1. In cell culture photomicrographs, the microscopic slides sometime show that the exact same identical individual culture well, shows some clusters have taken up vast amounts of a drug, while right next door, clusters of the same size, same appearance, same everything haven't taken up any of the drug.

It doesn't matter if there is a "target" molecule in the cell that the targeted drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial.

These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.

Posted at 2:10PM on Dec 29th 2006 by Greg Pawelski

2. While the benefit appears small - a four month delay in progression,
it is clear that the impact was real. Here are two key encouraging
points:First, the median advantage in progression was 4 months,
meaning that some patients did much better. For those patients, this
combination could be invaluable. Now researchers can work on
determining who will be an excellent responder and who will not,
hopefully enabling efficient targetting of this therapy, which is
Greg's point in comment #1 about personalizing therapy.

Second, the
results remind me of the results for docetaxel plus prednisone versus
mitoxantrone plus prednisone, the standard therapy, for prostate
cancer patients at a certain advanced stage (no longer responding to
hormonal blockade therapy)(Tannock IF...Eisenberger MA, NEJM, 2004).
The advantage over the standard therapy was proven, but was small; per
a key line from the results: "The median survival was 16.5 months in
the mitoxantrone group, 18.9 months in the group given docetaxel
every 3 weeks, and 17.4 months in the group given weekly docetaxel."
The conclusion: "When given with prednisone, treatment with docetaxel
every three weeks led to superior survival and improved rates of
response in terms of pain, serum PSA level, and quality of life, as
compared with mitoxantrone plus prednisone."So what was gained for
this arguably meager response? For one thing, a new and better
standard emerged. For another, researchers had a new promising agent
with which to work, one at least as good, in fact better, than the
then current approach, as well as a benchmark for then ongoing Phase
II work (led by T Beer) headed toward Phase III (now known as the ASCENT trial), and
for other such similar research. In the Beer Phase II study of
docetaxel plus calcitriol, published in 2003, the response rate (at
least a 50% reduction in PSA) was 81%, much better than for the
docetaxel plus prednisone Phase three work: "Among these three
groups, 32 percent, 45 percent, and 48 percent of men, respectively,
had at least a 50 percent decrease in the serum PSA level...."

This is a long way of saying that a proven four month advantage can mean a lot in oncology research.

Jim (website: http://www.mycancerplace.com/profile.php?id=147 )

Posted at 5:44PM on Dec 29th 2006 by Jim Waldenfels

3. Here's a PS:

While Phase III trials take a while to complete and report, there is ongoing work with at least one of these drugs that is being reported at conferences in abstracts, a method of publication that is usually below the radar of PubMed. I looked up both of them in the Proceedings (set of abstracts of posters and presentations) of the last national conference of the American Association for Cancer Research (April 2006) and found one of the drugs (capecitabine) listed seven times in the index. You can look up these abstracts at the AACR site, www.aacr.org, abstract #s 5322, 5320, 3119, 2145, 513, 403, and 2150.

Jim

Posted at 5:44PM on Dec 29th 2006 by Jim Waldenfels

4. The heterogeneity of cancer means that a particular drug will rarely be effective against all tumors of a particular type, and the degree of efficacy will vary between patients.

Also, as a result of their original mutations, many tumor cells acquire the ability to adapt rapidly to changes in their environment, sometimes by further mutation, often by molecular changes which induce resistance to the drugs used to treat them. Further courses of chemotherapy then select for resistant cells, and the treatment eventually fails to control the tumor.

To overcome the problems of heterogeneity and prevent rapid cellular adaptation, oncologists need to tailor chemotherapy to individual patients. This is done by testing the tumor cells to see if they are susceptible to particular drugs, before giving them to the patient.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

Posted at 9:15PM on Dec 29th 2006 by Greg Pawelski

5. Even if Xeloda and Tykerb only add an average of 4 months to the patients life it is still worth the cost (whatever that may be). My wife has metastatic breast cancer and is currently taking Xeloda and Avastin. At the cost of $1000 per bottle I can see why the insurance companies complain about the cost, but you cannot put a price on human life. 4 extra months of time w/ my wife would be priceless to me.

Posted at 8:19AM on Dec 31st 2006 by Mark Weber

6. Monoclonal Antibodies Vs.Tyrosine Kinase Inhibitors

Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

However, the monoclonal antibodies are "large" molecules that attach to specific proteins on the "outside" of cancer cells, not having a convenient way of getting access to a large majority of the targeted cells. There is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth.

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells. But, is something more elemental going on? Does the drug even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? Some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. Are the cells ultimately killed, or aren't they?

Each of these new targeted drugs are not for everybody (just like conventional cancer drugs are not for everybody). Even when the disease is the same type, different patients' tumors respond differently to the same agents. As the saying goes, "don't throw out the baby with the bath water." If a drug works extremely well for only 10% of cancer patients, identify which 10%. If one drug or another is working for "some" people (not average populations), then obviously there are others out there who would also benefit.

Posted at 8:19AM on Dec 31st 2006 by Greg Pawelski

7. Mark, I'm so with you. It's a shame that so many medications are beyond the financial reach of a lot of people. But for those with the means... a few extra months must be SO worth it. Not to mention, what if new strides in treatment are made in those few months?
Regards,
Richard Day Gore

Posted at 10:49AM on Jan 8th 2007 by richard day gore

8. One must be objective and decide at what point the benefits of drugs truly outweigh the risks they present. Some of the risks are minor and others are tolerable in that they are reversible, short-term or non-life threatening. Many of the risks are extremely serious and are difficult to balance against relief from anything but the most severe symptoms. For some people the risks may be acceptable, for others, not.

Posted at 10:23AM on Jan 21st 2007 by Gregory D. Pawelski

9. I need to respond to one sentence in the above post:
"While some say they are worth every penny if they offer a cure, others question the cost if they only delay the disease progression for a few months."
First, Herceptin and these other drugs will not CURE metastatic breast cancer. They can put it into clnical remission, however. And the second half of the sentence about delaying disease progression for ONLY a few months. I've been on Herceptin, in combination with other drugs, for more than five years now. That's five years of living with metastatic breast cancer with pretty good quality of life.

These drugs are absurdly expensive, however. To read more, see:

The (High) Cost of Cancer Treatment
http://www.assertivepatient.com/2007/02/the_high_cost_o.html

Thanks,

Jeanne

Posted at 9:32AM on Feb 19th 2007 by Jeanne Sather