New biologic therapies are a mixed blessing, said participants in a debate on whether access to these new drugs will improve survival. The new drugs are quite costly, and although some of them may significantly improve progression-free survival (PFS), with few exceptions, they have yet to show a substantial benefit in overall survival (OS).

"We are here because treatment costs have skyrocketed for innovative therapies and there will be new rules for the game. In different countries it can take up to 1 year for access to these drugs as well as reimbursement," said Thomas Szucs, MD, University of Basel, Switzerland, who moderated the debate during the 35th ESMO Congress, held recently in Milan, Italy.

Ivar S. Kristiansen, MD, of the University of Oslo, Norway, assumed the Pro position and Franz Porzsolt, MD, University of Ulm, Germany, argued the Con position. However, there was less disagreement than agreement between these participants.

Lesson from Cardiovascular Investigations

Dr. Kristiansen pointed out that clinical trials of ACE inhibitors and statins demonstrated only small improvements in survival, yet 2 decades after their introduction, mortality in Norway declined more than 50%.

"Clinical trials [of cardiovascular drugs] at the time showed only modest survival gains, yet overall, these drugs have made a big difference," he said. "This could be the case with the new biologics," he suggested.

"Various trials of biologic therapies demonstrate a prolongation of 0.1 to 0.4 years in OS, which critics call a modest gain. However, this is similar to the cardiovascular clinical trials," Dr. Kristiansen stated.

Clinical trials of new cancer drugs tend to show bigger differences in PFS compared to older drugs but only small, if any, differences in OS.

Dr. Kristiansen took issue with use of PFS as an endpoint in clinical trials. "Most trials [of new biologics] focus on PFS, but oncologists should require data on OS for new drugs, not a surrogate endpoint of PFS," he stated.

Cost-Benefit Considerations

Even though novel agents are available, many patients in different countries don't have access to these drugs because the governments are not willing to pay for them, Dr. Kristiansen reminded listeners.

Two novel agents have fared differently with regard to reimbursement in Norway, he continued. Trastuzumab (Herceptin) was found to prolong life by 2.7 years in one study of HER2-positive breast cancer, at an estimated cost of €19,000 per quality-adjusted life-year (QALY). Bevacizumab (Avastin) was found to prolong life expectancy by 0.41 years in a study of metastatic colorectal cancer, at an estimated cost of €83,000  per QALY. The threshold for cost-effectiveness in Norway is €62,500 per QALY, so the government will pay for trastuzumab but not for bevacizumab in metastatic colorectal cancer.

"The cost of novel treatments should reflect the benefit," he stated. "If patients are denied access because of cost, the drug prices may be too high. We need a reasonable balance between cost and benefits," he told listeners.

Although he believes that all patients should have the opportunity to attain their full health potential, worrying inequalities exist in the European Union countries with regard to levels of cancer control and care, he stated.

Endpoints Reconsidered

Taking the Con position, Dr. Porzsolt said that an unpublished study he was involved in found that out of 106 clinical trials using time to progression (TTP) as an endpoint, only 43 showed a significant difference in TTP, and of those only 44% also demonstrated a statistically significant difference in OS. Out of 74 studies using PFS as an endpoint, 31 showed a statistical difference in PFS, and of these, only 50% had a significant OS benefit.

These studies had inconsistent definitions of TTP and PFS. More than one-third (37%) did not define TTP, 37% used PFS as an endpoint but claimed TTP findings, and 26% had a definition of TTP. This paper will be submitted for publication in a peer-review journal, Dr. Porzsolt said.

"The totality of evidence from these studies suggests that if a novel drug prolongs TTP/PFS, the chance of the drug also prolonging OS is 50%. If a novel drug does not prolong TTP/PFS, the chance that it won't prolong survival is around 90%," he stated.

Perceived Value

The perceived value of treatment appears to be different for physicians and patients, he continued. "Studies show that doctors and patients care about different things. In general, doctors are focused on disease control, while patients are more concerned about quality of life," he told listeners.

In addition to differences in perceived values, information from doctors may be confusing to patients. For example, physicians often present relative risk reductions with a new treatment, whereas patients generally want to know the absolute risks and benefits.

Another issue is the connection between cost and effectiveness in doctors' minds. Dr. Porzsolt cited a study of 82 medical students randomly assigned to what they were told was an expensive or cheap painkiller, but they all actually received placebo.1 All participants received electric shocks before and after taking the pill. A greater reduction in pain was observed among those randomly assigned to the so-called expensive drug.

"This study should go in every medical textbook. This demonstrates the power of information. An expensive treatment can generate hope and perceived safety, as well as somatic effects like reduction in pain," he stated.

Bottom Line

The major issue with novel therapies is whether cost is in line with the benefit. The bottom line is that novel drugs don't necessarily improve survival, he summarized.

"If it were possible to identify patients with the highest chance of response to a new therapy, economic risks could be reduced. But this happens so far only in 'Wonderland,'" he said, "unfortunately not yet within the current health-care systems." ■

Reference

1. Waber RL, Shiv B, Carmon Z, et al: Commercial features of placebo and therapeutic efficacy. JAMA 299:1016-1017, 2008.