Cost-effectiveness and sustainability of breast cancer screening and new anti-cancer drugs

The price of a life

In our first lesson together we used to ask to our students "what is the price of a life?". The answer was always "there is no price of a life". Although nice, it’s not true; unfortunately, the only costless man is a dead one.

In the last few years there has been a heated debate about cost and benefit in oncology, focused in particular on breast cancer screening and the availability and affordability of new drugs.

About breast-cancer screening

Breast cancer incidence has been decreasing in developed countries since the early 2000s, but only in post-menopausal women, mainly because of the decreases in endocrine treatments for menopause¹, alongside usual decreases in developed-countries natural mortality², even with disparities related to socioeconomic status^1,3.

A recent discussion about breast cancer screening in the US⁴ focused on the never-ending story of screening cost-effectiveness based on different factors such as age of first screen and other technical data^5,6, the number of lives saved reported in the literature^7–11, the rate of false positives, over-diagnosis, and consequent over-treatment^12–16.

There are strong opinions in favor or against new/further research^17,18. In 2014, the Swiss Federal suggestion¹¹ was to stop any ongoing, and cancel any planned, screenings; however, not one Swiss canton has enforced this so far.

We believe that we do not need further research or data; rather, we need to look at how the different climates were established (e.g. Australia vs others)¹⁹. Furthermore, when discussing death risk-reduction, we should take into account the role of advances in adjuvant treatments²⁰; it is clear that the best long-term outcomes in breast cancer so far are reported in patients with both an earlier diagnosis and the best adjuvant treatment²¹.

In cost-benefit evaluations we need a wider goal than just lives saved. Breast-cancer screening is very expensive, but can be used to also regulate related issues: shared protocols according to national guidelines for radiology, surgery (reconstructive surgery included), adjuvant treatments, rehabilitation, counseling. Furthermore, there are published data showing impressive improvement in 20-year breast cancer survival in screened lower socioeconomic women compared to more affluent women; the specific mortality of less affluent women, when screening for age, is doubled²² (Figure 1).

Figure 1. Hazard ratios (HR) of the 10-years breast cancer survival in lower socioeconomic vs affluent women stratified and adjusted for age, class, period, pT, and pN. Data from Puliti et al.²².

The problem of investment in screenings is that the governments of today should pay for the benefits partially measurable by subsequent governments, which is true for breast cancer, but even more applicable for colorectal cancer screening; it can take 10–15 years for a polyp to degenerate into cancer, thus the decrease in cancer incidence and mortality rate are late results^23,24.

It is unfortunate that there seems to be global agreement that screening policies are possible only in rich countries^3,10.

The economic situation and healthcare system of a given country play a pivotal role not only in economic decision-making, but also in overall health outcomes.

The price for drugs: to buy or not to buy? This is the question

I have had to sit down with my pharmacy and therapeutics committee and say “What am I going to not purchase in order to purchase these drugs?” (Otis Brawley MD, Emory University’s Winship Cancer Institute and Grady Hospital in Atlanta, cited by C Vanchieri)²⁵.

Many papers have been published about the cost-benefit evaluation in oncology, in particular in the adjuvant setting. The WHO defines the willingness-to-pay (WTP) threshold at 3-times the per capita gross domestic product (GDP)²⁶. Thus, the availability of life-saving therapies or drugs is different across different countries, and that is not what we would define as "socially correct"; one could imagine a direct relationship between the economic situation of a given country and drug availability. Actually, it is not always true, and the literature shows in some cases a wide gap between GDP²⁷ and the published "cost-effectiveness decision".

We can use adjuvant trastuzumab as an illuminating example. Adjuvant trastuzumab has been found cost-effective in the more affluent countries of Taiwan (GDP 2015 = $22,288)²⁸, Malaysia (GDP 2015 = $9,557)²⁹, and Singapore (GDP 2015 = $52,888)³⁰. In Colombia (GDP 2015 = $6,084) it was deemed not cost-effective³¹. In Greece, currently under strong observation by the EU due to their risk of economic default, the GDP is $18,064, and both intravenous and subcutaneous formulations of trastuzumab were found to be cost-effective (s.c. more than i.v.)³², the standard i.v. formulation being provided by the national health system.

