New Paradigms of Cancer Treatment

[gpawelski]

The contribution of both cell culture and genomic analysis in individualizing cancer treatment is revolutionalizing cancer care by identifying the right drug for each individual patient, thus personalizing chemotherapy treatment. It will help to improve the efficiency of chemotherapy without changing the drugs currently used in standard practice. Rather, it will simply provide an approach to better select a repertoire of available drugs.

Gene Expression assays are panels of markers that can predict the likelihood of cancer recurrence in various populations. A Cell Culture Assay is a test for drug activity against a tumor. What a patient diagnosed with cancer would like ideally is to know whether they would benefit from adjuvant chemotherapy. If so, which active drugs have the highest probability of working and are relatively non-toxic in a given patient.

Whether a patient would benefit from adjuvant therapy depends on two things: (1) whether the tumor is "destined" to come back in the first place and (2) whether the tumor is sensitive to drugs which might be used to keep it from coming back.

By testing the gene expression markers of a patient, oncologists can identify those patients unlikely to benefit from adjuvant chemotherapy from those that would. If a patient is found to be "low risk" of a recurrence they do not need chemotherapy. If the patient is found to be "high risk" and needs adjuvant chemotherapy, by testing the patient's "live" tumor cells the oncologist can select drugs that have a higher probability of being effective for an individual patient rather than selecting drugs based on the average responses of many patients in large clinical trials.

The gene expression markers (assays) actually can be calibrated to provide information both about the possibility of recurrence and also chemosensitivity. The problem is dissecting one from the other. Studies to date have just looked at whether people had a recurrence. You can identify gene expression patterns which correlate with chemosensitivity by combining gene studies (molecular profiling) with cell culture studies (whole cell profiling). Use the cell culture assay as the gold standard to define the difference between sensitivity and resistance. Then you can see which pattern correlates with which for individual tumors and individual drugs.

When the decision is made to treat a patient with chemotherapy, most patients are treated with a combination of drugs. The "whole cell profiling" method differs from existing DNA and RNA tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic and morphologic endpoints. Other tests, such as those which identify DNA or RNA sequences or gene expression of individual proteins often examine only one component of a much larger, interactive process.

What effect will different individual drugs have in combination in different, individual tumors? No gene-based test can discriminate differing levels of anti-tumor activity occurring among different therapy drugs. Nor can available gene-based tests identify situations in which it is advantageous to combine the new "targeted" drugs with other types of cancer drugs.

This is where cell culture assays will always be able to provide uniquely valuable information. Cell Culture Assays have contributed to the molecular understanding of chemosensitivity and resistance. But it's not one versus the other. The best thing is to combine these different tests in ways which make the most sense. We can't afford anymore trial-and-error treatment. Not only is this an important predictive test, it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a "gold standard" correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

We are getting a rapidly-expanding list of treatments which are partially effective in a minority of cancer patients, ineffective in a majority of them, remarkably effective in a few, isolated patients, while being enormously expensive. The fastest way to improve things is to match treatment to the patient, like these technologies can provide.

There are hundreds of therapeutic drug regimens which any one or in combination can help cancer patients. The system is overloaded with drugs and underloaded with the wisdom and expertise for using them. We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perform "well-designed," prospective, randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination.

The problem is not with using the prospective, randomized trial as a research instrument. The problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance (do most cancers prefer Coke or Pepsi?). The failure of 30 years' worth of clinical trials research into "one-size-fits-all" therapy will eventually force a consideration of new approaches. Giving all the more credence to "test the tumor" first.

[endangered but surviving]

What questions do you ask to find out if your doctor can or will do these tests?

I inquired about this and was told only certain labs are capable of producing reliable results.

How do we begin?

joyce

[gpawelski]

Some of these technologies are already present, some have been available for over fifteen years, some will be out shortly. The three that I list are so complementary to each other. We are getting a rapidly-expanding list of treatments which are partially effective in a minority of cancer patients, ineffective in a majority of them, remarkably effective in a few, isolated patients, while being enormously expensive. The fastest way to improve things is to match treatment to the patient.

