As I mentioned the other day, I have another article on oncology in the queue which got pressed for space as the election heated up. Larry Weisenthal, MD, is a board certified medical oncologist with a 25 year history of full time work in the field of cell culture drug resistance testing (otherwise known as “chemosensitivity testing”). More about Larry may be found by looking at his CV. He writes:

The issues and data relating to chemosensitivity testing defy concise summary and can be reviewed on my website. For the moment, I just want to make a brief response to the comments of Harvey Fry (on THCB a couple of months back). Harvey had written about chemosensitivity testing:

I fought for chemo-sensitivity testing of cancers over 20 years ago, and finally lost because of the problems with the tests. First, it’s often hard to get a representative sample of tumor cells by biopsy. Then it’s hard to get them to grow. Then you’re not sure whether the cells that grew out are the tumor cells, or normal matrix, like fibroblasts. Then there’s the delay in starting treatment while waiting for the cells to grow out. Then there’s the question of whether cells in metastases have the same response as those in the primary. But the killer was that the clinical response was not that well predicted by the cell survival tests in the lab. And of course, there was the expense.

Unless there has been some major advance in the intervening years, I can understand the reluctance of some oncologists to go back to it. Alternatives to growing the cells and seeing what kills them may now exist, but they are only surrogates for the real end-point of interest.

Firstly, Dr Fry obviously has no understanding whatsoever of the current technologies, which are based on cell death and not cell growth. To put things into historical perspective, interest in “culture and sensitivity testing” for cancer received a tremendous boost with the publication of a preliminary paper describing a cell growth assay in the New England Journal of Medicine in 1978. When the NEJM talks, people listen. Within a year, hundreds of laboratories were working with this particular cell growth assay, and it did, indeed, pose the problems cited above by Dr. Fry. These problems were exposed in a devastating, negative editorial, published in the NEJM in 1983. The NEJM giveth; the NEJM taketh away. All the laboratories shut down; research in the field virtually ceased, and the take home message in the minds of most clinicians was that the assays had been discredited. Dr. Fry’s comments reflect this thinking.

In 1983, other publications introduced assays based not on cell growth, but on cell death. This was a good 5 years before dissemination of understanding of the concept of apoptosis (a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functionally deranged, but which doesn’t function properly in cancer cells, allowing them to grow abnormally without committing suicide, but which can be triggered to occur by effective anti-cancer drugs). Because clinical oncologists did not understand about apoptosis, these pioneering publications with cell death (instead of cell growth) endpoints were ignored, and neither clinical trials nor the application of cell death drug resistance assays were supported by academic and private practice clinical oncologists.

Despite the theoretical concerns expressed by Dr. Fry, the clinical utility and clinical accuracy of cell culture drug resistance testing with cell death endpoints has now been proven beyond doubt. These data may be reviewed on-line at: http://weisenthal.org/oncol_t.htm. The issues and data are also available in a 27 minute video excerpt of my testimony before an official Medicare technology assessment committee meeting in Baltimore.

Regarding the “expense” part of it. The tests cost in the neighborhood of $2,000, so it’s a legitimate consideration, but expense has to be put in context. A couple of quick examples:

1) A patient was an ovarian cancer patient with primary resistance to paclitaxel/carboplatin who then underwent tandem stem cell transplant/high dose chemotherapy regimens (at a cost of more than $250,000) without ever achieving a response. At a time when she had bulky, non-cytoreducible abdominal and pleural disease, CCDRT confirmed resistance to single agent cisplatin, carboplatin, and gemcitabine, but good activity for the gemcitabine/carboplatin combination. She subsequently received gemcitabine/carboplatin as an outpatient, achieved a durable complete response, and returned to work full time as an oncology nurse, where she remained well, for four years. The cost of ineffective therapy for this one patient alone would have paid for 125 assays.

2) One of our most “loyal” referring oncologists is financially independent and therefore he is free to manage his patients without any conflicts of interest relating to the fact that prescribing chemotherapy instead of counseling against it has financial repercussions to the oncologist and prescribing certain forms of chemotherapy over certain others likewise has financial repercussions. In the absence of information that some drugs are more likely than others to work, it is “ethical” to choose more remunerative forms of chemotherapy. The assay presents great problems for non-independently wealthy oncologists, because they take away their freedom to choose. The above oncologist recently told me of an interesting anecdote. He had a patient scheduled to come to his office on a recent Wednesday for chemotherapy. This treatment would have earned the oncologist $6,000 for a single patient, for a single afternoon’s worth of treatment. But the patient missed the appointment. The next day was the beginning of the oncologist’s vacation. So he had to arrange for the patient to be treated at the nearby, world famous, NCI-designated comprehensive cancer institute, which billed $28,000 for the treatment and which received 75% of this total (the oncologist knows this, because it had happened before).

The cost of drugs is enormous. And this is only part of it. Patients are “followed” with serial CT scans, MRIs, and even PET scans, just to ascertain if the tumor is growing or shrinking. And the hospitalizations for toxicity, etc. The point is that the cost of ineffective therapy is truly enormous, and the assays are particularly good at identifying ineffective therapy.

