gdpawel
Senior User
Joined: 15 Jan 2005
Posts: 123
Location: Pennsylvania
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 Posted: Sat Jan 15, 2005 8:34 pm Post subject: Chemosensitivity Testing |
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Patients with recurrent ovarian cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. Currently, physicians select a drug and must wait about six months to see whether it is effective on a particular patient. For many cancers, especially after a relapse or when a particular treatment is ineffective, more than one standard treatment exists.
Chemosensitivity testing can help physicians predict whether a patient will respond to a specific drug, much like they test bacteria for sensitivity to antibiotics, 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.
Assay-testing is based on a biological principle that when a drug is effective, it will induce apoptosis (cell death) in the cancer cell. If the cancer cell is resistant to a drug, apoptosis will not occur. Assay-testing for apoptosis will determine whether a drug kills the tumor. Chemosensitivity testing (assay-testing) can take the guesswork out of cancer treatment. Patients with refractory cancer and have very limited time left to live, six months can feel like an eternity when they may have to start a whole new course of treatment if the original treatment proves ineffective.
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.
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 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 (200mg or 10mm in size) 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 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. These private laboratories have been offering these assays as a non-investigational, paid service to cancer patients, the average cost being about $2,000, in a situation where 20 different drugs and combinations are tested, at two drug concentrations in three different assay systems.
Assay-tests could be performed from ovarian cancer cells in pleural fluid (fluid from the cavity that surrounds the lungs) which is evidence of Stage IV ovarian cancer, or from Ascites (an abnormal accumulation of fluid in the abdomen), and of course lymph nodes. A worse case scenario is the spinal fluid (spinal tap) but only to diagnose Leptomeningeal Carcinomatous (ovarian). The labs will provide you and your physician with in depth information and research on the testing they provide.
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. In fact, approximately 10,000 individual patient specimens are currently being submitted for testing by more than 1,000 clinical oncologists, surgeons and pathologists annually in the United States. It seems probable that a self-educated oncologist, genuinely on the cutting-edge would tend to be aggressive in actual treatment beyond mere rhetoric and make use of running tests on the biopsy before selecting a chemotherapy option.
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 is a genetically programmed cell death pathway which exists in all cells, which is supposed to cause them to commit suicide if they become functionally deranged, but doesn't function properly in cancer cells, allowing them to grow abnormally without committing suicide, which can be triggered to occur by effective anti-cancer drugs).
Because clinical oncologists did not understand apoptosis then, 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.
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. After all, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.
Listing of Specialized Laboratories in the United States:
These labs will provide you and your physician with in depth information and research on the testing they provide. They follow careful quality controlled methods that adhere to College of American Pathologists and Clinical Laboratory Improvement Amendments (CLIA) guidelines.
Analytical Biosystems, Inc., Providence, Rhode Island. 1-800-262-6520
Anticancer, Inc., San Diego, CA. 1-619-654-2555
Cancer Therapeutics, Inc., Thomasville, GA. 1-229-224-6839
DiaTech Oncology, Brentwood, TN. 1-615-294-9033
Genomic Health, Inc. Redwood City, CA. 1-650-556-9300
Genoptix, Inc., San Diego, CA 1-858-523-5000
Human Tumor Cloning Laboratory, San Antonio, TX. 1-210-677-3827
Impath, Inc., New York, NY. 1-800-447-8881
Nu Oncology Labs, Virginia Beach, VA. 1-757-554-0926
Oncotech, Inc., Irvine, CA. 1-714-474-9262 / FAX 1-714-474-8147
Oncovation LLC, New York, N.Y. 1-212-514-2422
Precision Therapeutics, Pittsburgh, PA. 1-866-243-6639
Rational Therapeutics Institute, Long Beach, CA. 1-562-989-6455
Sylvester Cancer Institute, Miami, FL. 1-305-547-6875
Weisenthal Cancer Group, Huntington Beach, CA. 1-866-364-0011
Resources: Various Bio-Assay Journals
Last edited by gdpawel on Fri Jul 08, 2005 1:13 am; edited 2 times in total |
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gdpawel
Senior User
Joined: 15 Jan 2005
Posts: 123
Location: Pennsylvania
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| Posted: Sun Apr 10, 2005 9:28 pm Post subject: Total Cell Kill/Cell Death Assays |
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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.