Under the posting, Cell Culture Assay Tests on this web site, it is stated that the choice of a lab is a technical consideration. All of the labs that are listed are experienced and capable of providing very useful information. However, the labs vary considerably with regard to technologies, approach to testing, what they try to achieve with the testing, and cost. One example is given of a price of $3,500 in a lab situation where 20 different drugs and combinations are tested, at two drug concentrations in three different assay systems.

Many oncologists wouldn't have had any training to read and interpret results of this testing. By investing a little time on the phone speaking with one of the lab directors, you should gain enough knowledge to present the concept to your own physician. At that point, the best thing is to ask the physician, as a courtesy to the patient, to speak on the phone with the director of the laboratory in which you are interested, so that everyone (patient, physician, and laboratory director) understand what is being considered, what is the rationale, and what are the data which support what is being considered.

In 1983, medical publications introduced assays based on "cell-death" (not cell-growth). This was a good five years before understanding the concept of apoptosis. Apoptosis assay is based on a biological principle that when a drug is effective, it will induce "cell-death" in the cancer cell. If the cancer cell is resistant to a drug, apoptosis will not occur. Because clinical oncologists did not understand apoptosis until around 1988, 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. The clinical utility and clinical accuracy of cell culture drug resistance testing with "cell death" endpoints has now been proven.

Find that self-educated oncologist who will make use of the many available off-label drugs in formulating a custom-designed novel regimen, as well as running tests on the biopsy before selecting the chemo option. After all, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years. The cost of drugs is enormous. Patients are followed with serial CT scans, MRI's and even Pet Scans, just to see if a tumor is growing or shrinking. Not to mention the hospitalizations for toxicity, bone marrow transfusions, etc. The point is, test the tumor "before" you start.

[gpawelski]

In chemotherapy selection, Gene and Protein testing examine a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predisposition to drug response.

Functional Profiling tests not only for the presence of genes and proteins but also for their functionality, for their interaction with other genes, proteins, and processes occurring within the cell, and for their response to anti-cancer drugs.

Genes create the blueprints for the production of proteins within the cell. A protein is a molecule that makes a cell behave in a certain way. It does so by interacting with other proteins in a complex series of steps.

The goal of Gene testing is to look for patterns of normal and abnormal gene expression which could suggest that certain proteins might or might not be produced within a cell. However, just because a gene is present it does not mean that an associated protein has been produced.

Protein testing goes one step further by testing to see if the relevant protein actually has been produced. However, even Protein testing cannot tell us if a protein is functional or how it will interact with other proteins in the presence of anti-cancer drugs.

Gene and Protein testing involve the use of dead, formaldehyde preserved cells that are never exposed to chemotherapy drugs. Gene and Protein tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene and Protein tests cannot discriminate among the activities of different drugs within the same class. Instead, Gene and Protein tests assume that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene and Protein tests tell us anything about drug combinations.

Functional Profiling tests living cancer cells. Functional Tumor Cell Profiling assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. Functional Tumor Cell Profiling can discriminate differing anti-tumor effects of different drugs within the same class. Functional Profiling can also identify synergies in drug combinations.

Gene and Protein tests are better suited for ruling out "inactive" drugs than for identifying "active" drugs. When considering a cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect.

Although presence of a targeted defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. Of course, this assumes that the mechanism of drug activity is known beyond any doubt, which is not always the case.

Although Gene and Protein testing currently are limited in their reliability as clinical tools, the tests can be important in research settings such as in helping to identify rational targets for development of new anti-cancer drugs.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy.

[gpawelski]

Laboratory tests are judged by "accuracy" and "reproducibility" and never by their effect upon treatment outcomes. Improved outcome studies of laboratory tests are never carried out. Most tests used today in oncology have comparable "sensitivities" and "specificities."

Pet Scans were not approved because they saved lives in a controlled clinical trial that compared the outcome of patients who received care with or without the benefit of a Pet Scan. They were approved because their performance characteristics (sensitivity/specificity) are reproducible, favorable and provide useful information to treating physicians.

