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Chemo Sensitivity and Resistance Assays

gdpawel's picture
Posts: 538
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

Posts: 39
Joined: Dec 2004

I didn't realize this method existed? How much is it used, do you know? The article implies that patients use it vs the physician; is there an address to send the tumors to for sensitivity and resistance? What has been the outcome, when this has been used? Any other articles?
Thank you for submitting such a thought provoking technique.

gdpawel's picture
Posts: 538
Joined: May 2001

It's not patient vs. physician, it is empiric-directed vs. assay-directed. Empiric one-size-fits-all treatment needs to recognize that breast, lung, ovarian and other forms of cancer represent heterogenous (dissimilar) diseases, where the tumors of different patients have different responses to chemotherapy. It requires "individualized" treatment based on testing the "individual" properties of each patient's cancer.

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. For many cancers, especially after a relapse, more than one standard treatment exists. There is rarely a situation where you would get everyone to agree that there's only one form of therapy. Physicians select drugs based on their personal experience, possible side effects and the patient's condition, among other factors. The system is overloaded with drugs and underloaded with wisdom and expertise for using them.

Chemosensitivity testing (assay-testing) has been utilized since the early nineties. In fact, a Dr. William Grace, a practicing oncologist and director of cancer research and chief of medical oncology at St. Vincent's Hospital and Medical Center (New York City) has been utilizing assay-testing since 1995. He believes it is unethical not to use chemosensitivity testing in his practice. It is a real credit to oncologists who utilize assay-testing in their managment of their cancer patients, despite the fact that their use constrained their freedom to choose and doubtlessly reduced their incomes. However, patients should receive what is best for them and not what is best for their oncologists.

The one time I forget to post the numerous labs that perform these tests, is the one time someone specifically asks for them. These labs will provide you and your physician with in depth information and research on the testing they provide:

Analytical Biosystems, Inc., Providence, Rhode Island. Ken Blackman, PhD. Solid Tumors Only. 1-800-262-6520

Anticancer, Inc., San Diego, CA. Robert Hoffman, PhD. Solid Tumors Only. 1-619-654-2555

Impath, Inc., New York, NY. David Kern, MD Solid Tumors and Hematologics. 1-800-447-8881

Oncotech, Inc., Irvine, CA. John Fruehauf, MD. Solid Tumors and Hematologics. 1-714-474-9262 / FAX 1-714-474-8147

Sylvester Cancer Institute, Miami, FL. Bernd-Uwe Sevin, MD. Solid Tumors Only. (especially GYN). 1-305-547-6875

Human Tumor Cloning Laboratory, San Antonio, TX. Daniel D. Von Hoff, MD. Solid Tumors Only. 1-210-677-3827

Oncovation LLC, New York, N.Y. Howard Bruckner, M.D. Solid Tumors Only. 1-212-514-2422

Rational Therapeutics Institute, Long Beach, CA. Robert A. Nagourney, MD Solid Tumors and Hematologics. 1-562-989-6455

DiaTech Oncology, Brentwood, TN. Vladimir D. Kravtsov, MD, PhD Medical Director 1-615-294-9033

Weisenthal Cancer Group, Huntington Beach, CA. Larry M. Weisenthal, MD, PhD. Solid Tumors and Hematologics. 1-714-894-0011 / FAX 1-714-893-3659

A 43-year old Philadelphia pharmaceutical consultant, Dr. Mark Fisher, was diagnosed with late-stage lung cancer two years ago, he insisted his cancer be tested with a CSRA (chemosensitivity testing). In the lab, his tumor didn't respond to standard drugs, and instead the test showed an odd combination of five different drugs had the biggest impact (Gemzar, Carboplatin, Navelbine, high dose Tamoxifen and Iressa). The drugs eliminated cancer from his body and he underwent Gamma-Knife radiation therapy for a brain metastasis. "The thing that has surprised me since my chemo is the number of people I've met who haven't even heard of it," says Dr. Fisher. I saw that he once posted his experience on this web site, I believe about a year and a half ago. He wanted so much to expose this technology as much as he could. Dr. Fisher says that his oncologists appears to be a firm convert to the benefits of this prescreening, and has expressed an interest in being involved in conducting a clinical trial.

Google Human Tumor Assay Journal and get the url address for a web site with extensive other information.

Posts: 39
Joined: Dec 2004

Unless my sentinel nodes test positive (praying and hoping that they won't), my breast cancer probably won't need chemotherapy. However, my mother in law recently died of colon cancer. Her chemo regime was not working, so the hospital sent her tumor to the mayo clinic. It came back, stating that a particular chemo might work.....do you think that her tumor was sent to a chemo S & R assay?

gdpawel's picture
Posts: 538
Joined: May 2001

For women with non-invasive breast cancer, hormonal (anti-estrogen) treatment may be recommended for its ability to reduce the risk of a recurrence of the same cancer, and reduce the risk of developing a new cancer in the same or the other breast. The most common agent prescribed in this category is tamoxifen (also called Nolvadex). Chemotherapy is never used for non-invasive breast cancer, since this type of cancer does not spread beyond the breast.

Systemic treatment may benefit "some" women who have invasive breast cancer without lymph node involvement. Hormonal (anti-estrogen) therapy is usually recommended when the cancer tests positive for either estrogen or progesterone receptors ("hormone-receptor-positive" cancer). Hormonal therapy may be given alone or in addition to chemotherapy. Again, Tamoxifen is the most commonly prescribed agent.

In regards to your mother-in-law (my condolences), I seriously doubt that they assay-tested her tumor. As I mentioned above, conventionally, oncologists rely on clinical trials in choosing chemotherapy regimens, empiric one-size-fits-all treatment protocol. But statistical results of population-based studies might not apply to an "individual." Many forms of cancer represent heterogenous (dissimilar) diseases, where the tumors of different patients have different responses to chemotherapy. It requires "individualized" treatment based on testing the individual properties of each patient's cancer.

The re-vigor of assay-testing technology that could double the effectiveness of cancer drugs is even being stuied at Yale School of Medicine. Take a look:


gdpawel's picture
Posts: 538
Joined: May 2001

The clinical utility and clinical accuracy of cell culture drug resistance testing (chemosensitivity testing) with cell-death endpoints has now been proven beyond doubt.

Data on it may be reviewed at

http://www.htaj.com/chemosensitivity_and_resistance_testing.wmv (a 27 minute video on .wmv format)

and http://weisenthal.org/faqw.htm

The cost of drugs is enormous. Patients are followed with serial CT scans, MRIs 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, the cost of ineffective therapy is truly enormous and assay-testing is particulary good at identifying ineffective therapy.

gdpawel's picture
Posts: 538
Joined: May 2001

The traditional criteria ever used to evaluate laboratory tests has been the predictive 'accuracy' of the test. The American Society of Clinical Oncology (ASCO) reviews of cell culture assay tests 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.

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 Pet Scans to measure tumor response to treatment. 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.

ASCO says that there is no literature establishing clinical 'efficacy' of assay 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.

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'. This is a diagnostic test and should be held to that criteria, and not to that of therapy.

This laboratory test is 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.

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.

Molecular assays have established absolutely no data relating to assay 'efficacy', and with much less data relating to assay 'accuracy' than exist to support the application of cell culture assays.

ASCO is an organization which has been zealous in its support of an inherently corrupt system which won't allow drugs to be chosen on the basis of tumor biology but instead protects the ability of oncologists to choose drugs largely on the basis of profit margin or least inconvenience to research clinics.

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

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