There are a family of assays based on the concept of total cell kill, or cell death occurring in the entire popluation of tumor cells.
A fresh specimen is obtained from a viable neoplasm. The specimen is most oftern a surgical specimen from a viable solid tumor. Less often, it is a malignant effusion, bone marrow, or peripheral blood specimen containing "tumor" cells. These cells are isolated and then cultured in the continuous presence or absence of drugs, most often for 3 to 7 days. At the end of the culture period, a measurement is made of cell injury, which correlates directly with cell death. There is evidence that the majority of available anticancer drugs may work through a mechanism of causing sufficient damage to trigger so-called programmed cell death or apoptosis.
There are four endpoint measurements of cell death that have been applied, as measured by differential staining:
1. DISC assay. The delayed loss of cell membrane integrity.
2. MTT assay. The loss of mitochondrial Krebs cycle activity.
3. ATP assay. The loss of cellular ATP.
4. FDA assay. The loss of cell membrane esterase activity and cell membrane integrity.
These four endpoints can and do, in most cases, produce valid and reliable measurements of cell death, which correlate very well with each other on direct comparisons of the different methods. This is not surprising any more than should the fact that auscultating heart sounds, observing spontaneous breathing, palpating a carotid pulse, measuring core body temperture, and recording an electroencelphalogram or electrocardiogram are all good and reliable methods of determing patient death.
Different investigators have favored different cell death endpoints, depending on the laboratory and clinical situation. What is important is that each of the cell death endpoints do give essentially the same results (except in the case of isolated drugs like taxanes and 5FU). So, it is entirely reasonable and proper to consider as a whole the clinical validation data which has been published over the last 15 years, using the above four endpoints.
Cell death assays are not intended to be scale models of chemotherapy in the patient, anymore than the barometric pressure is a scale model of the weather. But it's always more likely to rain when the barometer is falling than when it is rising, and chemotherapy is more likely to work in the patient when it kills the patient's cancer cells in the laboratory. It is no different than any other medical test in this regard.
Last edited by gdpawel on Thu Jul 28, 2005 11:36 am; edited 1 time in total |
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gdpawel
Senior User
Joined: 15 Jan 2005
Posts: 123
Location: Pennsylvania
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| Posted: Sun Aug 28, 2005 6:53 pm Post subject: Re: Chemosensitivity Testing |
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Cell Culture Drug Resistance Testing (CCDRT) first began testing gemcitabine plus cisplatin combination in the mid-90's at the specific suggestion of Dr. Robert Nagourney, Director of Rational Therapeutics, Inc.. Before then, it was virutually unexplored and many patients received treatment with this regimen because of the CCDRT results long before any clinical trials in their particular disease types had ever been published. Dr. Nagourney's contributions in terms of recognizing the profound synergy of this combination and promoting the use of this combination have been very important in getting clinical trials with this regimen started in a broad spectrum of cancers.
There was a summary paper from a National Cancer Institute study, presented at the American Society of Clinical Oncologists (ASCO) Annual Conference in 1998, which looked at thirteen different studies that searched into "in vitro" (chemosensitivity assay) drug sensitivity testing for patients with cancer. It was noted that with the many different cancers represented in these studies, chemotherapy response rates went up from 3 to 66% (using standard chemotherapy drugs and procedures) and from 21 to 81% (using "in vitro" testing for the most responsive drug) and patient survival increased from 4.5 to 11.2 months (using standared procedures) and from 6.2 to 38.5 months (using "in vitro" testing).
A prospective, randomized clinical trial of physician's choice chemotherapy versus ATP assay-directed chemotherapy in non-surgically debulked, platinum-resistant ovarian cancer was presented by Ian Cree, M.D., Ph.D., Director, Translational Oncology Research Centre, Portsmouth, England at the May, 2005 ASCO meeting in Orlando, Florida. The results were highly suggestive of an effect due to the assay, and the most successful drug regimens used were nearly all developed using the assay. UK results in cancer are always lower than in the US for a variety of reasons. Part of this is probably lead time bias, but data on surgical debulking may be part of the explanation. Patients in the US get a whole lot more surgery along the way than in Germany and England, and it's not sure that it's our chemo which is doing the job or our surgery. |
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