Merrell,

I would say about the only thing we may know with certainty is that the fact she is alive has nothing to do with which country she lives in. The NEJM article states there is no significant difference in death rate between the two treatment groups.

Further more, if her chances of living were 1 in 2, then she is not equivalent to the control group - only 37 of 1693 died in the first year (2%) - so she can't claim that the results of the group treated with Taztuzumab would apply to her. And there is no way of knowing, with any reasonable confidence, that the fact she is disease free has anything to do with getting Taztuzumab. Note that the control group had 7 chances in 8 of having no reoccuring event in one year.

One wonders about the two year study. I get the impression they pulled the control group after one year and put them on Taztuzumab after these results.

I think that in the world of oncology, trastuzumab (Herceptin) is widely perceived as a paradigm shifting drug therapy, and yes, oncologists were electrified by the results of the adjuvant therapy trials of trastuzumab. Whereas patients with Her-2 neu positive tumors were regarded as having very poor prognoses, we have done a 180 where being Her-2 positive is now regarded as a good thing, now that we are in a position to offer trastuzumab as a therapy for metastatic disease and as an adjuvant therapy because it is such an effective drug. And I personally believe that Dennis Slamon should receive a Nobel for his work in the development of this drug.

Medical oncologists are well aware of the Finn-Her study, and are intrigued by its positive findings. It's my understanding however that the study was not powered to conclusively state that 9 weeks of therapy is not inferior to one year of therapy. I think when the results of the HERA study, comparing 1 to 2 years of trastuzumab are available, there will be interest in doing the follow up study to determine if 9 weeks is equivalent to one year, IF the HERA study shows 1 year is as good as 2 years.

As the increasing number of drug studies developed through collaborations between academic medical centers and drug companies continue, it is important to understand the influence that industry involvement may have on the nature and direction of cancer research.

It is suggested by some that we make the search for minimum effective doses of these treatments one of the key goals of cancer research. Cancer sufferers are taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need. The difference between minimum effective dose and maximum tolerated dose is potentially very large.

This seems particularly true for agents such as Herceptin, where the results of the smaller, government-funded Finn-Her study appeared to mirror the results of the larger pharmaceutical company-sponsored HERA study and caused significantly less cardiac toxicity with a much smaller overall dose.

More must be spent on analyzing drug data, and perhaps the need for larger and more detailed studies to figure out why there is an association between pharmaceutical involvement and positive results.

Just to note that New Zealand now provides for 12 months Herceptin treatment as a result of the change in Government in Novemeber 2008. Herceptin became a political issue in the 2008 General Election. PHARMAC have been asked by Government to review more research into length of time Herceptin should be used.

I too am frustrated that this piece (and a couple others, for that matter, in the February issue) are in Atlantic. Pretty clearly a PhRMA puff piece. It read like a blog entry, with a strong advocacy position, presenting supporting information with utmost certainty, and ignoring or minimizing information that doesn't agree with the author's point of view. The article is in stark contrast to the thoughtful and in-depth article that occurs later in the magazine about how the market crash will reshape America. I like blogs (especially GoozNews!) but there is still a role for the type of writing that used to be the cornerstone of the Atlantic magazine.

When an oncologist recommends a treatment the reason behind the recommendation may be complex. It can be a result of the doctor's training and experience in combination with the investments made by the hospital or the doctors own research interests or their financial relationships with various outside entities. In short, a patient and their family must be their own best advocate and get at the heart as to why a specific treatment regimen is being suggested.

Cancer sufferers are taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need, Dr. Ian Haines reported in the Journal of Clinical Oncology. Emerging evidence shows that many of the highly expensive targeted cancer drugs (Herceptin and Avastin) may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses.

Dr. Haines stated in the Journal that "it would seem that pharmaceutical companies are attracted to studies looking at the maximum tolerated dose of any treatments." He suggested that we make the search for minimum effective doses of these treatments one of the key goals of cancer research. He gave as an example, Avastin, used to fight colon and lung cancers, the dose being tested is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram.

An increasing number of drug studies are developed through collaborations between academic medical centers and drug companies. In fact, pharmaceutical-industry investment in research exceeds the entire operating budget of the NIH. It is important to understand the influence that industry involvement may have on the nature and direction of cancer research. Studies backed by pharmaceutical companies were significantly more likely to report positive results.

Over the past couple of years, if you watched TV with any regularity, it would have been difficult to miss the direct to consumer advertising that touted the benefits of some drugs over others, especially for patients undergoing treatment for cancer. Even to the point that buses covered with "shrink wrapped" advertising being strategically placed outside major cancer centers for patients and their families to see (EPO anyone?).

Drugmakers are going directly to the consumer at a time when their products are indeed at the margins of evidence-based medicine. On one hand, pharmaceuticals advertise extensively and the advertising is manipulative in the extreme. On the other hand, even NCI-designated cancer centers do this sort of direct to consumer, hard sell advertising. And in cancer medicine, the media advertising is no more misleading than the one-on-one communication which often goes on between a chemotherapy candidate and an oncologist.

More must be spent on analyzing drug data, and the need for larger and more detailed studies to figure out why there is an association between pharmaceutical involvement and positive results. Would Ms. Postrel be opposed to the creation of a comparative effectiveness institute to conduct these and other trials, showing shorter courses of therapy would offer the same benefits at lower cost and fewer side effects?

Yes, she would oppose such trials. That was the point of her article.

