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Chemo Sensitivity and Resistance Assays

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Chemotherapy Sensitivity and Resistance Assays

When a patient has an infection, doctors often send a sample of infected blood or tissue to a lab where they can grow the bacteria and see which antibiotics are most effective (called Bacterial Culture and Sensitivity Testing). Chemosensitivity testing is an attempt to do something similar for cancer; fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. It is highly desirable to know what drugs are effective against your particular cancer cells before highly-toxic agents are systemically administered to your body.

One approach to individualizing patient therapy is chemosensitivity testing. Chemosensitivity assay is a laboratory test that determines how effective specific chemotherapy agents are against an individual patient's cancer cells. Often, results are obtained before the patient begins treatment. This kind of testing can assist in individualizing cancer therapy by providing information about the likely response of an individual patient's tumor to proposed therapy. Chemosensitivity testing may have utility at the time of initial therapy, and in instances of severe drug hypersensitivity, failed therapy, recurrent disease, and metastatic disease, by providing assistance in selecting optimal chemotherapy regimens.

All available chemosensitivity assays are able to report drug 'resistance' information. Resistance implies that when a patient's cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow. Some chemosensitivity assays also are able to report drug 'sensitivity' information. Sensitivity implies that when a patient's cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.

The goal of all chemosensitivity tests is to determine the response of a patient's cancer cells to proposed chemotherapy agents. Knowing which chemotherapy agents the patient's cancer cells are resistant to is important. Then, these options can be eliminated, thereby avoiding the toxicity of ineffective agents. In addition, some chemosensitivity assays predict tumor cell sensitivity, or which agent would be most effective. Choosing the most effective agent can help patients to avoid the physical, emotional, and financial costs of failed therapy and experience an increased quality of life.

Fresh samples of the patient's tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. Chemosensitivity testing does have predictive value, especially in predicting what 'won't' work. Patients who have been through several chemotherapy regimens and are running out of options might want to consider chemosensitivity testing. It might help you find the best option or save you from fruitless additional treatment. Today, chemosensitivity testing has progressed to the point where it is 85% - 90% effective.

Chemosensitivity testing might help you find the best option, or save you from fruitless additional treatment. Another situation where chemosensitivity testing might make particularly good sense is in rare cancers where there may not be enough experience or previous ideas of which drugs might be most effective.

Finally, there has been a veritable deluge of new approvals of cytotoxic drugs in recent years as the tortuous FDA process has been speeded and liberalized. In many cases a new drug has been approved on the basis of a single very very narrow indication. But these drugs may have many useful applications - and it's going to take years to find out. Chemosensitivity testing offers a way of seeing if any of these new drugs might apply to your specific cancer.

Another Name

Cell Culture Drug Resistance Testing (Chemotherapy Sensitivity and Resistance Assays) refers to laboratory testing of a patient's own cancer cells with drugs that may be used to treat the patient's cancer. A group of lab tests known as human tumor assay systems (HTAS) can aid oncologists in deciding which chemotherapies work best in battling an individual patient's form of cancer. The assay is a lab test performed on a biopsy specimen containing living cancer cells. It's used to determine the sensitivity or resistance of malignant cells to individual chemotherapy agents. Depending on how well the tumor cells respond to each chemotherapy agent, they are rated as sensitive, resistant or intermediate to chemotherapy. The concept is that you are better off using a chemotherapy drug that your tumor reacts to strongly than one your tumor resists.

There have been over 40 publications in peer-reviewed medical literature showing correlations between cell-death assay test results and the results of clinical chemotherapy 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 to 9 times more likely to work than assay-inactive drugs. A large number of peer-review publications also reported that patients treated with assay-tested 'active' drugs enjoyed significantly longer survival of cancer than patients with assay-tested 'negative' drugs.

How May a Patient Arrange to Have Their Tumor or Leukemia Tested?

Both fluid and solid tumor specimens may be sent out via Federal Express or another overnight courier service for testing at one of more than a dozen labs around the country. Note that the choice of a lab is not a geographical consideration, but a technical consideration. All of the labs 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. By investing a little time on the phone speaking with the lab directors, you should have enough knowledge to present the concept to the patient's 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.

Some Resistance

The fact that some doctors don't agree isn't stopping many cancer patients from taking this matter into their own hands, and sending their live path specimens off to one of the above private labs for assay-testing to be done. There has been much discussion about whether assay (in vitro) tests are of any use, as the in vivo response to a drug may very well be different in the body than in the petri dish. But, they said the same for Bacterial Culture and Sensitivity Testing. Doctors cannot remember a time when they didn't have this technology. It is a 'gold' standard. So will Chemosensitivity Testing.

Source: Human Tumor Assay Journal

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

The traditional criteria ever used to evaluate laboratory tests has been the predictive 'accuracy' of the test.

None of the available laboratory tests used in the selection of treatments for cancer patients have ever been tested for 'efficacy'. This includes estrogen receptor, progesterone receptor, Her2/neu, immunohistochemical staining for tumor classification, bacterial culture and sensitivity testing, CT, MRI and FDG Pet Scans to measure tumor response to treatment.

