CSRA's

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.

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. The earlier in the course of the disease that the most active treatment is given, the better the result for the patient.

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.

It is true that what happens in the lab is not necessrily 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.

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, 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.

The cell culture assay tests provide much more powerful prognostic information. They 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 given treatment is associated with a below average probability of response and/or survival.

gdpawel said:

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.

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.