Greg, you raise an important point: manufacturers of new anti-cancer drugs have a number of powerful incentives to overestimate dose requirements and length-of-treatment requirements in their initial proof-of-efficacy trials. Because the disease is life-threatening, toxicities would have to be extremely high before risks outweighed benefits. Moreover, maximizing the dose to the limits of toxicity may maximize the chance of showing efficacy, especially when the benefits of use are marginal, as is the case with so many of the newer anti-cancer drugs (not Herceptin, which was pretty much a slam dunk for HER2-positive tumors because its underlying science is sound). And, finally, treating longer means additional fees, not just for the drug maker, but for the oncologist who administers the infusion drugs in their offices under the ASP (market price plus 6 percent) Medicare reimbursement system.

The only ones with an interest in testing whether shorter treatments with lower doses are just as effective are patients, insurers and government agencies, who collectively foot the bill. That's why the government -- through a comparative effectiveness agency -- must be created to answer the question.

Every medicine has many side effects. Each sideffect of every medicine should have a value placed on it based on inputs from a large group of doctors, nurses, people with the side effects and their close family members. The percentage of time each side effect occurs (minus the percentage of placibo) multiplied by the value shows the values of risks for a particular medicine.
FDA and similar international bodies should determine the efficacy of each medicine and the percentage of efficasy should be multiplied by the value placed on the medicine to be taken. This would show the value of the benefit.
A responsible estimate of the risk/benefit ratio
could then be made. Many medicines (especially in off label use) would be shown as poor risk/benefit risks.
Years ago, a person with some political clout really pushed to try and get an epilepsy drug approved off label for many minor conditions.
Luckily the FDA stood their ground and a lot of poor risk/benefit ratios were avoided.

This article made me furious, it's point only seems to be to muddy the waters in the health care debate. She implies that the US is a place where everyone gets all the expensive cancer treatments they need, and that's that. No mention of the 46 million people in the US without insurance (vs. New Zealand's total population of 4.1 million). I could go on, but suffice to say I doubt I'm renewing my subscription to the Atlantic. It's clear that it has little interest in an honest debate about health care in the US.

I've been thinking a lot about our acceptance of unwanted effects both in clinical trials and in treatment. We should not accept these downside effects.

Natural therapies (now called complementary or integrative) can make a real difference, why let people suffer?

I cringe when I read about a trial of Herceptin where cardiotoxicity occurs. Why? It is needless when there are herbal methods to protect the heart and much more currently available.

Oh, but what pharmaceutical can make money on this? And they tell me "Ann, we can't patent that".
Should patient advocates follow BIG Pharma's lead? I don't think so.

Merrill, we are very much on the same page when it comes to most of what you say. However, I feel Herceptin's underlying science is not sound. The benefits of the newer targeted therapies are marginal, even Herceptin. These targeted therapies may impart a clinical benefit by stabilizing tumors, rather than shrinking them (substituting shrinkage for stabilization).

Targeted therapies need approaches to determine optimal dosing, to assess patient adherence to therapy, and to evaluate treatment effectiveness. To determine the dosing and effectiveness of targeted therapies, physicians are turning to pharmacodynamic end points, such as tumor metabolic activity on Pet Scans, levels of circulating tumor and endothelial cells (CTCs), and serial levels of target molecules in tumor tissue, adding more complexity, trying to identify the subset of patients most likely to benefit from specific drugs.

The molecular pathways most often targeted in the treatment of solid tumors are those of the epidermal growth factor receptor (EGFR, also known as HER1), vascular endothelial growth factor (VEGF), and HER2/neu (the Herceptin gene). Such pathways can be inhibited at multiple levels: by binding and neutralizing ligands (i.e., molecules that bind to specific receptor sites on cells); by occupying receptor-binding sites (thereby preventing ligand binding); by blocking receptor signaling within the cancer cell; or by interfering with downstream intracellular molecules.

Monoclonal antibodies, which are usually water soluble and large, target extracellular components of these pathways, such as ligands and receptor-binding domains. In contrast, small molecule inhibitors can enter cells, thereby blocking receptor signaling and interfering with downstream intracellular molecules.

What would be more beneficial is to test those pharmacodynamic endpoints with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry. Using a systems biology (cell function analysis) approach where compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.

Unlike a test for the presence of receptors to a specific antigen, which only "implies" dependence upon that antigen, a functional assay actually assesses the direct or indirect effect of the drug upon the whole cell, whether it is a tumor cell or an endothelial cell. Her2 just happens to be one molecule which has been implicated in the process but there may be more.

If it were the only protein involved, then one would expect that Her2 expression would correlate with Herceptin activity 100% of the time but it actually does so only about 20% of the time. The functional assay doesn't just focus on Her2 or any one protein or mechanism. Whether it's Her2 alone (unlikely) or in combination with other proteins and other mechanical factors, the assay works by assessing the net effect of all those factors.

The importance of mechanistic work around targets as a starting point for drug development should be downplayed in favor of a systems biology (cell function analysis) approach were compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.

Many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond. And optimal and reproducible Her2 testing continues to evade the diagnositcs of the disease. Numerous other genes, tumor, and patient factors contribute to the risk of the cancer coming back and the effectiveness of chemotherapy for breast cancer.

It could be vastly more beneficial to measure the net effect of all processes (systems) instead of just individual molecular targets. The cell is a system, an integrated, interacting network of genes, proteins, and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just one or a few targets (pathways/mechanisms).

There are many pathways/mechanisms to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indivudal trees.