Sensitivity and specificity are terms that apply to test accuracy. No test in oncology, including imaging studies such as MRI’s and PET scans, has ever been shown in a prospective randomized clinical trial to improve patient outcomes.

The existing standard has always been the accuracy of the test. This is true for every single test used in cancer medicine, from estrogen receptors to panels of immunohistochemical stains to diagnose and classify tumor to Her2/neu and CA-125 to cell culture assays to MRI Scans, CT Scans, Pet Scans and on and on.

Because Pet Scans are accurate and reproducible and because they correlate reliably with the clinical or biological phenomena which they are intended to detect or measure, many such tests are considered invaluable.

A cell culture assay is the one test in oncology which has the greatest immediate potential to improve therapy selection for "individual" patients. Data from studies demonstrate close correlation between prospective predictions of drug activity and patient chemotherapy response, and overall survival.

When individual patients are treated with drugs "active" in cell-death assays, they have vastly superior response and survival rates than when they are treated with drugs which are "not active" in the assays.

There is no proven "standard" first line therapy which has been shown to be superior to the many other choices which exist. The therapies are equivalent on a "population" basis, but not on an "individual" basis. Patients should have the "correct" treatment in the first line setting. This can be accomplished by individualizing cancer treatment based on testing the cancer biology.

Upgrading clinical therapy by using drug sensitivity assays can improve the "conventional" and "targeted" situation by allowing more drugs to be considered. The key to improving drug sensitivity tests is related to the number and types of drugs tested. The more cancer drug types there are in the selective arsenal, the more likely cancer medicine is to prove beneficial.

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of drug sensitivity assays are being encouraged by growing patient demands, scientific advances and medical ethics. Drug sensitivity tests are a powerful strategy that cannot be overlooked.

[gpawelski]

The concept of chemotherapy being a zero sum game in certain situations is very intriguing (e.g. metastatic breast cancer, platinum resistant ovarian cancer). You can push response rates higher with more intensive therapy, but you don't improve survival for the group as a whole. So every month of life you gain on one patient is a month lost in other patients.

The problem is that ineffective, aggressive chemotherapy can diminish not just the quality of life but also the quantity of life. Organ toxicity. Sepsis. Bleeding. Immunosuppression. Mutagenesis in genetically unstable tumor to more aggressive phenotypes. Perhaps mood lowering, with resultant changes in cytokines, such as IL-6. So the real challenge is to kill tumor, while avoiding as much of the above as possible. It seems obvious, but that's not the paradigm being used.

The paradigm used is treatment to dose limiting effect. But the goal shouldn't necessarily be maximum tumor kill (in situations where it's just not possible to kill all of it). Tumor kill is probably a steep rise to steady plateau. But survival is probably like an inverted "U" curve. You want to pick the right drugs and give them in such a way as to avoid the downslope of the inverted "U."

There appears to be a number of patients who have had long-term survival after high dose therapy, but there are a number of patients whose tumors are responsive to chemotherapy who have had long-term remissions from standard dose chemotherapy, as well as a number who show no difference in survival when treated with standard-dose or high-dose chemotherapy.

Does chemotherapy shorten survival of some patients, while prolonging the survival of others? You do help some patients, but for every patient helped, there's another one you may hurt.

You may want to reserve aggressive therapy for those patients who will derive more benefit than harm, while identifying the most promising treatment regimens for everyone. In patients with tumors very resistant to cytotoxic chemotherapy, the most promising treatments may be angiogenesis inhibitors, growth factor inhibitors, or more integrative medicine approaches.

More emphasis should be put on matching treatment to the patient (personalized medicine), through the use of individualized pre-testing, having more respect for minimal partial response or stable disease, when it can be achieved through use of the least toxic and mutagenic drug regimens, and reserve the use of higher dose therapy or aggressive combination chemotherapy to those patients with tumor biologies most amenable to attack and destroy by these aggressive treatments.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with "best guess" empiric chemotherapy.