There is no literature establishing clinical 'efficacy' of these laboratory tests, because the costs of such clinical trials are prohibitive, granting agency support is non-existent, and no other analogous tests have been or will likely ever be subjected to such an unreasonably high bar criterion for clinical use.

The only data supporting any of them relate to test 'accuracy', and there is a total lack of information regarding test 'efficacy'. (randomized trials with outcome measurements for diagnostic tests)

Also, no one is seriously proposing that any of the molecular tests now available (Oncotype DX, EGFR amplification/mutation) should have to be proven 'efficacious', as opposed to merely 'accurate', before they are used in clinical decisions regarding treatment selection.

The American Society of Clinical Oncology (ASCO) reviews of cell culture assay tests for establishing clinical 'efficacy' specifically excluded all studies reporting the predictive 'accuracy' of the tests. In other words, they excluded reports that only reported correlations between assay results and clinical outcomes.

Instead, ASCO reviews included old, previously-reviewed studies comparing outcomes of patients who had treatment based on assay results versus patients with empirically chosen therapy. The criteria of laboratory assay 'efficacy', as opposed to laboratory assay 'accuracy' sound reasonable, but it is unprecendented with regard to any other laboratory test ever evaluated.

Cell culture assay tests have been well proven to have predictive 'accuracy' with that of estrogen receptor, progesterone receptor, Her2/neu and the newer molecular tests. In light of the precious little in the way of guidance from clinical trials with respect to best empiric therapy (where the only thing that has been proven to correlate with treatment decisions is reimbursement to the prescribing oncologist) and the importance of basing cancer treatment at least in part on patient preferences, it is entirely reasonable to support judicious application of laboratory tests which have been well characterized with respect to test 'accuracy'. These are diagnostic tests and should be held to that criteria, and not to that of therapy.

These laboratory tests are a tool for the oncologist. The oncologist should take advantage of all the tools available to him/her to treat a patient. And since studies show that only 25-30% of patients do respond to chemotherapy that is available to them, there should be due consideration to looking at the advantage of human tissue assay tests to the resistance that has been found to chemotherapy drugs.

Cell culture drug resistance testing is for preventing use of known anti-cancer drugs that are not likely effective in the specific tumor. Cell culture drug sensitivity testing tries to determine specific drug and dose effectiveness. The distinction between sensitivity and resistance is more semantic than substantive.

In virtually all forms of cancer, clinical trials have failed to identify best drug regimens for use in all individuals with a given form of cancer.

Oncologists have been documented to use reimbursement (payment to the oncologist) as the most important criterion for selecting between the large array of otherwise equally acceptable regimens. (Jacobson, M.,O'Malley, A.J., Earle, C.C., et al. Health Affairs 25(2):437-443, 2006) & (Patterns of Care: 2005,Vol 2,Issue 1)

The established criterion on which to judge all laboratory tests used to help in the selection of cancer treatment is test 'accuracy' and not test 'efficacy'.

Cell culture assay tests with cell-death endpoints have been exceedingly and reproducibly well established to be usefully 'accurate' in correlation with and predicting for clinical outcomes, including tumor response and patient survival.

There should an expansion of Medicare and private insurance reimbursement to promote even greater utilization and development of laboratory-based mechanisms, like cell culture assays, for improving the match between tumors and an ever-increasing number of partially effective and very expensive drug therapies.

Erinb
Posts: 295
Joined: Apr 2010

Has anyone asked their oncologist to have this testing done? I mentioned it at the last visit and wasn't sure it the doctor was going to follow through. He said out of the 4 patients who have requested it, only one came back.

WHAT? Why do I find it shocking that he has done this for only 4 people?
The nurse from the office called two days ago and said we would be responsible for the cost if the ins. will not pay for it. We have to go in and sign a paper before anything can be ordered. Fine.

Why am I annoyed by what to me is ignorance or lack of compassion? Let's do chemo and try the 'guess and check theory' in the meantime the immune system suffers and 'hopefully' the chemo is working.

Ok I'm done. I feel better now.

I am reaching out to every possible avenue. I scheduled an appt. for my husband to see an integrative doctor on the 28 of this month. He doesn't specialize in cancer, but I hope he can give my husband some options other than more pills. I realize my husband may have to take chemo for the rest of his life, but am hopeful there is a way to lessen the side effects.
Erin

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

1. Total lack of knowledge. A very intelligent medical oncologist, of the clinical trial paradigm, had admitted to me that he was not any kind of expert on cell culture assays. That doesn't make him any less intelligent, just does not have any expertise on the assays. The literature is not understood by many NCI investigators and by NCI-funded university investigators. I've written previously on this board about how NCI failed in their attempt to study assay-directed therapy of lung cancer. I've explained why.

2. The entrenched clinical trial paradigm. A 2004 tech assessment of the assays was done by the American Society of Clinical Oncologists (ASCO), when they tried to establish clinical "efficacy" as the criteria of judging the tests. There is no literature establishing clinical efficacy of ANY laboratory tests. The only data supporting any of them relate to test "accuracy" not "efficacy. It's interesting. Their conclusions did not presume to tell clinical oncologists that the tests should or should not be used, but that use of the tests is not recommended outside of a clinical trial setting. This comes from a society that speaks for its predominate members, academics who perform clinical trials. Hey! It's okay to use these tests, but make sure they are done in a clinical trial setting. I wonder if ASCO has an office on "K" Street in Washington, D.C.?

