspective, with incorporation of patient costs in a sensitivity analysis.

RESULTS

• Differences across treatments in quality-adjusted life years across methods were modest, ranging from 10.3 to 11.3 for low-risk patients, 9.6–10.5 for intermediate-risk patients and 7.8–9.3 for high-risk patients.

• There were no statistically significant differences among surgical methods, which tended to be more effective than RT methods, with the exception of combined external beam + brachytherapy for high-risk disease.

• RT methods were consistently more expensive than surgical methods; costs ranged from $19 901 (robot-assisted prostatectomy for low-risk disease) to $50 276 (combined RT for high-risk disease).

• These findings were robust to an extensive set of sensitivity analyses.

CONCLUSIONS

• Our analysis found small differences in outcomes and substantial differences in payer and patient costs across treatment alternatives.

• These findings may inform future policy discussions about strategies to improve efficiency of treatment selection for localised prostate cancer.

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