Controversy Over Paper on Chemosensitivity Testing

As increasing numbers and types of anti-cancer drugs are developed, oncologists become increasingly likely to misuse them in their practice. There is seldom a "standard"therapy which has been proven to be superior to any other therapy. When all studies are compared by meta-analysis, there is no difference. What may work for one, may not work for another.

Cancer chemotherapy could save more lives if pre-testing were incorporated into clinical medicine. The respected cancer journals are publishing articles that identify safer and more effective treatment regimens, yet few community oncologists are incorporating these synergistic methods into their clinical practice. Cancer patients suffer through chemotherapy sessions that do not integrate all possibilities.

Distinguishing between patients with a "high" or "low" risk for early recurrence after surgical resection and identifying those who may respond to correct adjuvant therapy have been topics of great interest for many years. Both genetic and functional assay analyses share a role in the development of "personalized" patient care.

A genomic test can help to find out if a cancer patient will likely have a recurrence after surgery. If a recurrence isn't likely, they don't need chemotherapy. Genetic tests have been developed for breast and lung cancers. Hopefully, there will be more tests for other types of cancer to guide physicians as to which "high" risk patient will likely have a recurrence if treated with surgery alone (1).

If the test finds a patient to be at "high" risk, it is impossible to design a single chemotherapy protocol that is effective against all types of cancer. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability. A cell culture assay test, using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).

The current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new "targeted" therapies. Given the technical and conceptual advantages of "functional profiling" of cell culture assays together with their performance and the modest efficacy for therapy prediction on analysis of genome expression, there is reason for renewed interest in these assays for optimized use of medical treatment of malignant disease (2).

The chemotherapy regimen chosen by most community oncologists is based on the type of cancer being treated. However, there are factors other than the type of cancer that can be used to determine the ideal chemotherapy drugs that should be used to treat an individual patient.

It is highly desirable to know what drugs are effective against particular cancer cells before these toxic agents are systemically administered. Pre-testing on "fresh" specimens of cancer cells to determine the optimal combination of chemotherapy drugs could be highly beneficial.

Following the collection of "fresh" cancer cells obtained at the time of biopsy or surgery, a cell culture assay is performed on the tumor sample to measure drug activity (sensitivity and resistance). This will pinpoint which drug(s) are most effective. The treatment program developed through this approach is known as assay-directed therapy.

At present, medical oncologists prescribe chemotherapy according to "fixed" schedules. These schedules are standardized drug regimens that correspond to specific cancers by type or diagnosis. These regimens, developed over many years of clinical trials, assign patients to the drugs which previously worked for some percentage of patients.

However, cancer is a disease whose hallmark is heterogeneity. It is well known that drugs which work for one patient often don't work for another and patients who fail to respond to first line chemotherapy with one regimen often respond to second or third line therapy with alternative drugs. Why not identify the right regimen before ever exposing a patient to a single course of chemotherapy? A failed attempt at chemotherapy is detrimental to the physical and emotional well being of patients, is financially burdensome, and may promote the onset of clinically acquired multi-drug resistance.

A "fresh" sample tumor can be obtained from surgery or biopsy (Tru-cut needle biopsies). Tissue, blood, bone marrow, and ascites and pleural effusions are possibilities, providing tumor cells are present, and only live cells should be used. At least one gram of fresh biopsy tissue is needed to perfom the tests, and a special kit is obtained in advance from the lab. Arrangements are made with the surgeon and/or pathologist for preparation and sending of the specimen.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of live "fresh" tumor cells can improve the conventional situation by allowing more drugs to be considered. 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.

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" assays. Drug "sensitivity" testing is merely a point a little farther along on the very same continuum upon which "resistance" testing resides, which has been proven to be accurate and reliable, as reported in numerous peer-reviewed publications.

Good review papers exist on cell culture assays and are increasingly appreciated and applied in the private sector by European clinicians and scientists. The literature on these assays have not been understood by many NCI investigators and by NCI-funded university investigators, because their knowledge has been based largely on an assay technique (cell-growth) that hasn't been used in most private labs for over fifteen years (3).

Data show conclusively that patients benefit both in terms of response and survival from drugs and drug combinations found to be "active" in the assay even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

Patients receiving a drug that tested "sensitive" were 1.44 times [i.e. 44%] more likely to respond compared to all patients treated in studies, while patients testing "resistant" were 0.23 as likely to respond as all patients. Patients receiving treatment with drugs testing "sensitive" enjoyed a 6-fold advantage (1.44/0.23 = 6.23) over patients treated with drugs testing "resistant."

This data includes both patients with solid tumors (e.g., breast cancer, lung cancer) and hematological (blood system) tumors (e.g. leukemia, lymphoma). In the case of solid tumors only, the advantage to receiving sensitive versus resistant drugs was 9.3 fold. In the case of breast cancer, it was more than 10-fold. Furthermore, patients receiving "sensitive" drugs were shown in many studies to enjoy significantly longer durations of survival than patients treated with "resistant" drugs.

Patients treated with a "positive" (sensitive) drug would respond 79.1% of the time, while patients treated with a "negative" (resistant) drug would respond only 12.6% of the time. Once again, there would be a huge advantage to the patient to receive a "positive/sensitive" drug, compared to a "negative/resistant" drug (4).

Profiles from DNA and RNA expression analysis can help define patients at risk for early recurrence. Cell Culture Assays with "functional profiling" have a role in eliminating ineffective agents and avoid unnecessary toxicity and in directing "correct" therapy.

An ASCO tech review of drug sensitivity and resistance assays, concluded that the use of these assays for selection of chemotherapeutic agents for individual patients is not recommended outside the clinical trial setting (5).

However, Medicare contractor National Heritage Insurance Company spent six months reviewing everything about the cell culture assay, read all of ASCO arguments, and upon reviewing all available information, made the decision to reverse trend and go on record as formally approving the service and providing coverage.

They found that even back in 1999, the Medicare Advisory Panel concluded that cell culture assays tests offered clinical utility. After listening to detailed clinical evidence, the Medicare Coverage Advisory Committee found that these assay systems can aid physicians in deciding which chemotherapies work best in battling an individual patient's form of cancer (6).

Although Medicare had been reimbursing for cell culture drug "resistance" tests since 2000, it wasn't until the beginning of this year that they abandoned the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit. The decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis (7).