Chemosensitivity Testing

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.

My mother (69) has just been diagnosed with stage 4 serous endometrial cancer. She has had surgery - total hysterectomey, removal of the omentum, removal a portion of the large intestine that was blocked by a tumor. Lots of tiny tumors visible elsewhere in the abdomen. Cancerous fluid in her chest cavity. She is recovering well from surgery. The doctors say her focus now is on healing and getting strong enough for chemo, to start in about a month. Most likely the treatments would be Taxol/Carboplatin.

I'm intrigued by your suggestion of Chemosensitivity Testing. How new is this concept? It sure makes sense, especially with someone in advanced stages where weighing the variables of time, treatment, and quality of life is particulary critical. If when I bring this up with the oncologist is it likely to be
something new to him?

What is your backgroung and experience with cancer, cancer treatments, and Chemosensitivity Testing?

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 "below" 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.

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.

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 that I listed above 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.

I've been an advocate for a number of cancer subjects over the last four years. HBO Therapy for radiation-induced necrosis, abolition of the Chemotherapy Drug Concession as well as encouraging the technology of Chemosensitivity Testing. Dr. Larry Weisenthal, of the Human Tumor Assay Journal, was very instrumental in having me understand about the demise of my wife by Taxol/Carboplatin and the politics of cancer medicine.

For more information and a listing of many labs that do this testing:

http://www.weisenthal.org/

Gregory, I see your letters in all the cancer discussion sites and
you are very persuasive -- but no one else is writing in.
Chemosensitivity testing makes so much sense. Why do I see
so few real discussions about it? Where are the patients who
have tried it??

My mom's oncologist is recommending taxol/carboplatin, but
everything I find on the internet about advanced serous
endometrial cancer says that it has not been shown to be
responsive to standard treatments. Given this cancer's
advanced stage and lack of a clear protocol, I feel that it's
imperative that my mother's time and life not be wasted with
ineffective and/or harmful drugs. I don't want her to get
sucked up into some auto-pilot treatment plan, but she is in
another state and, while not totally passive, is not especially
inclined to question her doctor ("He seems like a good man...").
She and my father are open to my doing research to help them
with their decisions regarding treatment, but I feel I have to
have a lot of very persuasive information in order to prod them
to consider anything other than what the doctor says. So I'm
looking at CCDRT (cell culture drug resistance testing),
artemisinin, noscapine, low-dose naltrexone... It's difficult to
know where to put my energies. (Then there's my husband,
kids, job...)

One of the problems with CCDRT in my mom's case is that the
largest mass of cancerous tissue was removed a month ago
because she needed immediate surgery to remove a tumor that
was blocking her large intestine. At that time they also did a
hysterectomy and removed the omentum. We knew nothing
about CCDRT at the time of surgery. The remaining cancer is in
the form of lots of tiny tumors around her abdomen, so
obtaining enough sample tissue is problematic. The only
option then is tapping some of the cancerous fluid that we
know to be in her chest cavity.

I explain all this because, given the complicating factors, if I'm
going to press for my mom to have this procedure I want to
know that the resulting information will be highly useful!

Thank you for your efforts to help others sort through the
savage mess of modern cancer treatment...

Gregory P: I found your article both interesting and pertinent to my situation because my surgery (Total abdominal hysterectomy/bilateral salpingoophorectomy with cancer staging (multiple nodes, omentum and appendix removed also)in February showed Stage 1C/Grade I epithelial ovarian cancer. Wouldn't I have had to prearrange for the tissue to be chemosensitivity tested prior to the surgery? I do not think there is anything left of the tissue at this time, execpt the path slides. My prognosis is very good due to early stage, and I have already received 1 treatment; I understand that currently, Taxol/Carbo is the standard first line treatment.


Chemosensitivity testing seems to make so much sense;however,here are my questions:

1. if/when you do advise other drugs in lieu of Taxol/Carbo, do you offer statistics on them? For example, is there an 80-90% cure rate, etc? In one of your message board postings, you mention one woman who would NOT have benefited from Taxol/Carbo, but I don't see stats on other groups.


2. wouldn't I have had to know about the chemosensitivity testing PRIOR to the surgery? If so, why didn't the surgeon suggest that to me?