3. Takes away "their" freedom (not yours). Without information provided by these assays, oncologists have the freedom to choose between a multiple of different drug regimens, all of which have approximately the same probability of working. Some of these regimens are highly remunerative to oncologists. Other regimens are much less. Assay-directed testing takes away a lot of this freedom to choose and narrows the selection to those drugs that have the highest probability to be successful but may have less remuneration for the oncologist. This cuts into the oncologist's bottom line, though it benefits the patient.

An international study published in the August 5, 2004 issue of the New England Journal of Medicine reported that cell culture assay tests with a cell-death endpoint are effective in identifying gene expression patterns that correlate with clinical drug resistance. The study, titled, "Gene Expression Patterns in Drug Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment" employed the cell-death assay to examine drug resistance at the molecular level.

The investigators exposed cells to drugs and cultured in a 96 hour suspension cell culture drug resistance assay (MTT) to define sensitivity and resistance. They used the data to define gene expression patterns associated with sensitivity and resistance to each of 4 drugs commonly used in the treatment of childhood leukemia. They were able to show that the gene expression definitions of sensitivity and resistance were significantly and independently associated with treatment outcome.

This work could not have been done without prior work in more than a thousand cell culture drug resistance test assays from children with leukemia to define sensitivity and resistance for each of the four drugs. Cell culture assays are the Rosetta Stone which allows for identification of clinically relevant gene expression patterns which correlate with clinical drug resistance for different drugs in specific diseases.

Why is it so necessary to protect the patient from the information provided by a perfectly rational laboratory test, supported by a wealth of entirely consistent data? If used to assist in the selection of a regimen chosen from a series of otherwise reasonable alternatives, then patients will never be harmed and best available evidence strongly indicates that they will often be helped.

I think that a savvy cancer patient should ask his oncologist to show the patient the survival curves for a given recommended form of treatment, including the survival of patients treated on phase II and phase I trials which the doctor may recommend. The patient could also ask the laboratory for the survival curves of patients for whom laboratory tests have been ordered. In the absence of survival data directly pertaining to the recommended treatment or test, the patient could then listen to explanations of why such data are not available. And then decide as to the best course of action.

DMSurvivor
Posts: 1
Joined: Jan 2011

The Cancer and Wellness Ctr in Dallas, Tx. can get this test done for you. It is amazing and has helped many patients that I personally know. The best, most information and experience performing the chemosensitivity test is sent to Europe. They are about 7-10 years ahead of us in the depth of information, use and expertise of this test. I was given a few months to live three years ago. My son found Dr. June Meymand at the Cancer and Wellness Ctr. She did an analysis on my blood lab values and developed a nutritional program just for my body and she also recommmended this test. Once a year I have a touch and go period I go through which I am currently experiencing. I stay at the center and let them take care of everything. Unbelievable care and nurturing! In about 6 weeks I am good to go again. This test has helped tremendously.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Getting tumor cells from blood maybe feasible for solid tumors, though ususally only when the tumor is very advanced, and then only in small numbers.

It seems plausible that in Germany a new procedure can get enough specimen from circulating tumor cells for solid tumors. It may be possible using PCR (Polymerase Chain Reaction) or similar technology for specific agents such as Herceptin.

Only minute quantities of DNA are necessary for PCR. DNA can be amplified from a single cell. PCR amplification techniques raise considerable concerns regarding contamination from one specimen to another, creating the potential for false positive results. Clinical interpretation of PCR results may also be challenging.

But, PCR may be useful when culture is difficult due to the low numbers of the organisms, for lengthly culture requirements, or when there is difficulty in collecting an appropriate sample. Don't know if the results would be indicative of what would happen inside the human body.

They ususally proliferate (grow) cancer cells from a small sample and subject those cells to chemo. Cells 'grown' in the lab will not behave the same way as the actual cancer cells do in your body's own environment. Because they test on subcultured cells (as opposed to fresh tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cell grown in the lab will not behave the same way as the actual cancer cells do in your body's own environment.

Older technology assay tests failed because scientists looked to see which drugs inhibited the cancer cells' growth (cell-growth endpoint), not which chemotherapies actively killed the tumor cells (cell-death endpoint). Cancer wasn't growing faster than other cells, it's just dying slower. The newer assay testing technology connects drugs to patients by what 'kills' their cells, not by what 'slows' them down.

All of the work in the past almost twenty years in the cell culture field has been carried out largely on three dimensional clusters of cells (not monolayers). Work is done exclusively with three dimensional, floating, tumor spheroids. When you test the cells as three dimensional spheroids, they are many-fold resistant in vitro, just as they are in vivo (multicellular resistance).

Even Johns Hopkins has discovered that 3D analysis is more accurate.

http://www.medicalnewstoday.com/articles/192565.php

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