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The Clinical Reality of Metastatic Cancer


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The cancer research arena has reached a sorry state of affairs. The tiniest increase in the survival time or median time to progression of drug-treated cancer patients is touted as a cure.

One example is the clinical reality for metastatic colorectal cancer. The FDA-approved combination regimen of irinotecan, bolus fluorouracil, and leucovorin (IFL) plus Avastin increases median overall survival by 4.7 months.

This small increase comes with a host of side effects, which impinge upon the quality of life, as well as placing a burden on the patient, as well as the healthcare system.

The clinical reality is that there is no cure for metastatic colorectal cancer. The much-vaunted blockbuster drug Avastin is simply an antibody supplement incorporated into an already complex chemotherapeutic drug regimen that may slow down the cancer process depending on the genetic constitution of that individual.

The clinical reality for metastatic breast cancer is similar. The treatment with Herceptin followed by lapatinib and capecitabine only increase the median time to progression from 4.4 to 8.4 months. Furthermore, 70% of patients do not respond to Herceptin, and resistance develops in virtually all patients.

The sobering fact remains, both advance diseases remain incurable, which contrasts with the glowing reports on Avastin and Herceptin emanating from the financial and tabloid media.

What are the responses of government agencies and academic institutions to this clinical reality? Yes, progress is slow, it's a complex problem, but we are moving in the right direction.

If billions of dollars are poured into DNA sequencing of primary tumors, then we hope to find the critical mutations that cause cancer and then make drugs so that each patient can have a unique treatment.

The major problem with this is the primary tumor is so heterogeneous that each cell within it is likely to have a unique genomic signature at the level of mutations, as well as at the level of gross genomic imbalances and methylation signatures.

And the cells that will be dangerous to the health of the patient and depart to other organs make up only a minute fraction of the tumor. They are also genomically different to the cells in the primary tumor.

Which of the millions of mutations, methylation changes, and gemomic imbalances are in the cells that leave the primary tumor? This cannot be ascertained by bioinformatic and statistical methods. It involves isolating the cells that depart.

Also, which of the genomic alterations that are in the departing cells will be instrumental in the process of subsequent metastatic growth? Most of the cells that lease home don't survive the journey in the blood or lymph systems, and many cancerous cells that eventually do lodge in a distant organ simply remain dormant.

It would seem more prudent to invest in the development of diagnostic technologies for detecting cancer growths, as well as the properties of cells that are destined to metastasize.

When the front-line treatment for solid tumors is still chemotherapy (cytotoxic or targeted) and radiation, and the best that blockbuster drugs can achieve is to prolong the inevitable by either a few months or not at all, then it's surely time to stop the delusion.

Personalized cancer cures are not just around the corner and carte blanche DNA sequencing will produce just that - carte blanche. Is the future of cancer medicine one in which doctors become financial advisors, telling their patients whether they can or cannot afford expensive treatments of dubious survival value?

The solution is to get back to using old fashion human brainpower to develop noninvasive screening technologies for detecting the earliest possible cancerous growths. Resources and intellectual horsepower need to flow into areas that have clinical impact.

Source: George L. Gabor Miklos, Ph.D., Philip J. Baird, M.D., Ph.d., "Curing Cancer: Running on Vapor," May 1, 2007 edition of Genetic Engineering and Biotechnology News.

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A "growth factor" is about twenty small proteins that attach to specific receptors on the surface of stem cells in bone marrow and promote differentiation and maturation of these cells into morphotic constituents of blood. And blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Problems with blood composition or circulation can lead to downstream tissue (which is made up of cells) dysfunction. If pharmaceutical EPO stimulates the bone marrow to make red blood cells, it could feed the growth of tumors in cancer patients.

A metastasis occurs when cancer cells dissociate from the original tumor and migrate via the blood stream to colonize distant organs. This is the main cause of cancer death. For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives a signal from outside the cell. This signal takes the form of a substance called a growth factor, which, in addition to controlling movement, can activate a number of processes in the cell including division and differentiation.

The growth factor attaches to a receptor on the cell wall, initiating a sequence of changes in the cellular structure. The cell's internal skeleton - an assembly of densely-packed protein fibers - comes apart and the protein fibers then form thin threads on the outside of the cell membrane that push the cell away from its neighbors. In addition, a number of protein levels change: some get produced in higher quantities and some in less.

To understand which proteins are modulated by the growth factor and the nature of the genetic mechanisms involved in cancer cell migration, a map is needed all of the genetic changes that take place in the cell after the growth factor signal is received. One family of proteins stands out. Tensins are proteins that stabilize the cell structure. The amounts of one family member rise dramatically while, at the same time, the levels of another drop.