3. Does chemosensitivity apply to all stages and grades of ovarian cancer? Is it limited to recurrences?

Thanks for the information.

suzanneb

All the rigorous clinical trials that have been identified are the "best" treatments for the "average" patient. This has been referred to as the lowest common denominator theory of cancer treatment. But cancer is not an "average" disease. Cancer is far more heterogeneous in response to various individual drugs than are bacterial infections.

The heterogeneity of human cancer is shown both by the fact that some patients derive great benefit from treatments which fail to help (and often harm) the majority of patients who receive the treatment. And many patients fail to benefit from 1st line chemotherapy, only to derive great benefit from 2nd or even 3rd line chemotherapy. These patients should have received the correct treatment the first time around. Everyone would agree that the earlier in the course of the disease that the most active treatment is given, the better the result for the patient.

Cell culture assay tests provide powerful prognostic information. They can tell you that a given form of treatment has an above average probability of being associated with a clinical response and/or with being associated with above average survival. Likewise, they indicate that a given treatment is associated with a below average probability of response and/or survival. For many cancers, especially after a relapse, more than one standard treatment exists. The system is overloaded with drugs and underloaded with wisdom and expertise for using them.

In order to do this testing, sample or biopsy (200mg in size) of the tumor is necessary. In having a biopsy, request that enough tissue be gathered for this as well as for other tests intended for the sample. I only hope that you would have the understanding of a couragious physician that would look into these things for you and provide the needed connections. The specialized laboratories will provide your physician with in depth information and research on the testing they provide.

The previous standard always used to evaluate any type of medical test has always been the correlative and predictive "accuracy" of the test. How well does a Bacterial Culture and Sensitivity Test predict for clinical success or failure of penicillin therapy? Not only is test accuracy (not "efficacy") the established standard for evaluating every single test used in medicine, it is also the precise standard used by the FDA in approving a test kit for Cell Culture Drug Resistance Testing. The FDA didn't require proof of "efficacy" (as it has never required proof of "efficacy" for any medical tests).

It is true that what happens in the lab is not necessarily what happens in the patient. Individual testing of patients are not 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's no different than any other medical test in this regard.

Why is it so necessary to protect the patient from 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 patient should ask his doctor to show the patient the survival curves for a given recommended form of empirical 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.

It is likely that surgical skill is a more important determinant of prognosis than the aggressive nature of the cancer or its stage at diagnosis. In cancer treatment, surgery is generally used only if it can cure the cancer. It is most useful in cancers that have not spread. However, if the cancer has spread to only one area or is small, then it may be possible to remove it completely with surgery. Some surgeons view chemotherapy as a remedy for "bad" surgery. Chemotherapy just isn't good enough to make up for surgical mistakes (e.g. failure to get good margins, tumor spills during surgery, etc.). The most important prognostic factor is the surgeon!

Does anyone have any dosing information and clinical trial information about Noscapine. I am interested in any clinical trail results when used for ovarian cancer. It really sounds like a good drug.

I have a family member in a very similar condition to your description of your mother's cancer and our options are becoming more and more sparce. Did you ever try the sensitivity testing? If so, was it beneficial to the course of treatment selected in your opinion? In our case we may be past the point where chemo is an option (as of emergency surgery being performed tonight) ... but I'd like to know what your experience was.

There was a joint Michigan/Harvard study authored by Drs. Joseph Newhouse and Craig C. Earle, entitled "Does reimbursement influence chemotherapy treatment for cancer patients?" It confirmed that medical oncologists choosed cancer chemotherapy based on how much money the chemotherapy earns the medical oncologist.

The authors documented a clear association between reimbursement to oncologists for the chemotherapy and the regimens which oncologists select for their cancer patients. In other words, oncologists tended to base their treatment decisions on which regimen provided the greatest financial remuneration to the oncologist. (Jacobson, M.,O'Malley, A.J., Earle, C.C., et al. Health Affairs 25(2):437-443, 2006).

The study adds to the 'smoking gun' survey by Dr. Neil Love, entitled "Patterns of Care." One of the results of this survey shows that for first line chemotherapy of metastatic breast cancer, 84-88% of the academic center-based oncologists (who do not derive personal profit from infusion chemotherapy) prescribed an oral dose drug (capecitabine), while only 13% prescribed infusion drugs, and none of them prescribed the expensive, highly remunerative drug docetaxel.

