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Professor Ian Olver

17 June 2008

Targeted cancer therapies hold promise, but price a concern

Excerpts of the plenary lecture at the 1st KL International Breast and Colorectal Cancer Congress, 9-11 August, KL, by Professor Ian Olver, clinical director of the Royal Adelaide Hospital Cancer Centre and clinical professor in the department of medicine, University of Sydney, Australia.

There is a paradigm shift in the treatment of cancer as conventional cytotoxics, which interact with DNA to prevent cell replication, give way to targeted therapies. With targeted therapies, specific mechanisms of action result in an increase in the therapeutic index which, theoretically, ought to save us money.

Another saving with targeted therapies is from the
reduction of toxicity. Although there are some serious toxicities like cardiac toxicity with imatinib, or bowel perforation
with bevacizumab, these are, nonetheless, lesser side effects compared with those of conventional agents.

The appropriate use of newly approved targeted agents for cancer not only changes the expense of the drug, but also changes the way we diagnose tumors, with greater reliance on the pathologist to identify the target. This increases the pathology bill as we move from light microscopic techniques to microarrays. Microarrays will do more than just diagnose tumors. Since certain tumor mutations have been discovered to respond better than others, these molecular methods identify the appropriate therapy to use, even in specific tumor sub-states, and provide prognostic information. They increase diagnostic accuracy, thereby improving prognostication and identification of clinically distinct patient subsets to facilitate rational drug design. This differs from current practice where all patients are given chemotherapy in the hope that they will respond.

Technological advancements in targeted therapies also optimize current cytotoxic treatments by increasing specificity and improving safety. And we will be able to identify signaling pathways that define vulnerabilities, thus creating drug targets for single or combinations of targeted therapies. An example of the improved use of a cytotoxic is the knowledge that temozolomide efficacy in brain tumors depends on nine DNA repair stages of the tumor.

There are several other mechanisms for identifying vulnerable
targets. One of these is oncogene addiction, whereby malignant cells are physiologically dependent on the continued activity of a specifically activated oncogene for the maintenance of their malignant potential. Amutation in an oncogene, therefore, will be able to kill the tumor.

Even in supportive care, great advances in the control of nausea and vomiting have been made with the discovery that 5-HT3 receptors in the small bowel are responsible for acute chemotherapy emesis. The second great breakthrough came when we discovered that the neurokinin-1 receptor delays emesis. By targeting these receptors, we are able to eliminate nausea in 85 percent of cases.

However, greater drug specificity will give rise to a smaller spectrum of tumors against which it is effective. A large number of drugs will, therefore, be required to cover a large spectrum of cancers.

The trouble these days is that each drug is quite expensive initially; in a number of countries, its price exceeds the
capacity of governments to pay for it. What then should the balance be between pharmaceutical industry profits, and what the government and public have to pay?

Money matters
In the American Society of Clinical Oncology (ASCO) conference a couple of years ago, initial trastuzumab data in neo-adjuvant therapy of breast cancer showed an overall survival benefit. Everyone knew that trastuzumab should be added to chemotherapy in HER2+ breast cancer. However, in most countries, governments had yet to approve payment for the drug.

Funding of the drug became a problem. Basically, prior to any government funding, patients had to pay for themselves. If they did not, they would die earlier. They could get a health insurance fund to pay, but for the insurance industry, paying for high-cost drugs is not seen as health insurance, but disaster insurance.

So, patients ended up having to mortgage their
houses, while some chose to access their retirement funds early, which compromised their financial security. Those who were able to afford the drug thus missed out on spending that money on something that would have improved their lifestyles.

Modeling the payment
In a distributed justice model, societies that value life place special interest in the distribution of health resources. The basic principle is a fair distribution of risks and benefits across the community. People must be treated equally if they are equal in morally relevant characteristics. But even then, judgments still persist on who should be treated ie, young versus old.

Another concept in the humanitarian system of justice is free choice. This follows a free market system, exemplified by the US health system. It is an individualistic system that discounts the equal distribution of resources. Only patients who buy insurance will benefit from coverage. This system ensures that there are no restrictions on the market, so that all options are made available. But it is not kind to individuals without adequate funds.

The utilitarian system of justice goes by the concept of the greatest good for the greater number of people. It means balancing and maximizing quality with quantity. The question is thus: are we distributing healthcare or maximizing healthcare access evenly? Do we balance considerations for society with developments of new drugs for future society?

One method favored by most governments is a crossutility analysis, whereby changes in lifespan and quality of life are used to access the utility (which becomes the measure to allocate resources). It is particularly effective when other options are available, as governments will require alternatives to push prices down. Usually, once the government accepts a drug, all the alternatives would immediately see a drop in price.

If rationing is required, quality-adjusted life years become the measure. Since some patients derive greater benefit from a drug than others, it is not equal access but rather equal outcomes. Yet, its implementation could overwhelm a system because no system can pay for all drugs.

In the cost-effective model, a drug has to offer more than the given outcomes of its competitor. Therefore, higher prices are justified by higher outcomes. The measure is the incremental cost per unit of an additional outcome. However, it is not easy to place a monetary value on outcomes or regaining quality of life.

Setting the price
Pharmaceutical companies usually set a price based on what the market will pay to maximize returns to shareholders for research and development projects, and gain a profit within limited patent time. This leads to the question: will longer patent time reduce prices?

The problem is that pricing standards are set by what the US can pay, and this is far higher than what most countries can afford.

Health professionals have a role in reducing the price of drugs. In Australia, we help regulatory authorities scan the horizon for new drugs and to provide professional input on their likely clinical impact. And when professionals comply with drug rationing in terms of duration and indication, then the rationing strategies can be applied to a wider range of drugs and patients.

Finally, targeted therapies can be more affordable by using a risk-sharing model. With imatinib, for instance, a PET scan can indicate within the first six weeks if the patient is likely to respond. Pharmaceutical companies should foot the bill within this period and only once the drug is proven effective, should the government take on the rest of the bill.

Targeted therapies should be more cost-effective as they limit ineffective treatments by treating the right patients. Cancer treatment not only becomes less toxic, but can then be viewed as a chronic disease, with a greater chance of cure.


lan Olver graduated from the University of Melbourne in 1976 being awarded an MD in 1991 for a project on clinical trial methodology. He completed a PhD from Monash University in bioethics in 1997, exploring life and death issues. He trained
in medical oncology at Peter MacCallum Cancer Institute, the Alfred Hospital in Melbourne and the University of Maryland Cancer Centre. He worked for 6 years at the Peter MacCallum Cancer Institute and then moved to Adelaide becoming the Clinical Director, Royal Adelaide Hospital Cancer Centre and the first Cancer Council SA Professor of Cancer Care at the University of Adelaide. In May 2006 he was appointed CEO The Cancer Council Australia and a Clinical Professor in the Department of Medicine at the University of Sydney. He is an Honorary Associate, Department of Medical Oncology, Royal Prince Alfred Hospital in Sydney. He is the recent past chair of the Medical Oncology Group of Australia and currently sits on the Boards of Cancer Australia and the National Breast Cancer Centre. He sits on the Ethics Committee of the American Society of Clinical Oncology and chairs the Cancer Institute NSW Ethics Committee for multicentre clinical trials. He has published over 150 papers, 16 book chapters and 2 books, Conquering Cancer. Your Guide to Treatment and Research (Alien and Unwin, Sydney 1998) and Is Death Ever Preferable to Life? (Kluwer Academic Publishers, Dordrecht 2002).

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