In summary:

There have been over 40 publications in the peer-reviewed medical literature showing correlations between cell death assay results and the results of clinical hemotherapy in more than 2,000 patients. In every single study, patients treated with drugs active in the assays had a higher response rate than the entire group of patients as a whole. In every single study, patients treated with drugs inactive in the assays had lower response rates than the entire group of patients. In every single study, patients treated with active drugs were much more likely to respond than patients treated with inactive drugs, with assay-active drugs being 7-9 fold more likely to work than assay-inactive drugs. A large number of peer-review publications also reported strong correlations between the assay results and the survival of cancer patients. These data are completely non-controversial and have
never been challenged or refuted. Thus Dr. Fry’s comment that “the killer was that the clinical response was not that well predicted by the cell survival tests in the lab” is absolutely incorrect.

The material on my website is very complicated (it is targeted to health professionals more than to laypersons). For a short overview of the most important issues, I’d recommend the Frequently Asked Questions section, which was also quoted by Wall Street Journal Health columnist Tara Parker-Pope in her weekly question and answer column appearing in the September 21, 2004 issue of the WSJ.

Here’s the first in a series of articles I have in the queue about the oncology market. The first is from Greg Pawelski:

Under the new Medicare Prescription Bill (MMA) medical oncologists will be reimbursed for providing evaluation and management services, making referrals for diagnostic testing, radiation therapy, surgery and other procedures as necessary, and offer any other support needed to reduce patient morbidity and extend patient survival.

The fact that medical oncologists received no reimbursement for providing oral-dose therapy to patients had been the principal barrier to the availability of oral-dose protocol. The advent of oral agents ultimately means that medical oncology will need to change its identity, prior to the chemotherapy drug concession. Because oral-dose drugs hold the promise of being more selective, harming fewer normal cells, reducing side-effects and work to improve the quality of life for people with cancer, they will rightfully gain their appropriate share of the marketplace, again.

The new Medicare Bill offers patients benefits they did not have before, mainly some coverage for oral chemotherapy drugs. Since April of 2004, $200 million was available so that some Medicare cancer patients would have transitional coverage for these drugs, until the bill goes into full effect in 2006. Although some benefit was realized, more might have been achieved if the American Society of Clinical Oncology and other groups had lobbied as much for the oral chemotherapy drug issue as they did for office-practice expense reimbursement. They fought long and hard to retain the Chemotherapy Drug Concession.

Increasingly, oral-dose anti-cancer drugs are found to treat cancer effectively and seen as a necessary part of a patient’s cancer care. A number of these breakthrough cancer drugs came on to the market that are only in oral form and previously not reimbursed under Medicare. Patients were being forced to compromise their cancer care due to Medicare not covering many of these life-saving therapies.

The new legislation started the process of providing access to a full range of the latest cancer-related prescription drugs at manageable costs to enhance the quality and standard of treatment for cancer. Medicare recipients were being relagated to treating their diseases with older, more toxic infusional chemotherapy agents at a time when new and more promising cancer drugs were reaching the market.

Compared to infusional therapy, oral-dose anti-cancer drugs can make receiving cancer treatment more convenient for patients by allowing flexibility in taking medication without disrupting work or other activities. They can often result in less time (or no time) spent in office-based oncology practices because of the absence of intravenous administration and its related side-effects.

Targeted cancer therapies will give doctors a better way to tailor cancer treatment. There are a multiple of different cancer drug regimens, all of which have approximately the same probability of working. Treatments may be individualized based on the unique set of molecular targets produced by the patient’s tumor, and these important treatment advances will require individualizing treatment based on testing the individual properties of each patient’s cancer.

What was needed, was to remove the profit incentive from the choice of cancer treatments, which were financial incentives for infusion therapy over oral therapy or non-chemotherapy, and financial incentives for choosing some drugs over others. Patients should receive what is best for them and not what is best for their oncologists.

The new system is clearly an improvement from the standpoint of cancer patients, taxpayers, and advocates of basing drug selection on individual tumor biology, rather than on a least common denominator approach which invites “conflict-of-interest medical decision-making.” I think it is time to set aside empiric one-size-fits-all treatment in favor of recognizing that many forms of cancer represent heterogenous diseases, where the tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient’s cancer.

A group of emails from within Merck show that the scientists were questioning the data and the marketing people were telling the sales reps to obfuscate. This is really ugly stuff. Taken on its own the views from the scientists aren’t too bad, as they state the actual truth — that good drugs have side effects. But the trial lawyers will not care about that and Merck’s stock is down another 10% today. And you can just imagine the courtroom scene where the plaintiff’s attorney reads management’s instructions to the sales reps to “dodge” questions from doctors about the safety record of Vioxx versus its competitors.

Merck’s long-term is looking bleaker and bleaker. Even though Arcoxia, its new Cox-2 may make it through the FDA — it got a go slow but positive letter last week — the combination of the settlement for Vioxx and the fractured trust with doctors and patients really spells the end of Merck’s reign as the most trusted of the “scientific” pharmaceutical companies that it enjoyed when Vagelos was the CEO. Expect some other pharma to come after Merck within a few months, but perhaps after it’s got a little cheaper.