The High Cost of Cancer Care

An article by Scott Gottlieb, MD, in Forbes (Medicare Nixes Coverage for New Cancer Tests), described Medicare reimbursement for new molecular diagnostics. As many readers are aware, there have been a growing number of diagnostic tests developed and marketed over recent years designed to identify and monitor the progress of cancer. Many of these tests are multiplexed gene or protein panels that identify prognostic groups using nomograms developed from prospective or retrospective analyses. The 21-gene Oncotype DX and related Mammoprint, are among the most widely used. Related tests for lung, colon, and other cancers are in development.

With the explosion of assays designed to personalize cancer care, comes the expense associated with conducting these analyses. Medicare, as the largest provider of medical insurance in the United States, is at the leading edge of cost containment. Not surprisingly, HHS has a jaundiced view of adding tests without clear cost benefit.

The issue is far broader than cost analysis. It goes to the very heart of what we describe as personalized medicine. Every patient wants the right treatment for their disease. Every laboratory company wants to sell their services. Where the supply and demand curve meet however, is no longer set by market forces. In this instance, third party reimbursers set the fee and the companies then need to determine whether they can provide their service at that cost.

The problem, as with all economic analysis, is meeting patient’s unlimited wants with limited resources. Two solutions can be envisaged. On the one hand, medical care progressively moves to a scenario of haves and have nots wherein only wealthier individuals can afford to obtain those drugs and interventions that are beyond the price range of most. On the other hand, care is rationed and only those treatments and interventions that rise to the highest level of evidence are made available.

While the subject of this article was sophisticated diagnostic tests, it will only be a matter of time before these same econometric analyses begin to limit the availability of costly drugs like highly expensive targeted agents. In a recent editorial published in blood, leading leukemia experts pointed out that 11 of the 12 recently approved drugs each cost $10,000 or more per month.

As we examine the rather grim prospect of unaffordable or rationed care, a glimmer of hope can be seen. Using expensive and relatively insensitive molecular diagnostic tests to select expensive targeted agents could be replaced by less expensive testing platforms. The dramatic, yet brief responses observed for many targeted agents reflect the shortcoming of linear thinking applied to the manifestly non-linear human biology, characterized by cross talk, redundancies and unrecognized hurdles. To address these complexities phenotypic analysis (the phenotype being the end product of genomic, transcriptomic and proteomic events) provide global assessments of tumor response to drugs, combinations and signal transduction inhibitors. These more discriminating results identify cellular response at the level of biology, not just informatics. While it is theoretically possible that high-throughput genomic analyses using neural networks and high throughput computer analyses may ultimately provide similar information, it is unlikely that most patients will have ready access to a Cray computer to decipher their results.

We need to stop working hard and start working smart. The answers to the many questions raised by the Forbes article regarding resource allocation in cancer treatment may already be at hand.

The Avastin Saga Continues

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.