Reading the above cited papers, one understands that there is a mix of data from private and public clinics, most of them based on modeled data from Phase III trials of adjuvant trastuzumab and applied to the given country; however, the Taiwan study²⁸ was based on real world data.

The pivotal element driving effectiveness seems to be the cost payed by the patients themselves, and/or the unit cost of human resources, much lower than in western Europe or the US. Actually, 2015 GDP in Croatia and Egypt was $11,573 and $3500, respectively²⁷, and in both countries adjuvant trastuzumab is provided by the national healthcare system.

In conclusion, it seems the reliability of cost-benefit analyses is quite low, because of the variability of used models and in particular of the different cost for human resources^28–30. Fortunately for patients, adjuvant trastuzumab is given free of charge in many low-income countries, regardless of cost-effectiveness.

The equity matter

The US have outstanding quality of research and medical care on offer, but the healthcare system is definitely not equal. Even after "Obamacare" there are still 33 million Americans without health insurance (10.4%), 4.5 million of them children^33,34. The risk of death for several cancers is significantly higher for insolvent patients^35,36, bankruptcy and high debt in cancer survivors are twice that of the overall population³⁷, and there is growing concern about new-drug affordability³⁸. Access to care is unequal in many other countries, some in Europe, both high and low income³⁹. This is true not only for drugs, but also for other treatment strategies, for example, the rate of breast-conserving surgery and radiotherapy for very early breast cancer in the EU ranges from 20–64%, according to the amount of money spent⁴⁰.

Cost-benefit evaluation in the metastatic setting

For 1 month of palbociclib at online sale⁴¹ the price ranges from US$10,309–$10,632 via Kroge Pharmacy, CVS, or Walgreens. According to the data of a Phase III trial^42,43, the estimated cost per month-of-benefit could be ∼$15,000. The FDA granted accelerated approval, and annual sales of 3 billion dollars are estimated by 2020. Pfizer are currently running several programs for helping uninsured or low-income patients acquire the drug free of charge, or for as little $10 a month⁴⁴. A cost-benefit analysis presented at ASCO 2016 showed that the sustainability for palbociclib in the Swiss healthcare system (GDP 2015 = $80,675) could be accepted only after the price of the drug was reduced by 75%⁴⁵. Probably the same reasoning could be applied to the similar "new entry" drug ribociclib⁴⁶.

Equity and solidarity (provided by the government and not by charities) should reflect a world one would offer to their family. In countries with a so far "socially equal" healthcare system, such as Canada, Italy, the UK, Switzerland, and France, the overall outcome is excellent as shown by indicators such as child mortality within the first 2-years and life expectancy of the elderly. Healthcare is expensive, but the overall population benefits.

It seems also that the best results in terms of survival rate in oncology are related to the amount of money spent on treatment, independently, by the health system, whether social insurance-based or national system-based⁴⁷.

Both in high- and low-income countries health expenditure grows at a faster rate than the global economy⁴⁷, and there is no one country able to manage the costs without a radical revision of price definition with companies, like India did with Roche/Genentech regarding trastuzumab^48,49. We suggest a recent editorial by Saltz⁵⁰ with appealing section titles such as "If You Don’t Know the Cost, You Can’t Know the Value", "The Disconnect Between Value and Cost", "Perverse Incentives", and "The Rules of the Game, and the Gaming of the Rules". These are not just titles, but insightful statements.

Conclusion

In our opinion, an affordable, ethically and politically correct budget for healthcare is government issued as part of a social healthcare system. In this context, all governments should declare how much is affordable in relationship with the economic situation of the country and decide what drugs and treatments can be provided for free (as part of a life-long system of national taxation) and which cannot. In 2005, in a health supplement of a large Italian economics newspaper, “Il Sole 24 Ore”, Mustacchi⁵¹ wrote

Every country has its own level of expense sustainability for a given topic. Health is probably the most important issue after freedom and hunger. Nevertheless, there is a border of sustainability, according to differing economic status (GDP). It is possible that Italy will soon be in need to define this border, which is a typical governmental duty.

Ten years later, unfortunately, there is still definitely a price for a life.

Giorgio Mustacchi and Daniele Generali University Clinical Dept of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy [email protected]

Transparency

Declaration of funding

Nothing to declare.

Declaration of financial/other relationships

Nothing to declare.