Despite a familial similarity, there is a significant difference between them. The protein that drops off has two arms: One arm attaches to the protein fibers forming the skeleton, and the other anchors itself to the cell membrane. This action is what stabilizes the cell's structure. The protein that increases, on the other hand, is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than structural support, this protein acts as a kind of plug, blocking the anchor point, and allowing the skeletal protein fibers to unravel into the threads that push the cells apart. The cell is then free to move, and, if it's a cancer cell, to metastasize to a new site in the body.

In experiments with genetically engineered cells, scientists have showed that the growth factor directly influences levels of both proteins, and that these, in turn, control the cells' ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration.

Scientists at The Weizmann Institute of Science, Rehovot, Israel, carried out tests on tumor samples taken from around 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease, which is associated with elevated growth factor levels. The scientists found a strong correlation between high growth factor activity and levels of the 'plug' protein. High levels of this protein, in turn, were associated with cancer metastasis to the lymph nodes -- the first station of migrating cancer cells as they spread to other parts of the body.

In another experiment, the scientists examined the effects of drugs that block the growth factor receptors on the cell walls. In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells. The mechanism can predict the development of metastasis and possibly how the cancer will respond to treatment. This discovery may, in the future, aid in the development of drugs to prevent or reduce the production of the unwanted protein, and thus prevent metastasis in breast or other cancers.

Source: Weizmann Institute of Science

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  • 3 months later...

On most cancer message/discussion boards, one of the most common themes is that of "chasing mets" (metatasis). Cancer patients are chasing mets because of the wrong type of chemotherapeutic regimens for their type of cancer histology. But why do patients with histologically similar tumors respond differently to so-called "standard" drug treatments? That is one of the main problems associated with chemotherapy. Patient tumors with the same histology do not necessarily respond identically to the same agent or dose schedule of multiple agents.

Medical oncologists select a drug and must wait to see whether it is effective on a particular patient. Conventionally, oncologists rely on clinical trials in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. And when patients develop metastatic cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. For many cancers, especially after a relapse, more than one standard treatment exists.

A functional profiling assay is a diagnostic test (not a treatment) to help measure the "efficacy" of cancer drugs. They cannot make the cancer drugs do better, it can only measure the "best" probability of successful drugs. This is in stark contrast to "standard" or "empiric" therapy (also called physician's choice therapy), in which chemotherapy for a specific patient is based on results from prior clinical studies.

Laboratory screening of samples from a patient's tumor (if available) can help select the appropriate treatment to administer, avoiding ineffective drugs and sparing patients the side effects normally associated with these agents. It can provide predictive information to help physicians choose between chemotherapy drugs, eliminate potentially ineffective drugs from treatment regimens and assist in the formulation of an optimal therapy choice for each patient. This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free and overall survival.

It would be highly desirable to know what drugs are effective against particular cancer cells before cytotoxic agents are systemcially administered into the body. Functional profiling assays are clinically validated drug tests on living (fresh) specimens of cancer cells to determine the optimal combination of chemotherapy drugs. These assays are specifically tailored for each individual patient based on tumor tissue profiling, with no economic ties to outside healthcare organizations, and recommendations are made without financial or scientific prejudice.

Recommendations are designed scientifically for each individual patient. Various assays are performed on a tumor sample to measure drug activity (sensitivity and resistance). This will determine not only what drug or combinations of drugs will not effectively work, but which will be most effective for an "individual's" cancer. Then a treatment recommendation is developed through what is known as "assay-directed" therapy.

2nd, 3rd, even 4th line therapies (why?)

I often read on the boards about oncologists telling patients "if this drug doesn't work, we'll try this drug." And "if that drug doesn't work, we'll try this drug." In patients who have failed two, three or even four chemo drugs, why not give them the "right" drug or combinations the "first" time around?

In academic centers, patients are entered into clinical trials of square peg in a round hole therapy. This encourages the patient to receive 2nd, 3rd, and 4th line chemotherapy, regardless of the likelihood of meaningful benefit. The therapies are equivalent on a "population" basis, but not on an "individual" basis.

They continue to try and mate a notoriously heterogeneous disease into "one-size-fits-all" treatments. They predominately devote their clinical trial resources into trying to identify the best treatment for the "average" patient, in the face of evidence that this approach is non-productive.

According to NCI's official cancer information website on "state of the art" chemotherapy in recurrent or metastatic cancer, no data support the superiority of any particular regimen. There is no proven "standard" first line therapy which has been shown to be superior to the many other choices which exist.

The same situation exists in the setting of 2nd, 3rd, and 4th line therapy. Proven by the large number of patients who have progressive disease on 1st line therapy but who have good responses to 2nd or 3rd line therapy.

So it would appear that published reports of clinical trials provide precious little in the way of guidance. These patients patients should have received the "correct" treatment in the first line setting. This can be accomplished by individualizing cancer treatment based on testing the cancer biology.

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