Currently, physicians select an empirically-selected drug and must wait about six months to see whether it is effective on a particular patient. For many cancer, especially after a relapse or when a particular treatment is ineffective, more than one standard treatment exists.
What are the data which prove that an empiric, "one-size-fits-all" treatment identified by the clinical trials paradigm of randomized trials to identify the single best treatment to give to the "average" patient is clearly the most promising treatment to receive?
All available assay tests 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 assay tests are also able to report drug "sensitivity" (synergy) 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.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.
Some patients may not have easily-accessible tumors (needle biopsies do not gather enough specimen), making it difficult to harvest a large enough sample (200mg or 10mm in size). The tests are most reliable before a tumor has been exposed to chemotherapy. However, after a patient fails a previous chemotherapy treatment, the test still can be done once a patient waits at least four weeks.
There are four endpoint measurements of cell death that have been applied:
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. Caspase 3/7 assay. Directly measures key apoptosis expression markers.
(EDR assay is a cell-proliferation endpoint used to identify "inactive" drugs. It is not optimal to identify "active" drugs)
The DISC assay is the only assay that involves direct visualization of the cancer cells at endpoint. This allows for accurate assessment of drug activity, discriminates tumor from non-tumor cells, and provides a permanent archival record. Originators of the MTT and ATP assays modeled assay conditions on the DISC assay. The use of complementary tests improves accuracy and provides quality control. Also, certain drugs cannot be tested reliably in all assay systems. Use of different tests with different mechanisms helps to overcome this.
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.
Not all patients will have the same response to the same chemotherapy. Special laboratories can test tumor samples from individual patients to see which chemotherapy drugs have the best likelihood of killing tumor cells and optimizing survival. The results provide medical and surgical oncologists with patient-specific tumor information that may provide additional insight when determing the appropriate course of treatment for a patient.
Assay-testing focuses on the unique characteristics of a particular cancer. The test results help the physician to determine which anti-cancer drugs are "likely" to be effective against a particular cancer. The assay test also helps the physician to determine which anti-cancer drugs are "unlikely" to affect a cancerous tumor, which can help to avoid toxic and possibly ineffective therapy.
The tests have a specifity (for drug resistance) of 0.92 and a sensitivity (for drug resistance) of 0.71, which means that a treatment regimen "not" resistant in the assays is 7-9 fold more likely to work than is a treatment regimen which "is" resistant in the assays. A preponderance of evidence would indicate that it would be worthwhile to consider the assay results in drug selection.