In contrast, among the community-based oncologists (who do derive personal profit from infusion chemotherapy), only 18% prescribed the oral dose drug (capecitabine), while 75% prescribed infusion drugs, and 29% prescribed the expensive, highly remunerative drug docetaxel. (Patterns of Care: 2005,Vol 2,Issue 1).

While the Michigan/Harvard study showed results before the new Medicare reform, the Patterns of Care study showed results that the Medicare reforms are still not working. It is still an impossible conflict of interest.

And the existence of this profit motive in drug selection has been one of the major factors working against the individualization of cancer chemotherapy based on testing the cancer biology (chemosensitivity testing).

The two, scientific studies give us a dose of reality. Once a decision to give chemotherapy is taken, oncologists receiving more-generous Medicare reimbursements used more-costly treatment regimens.

Sources:

http://content.healthaffairs.org/cgi/content/abstract/25/2/4

http://patternsofcare.com/2005/1/editor.htm

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.

However, the extreme drug resistance assays (EDR) cannot "accurately" predict for drug sensitivity. This kind of assay is specifically designed to identify "inactive" drugs and should not be used to identify "active" drugs. It has a very high specificity for drug resistance. However, many effective drugs do not test in the extreme drug resistance range. It has a relatively low sensitivity.

It must be realized that these assays are complex procedures, fraught with the potential for error and misinterpretation. The results are only meaningful to the extent that the laboratory in question is experienced and diligent in its quality assurance practices. A patient interested in this testing should not hesitate to ask specific questions and to require specific answers of the laboratories under consideration.

The EDR is a rather simple, straightforward test, requiring only about 5 minutes per assay of physician/lab work. DISC, MTT, and ATP assays are more geared to identifying active drugs (drugs which will work, as opposed to drugs which won't work), and are a whole lot more labor intensive, requiring an average of 3 hours of physician/lab work.

In order to have an assay done, tumor cells must be accessible through biopsy (needle biopsy is not enough). Tissue, blood, bone marrow, and ascites and pleural effusinos are possibilities, providing tumor cells are present, and only live cells can be used. At least one gram of fresh biopsy tissue is needed to perfom the tests, and a special kit must be gotten in advance from the lab. Arrangements have to be made with the surgeon and/or pathologist for preparation and sending of the specimen.

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, the lab test that pinpoints a germ so the right antibiotic can be prescribed.. Doctors cannot remember a time when they didn't have this technology. It is a 'gold' standard. Oncologists are even equating the new Oncotype DX molecular test for breast cancer, with that of Bacterial Culture and Sensitivity Testing.

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.

Conventionally, oncologists make therapeutic decisions on an empirical basis rather than by thorough evaluation of pathological features and/or drug sensitivity tests. When tumors acquire multi-drug resistance, become refractory and cause relapse after first-line chemotherapy, their responses to routine drugs are greatly compromised.

Upgrading clinical therapy by using drug sensitivity assays can improve the conventional situation by allowing more drugs to be considered. Drug sensitivity tests support the idea that a marginal benefit in terms of overall survival is observed in cancer patients with normal prognoses, but there are marked survival benefits for cancer patients with poor prognoses.

The key to improving drug sensitivity tests is related to the number and types of drugs tested. The more anti-cancer drug types there are in the selective arsenal, the more likely the system is to prove beneficial. In order to acquire sufficient data, tumors should be tested with at least two assay endpoints, and most often three, for sensitivity tests in any one patient. On average, up to twenty drugs and combinations at two concentrations in three different assay systems, is an effective way to avoid false-positive or false-negative data. Careful choice of drug doses and administration intervals also improves outcomes.

Different methods of CCDRT results should be applied in choosing a particular drug regimen to be used in treating an individual patient's cancer. The different methods will sort the different reasonable treatment regimens into the different groups (above-average, average, below-average and very below-average), which would direct attention away from regimens "less" likely to provide benefit and toward regimens which are "more" likely to provide benefit.

Assays based on "cell-death" occur in the entire population of tumor cells, as opposed to only in a small fraction of the tumor cells occurring in "cell-growth." Cell-death assays (DISC, MTT, ATP and Fluorescein Deacetate) correlate very well with each other on direct comparisions of different methods.

Drug sensitivity assays do not harm patients in any way except in terms of cost. 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 not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Having some foreknowledge of a given agent's expected result before its administration would benefit the individual patient.