Oncologic In Vitro Chemoresponse Assays

[gpawelski]

Patients, physicians, insurance carriers, and the FDA are all calling for predictive tests that allow for rational and cost-effective use of chemotherapeutic drugs. Given the technical and conceptual advantages of Cell Culture Assays together with their performance and the modest efficicay of therapy prediction on analysis of genome expression, there is reason for a renewal in the interest for these assays for optimized use of medical treatment of malignant disease.

Researchers have seen that whether a tumor was a breast tumor, prostate tumor, lung tumor or lymphoma, it didn't correlate to how the cancers interacted with standard anticancer drugs. Their findings suggest that traditional cancer treatments, which have established different drug regimens for brain, prostate, lymphoma or ovarian cancer, for example, should be replaced with therapies that use drugs deemed to be of highest benefit based on the tumor's pharmacologic profile. Treatment choice would be determined by how each patient's tumor reacts to anticancer drugs, regardless of the tumor's anatomical origin.

The drug effect is independent of where the tumor came from in the body. Under current treatment selection methods virtually no chemotherapeutic drug has been successful in more than 50 percent of patients with advanced cancer. But instead of considering a drug that works only ten percent of the time a failure, it would be better to consider such a drug effective for one in ten tumors and to search for the agents among the current arsenal of chemotherapeutic drugs that will work for the rest. Having a good tumor-drug match not only would improve survival rates, it would be cost-effective, and the high cost of the newer cancer therapies reinforces the necessity of choosing the right therapy the first time around.

Conventionally, oncologists make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. For many cancers, more than one standard treatment exists. Physicians select drugs based on their personal experience, possible side effects and the patient's condition, among other factors. However, the system is overloaded with drugs and underloaded with wisdom and expertise for using them.

In patients with cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. 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 cancers, especially after a relapse or when a particular treatment is ineffective, more than one standard treatment exists.

A chemo-induced gene mutation can happen when the original chemo received does not work. The cancer comes back. When it does this, the cancer comes back more aggressively. The mutagenic effects (changes in form) of chemotherapy on a genetically-unstable tumor, drives the tumor into a state of more aggressive behavior. You might kill off a whole lot of cancer, only to cause a mutation in the remaining cancer, such that the remaining cancer behaves in a more aggressive fashion.

Cancers that are a product of these genetic mutations release cells from the usual controls of proliferation and survival, making them so much harder to fight it. Following this mutation, the cancer cells acquire the ability to proliferate without the normal restraints. As the cancer grows, it may infiltrate and destroy the surrounding tissue, and metastasize by penetrating into blood vessels, lymph nodes, and body cavities. Distant metastasis via the bloodstream may affect virtually any organ (the lungs, bones, liver, adrenals, and even the brain).

There are patients who have progressive disease after first-line therapy, only to enjoy a dramatic benefit from second or even third line therapy, and these patients would have been much better served by receiving the most probable active treatment the first time around. By utilizing cell culture assays, oncologists can choose the treatment which is most likely to work or that is what their patients want.

With cell culture assays, 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.

Cell culture assays are 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. These assays 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 cell culture 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. However, some assays 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.

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. 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 narrow indication. But these drugs may have many useful applications, and a cell culture assay offers a way of seeing if any of these new drugs might apply to your specific cancer.

A cell culture 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.

In studies, patients treated with drugs "active" in the assays had a higher response rate than the entire group of patients as a whole. Patients treated with drugs "inactive" in the assays had lower response rates than the entire group of patients. 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.

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 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. Some 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. 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.

These cell culture 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.

These tests have been extensively validated for "accuracy," without any controversy whatsoever. In more than 40 peer-reviewed publications, in a wide range of human tumors, ranging from acute and chronic leukemia to ovarian and breast cancer, patients treated with drugs which were active in the assays were more likely to respond to treatment than the group as a whole and dramatically more likely to respond to treatment than patients treated with drugs which were not active in the assays, with there being a 7 to 9 fold advantage to treatment with assay "positive" drugs, compared to assay "negative" drugs. In a number of studies, patients treated with assay "positive" drugs enjoyed significant survival advantages, as well.

The criteria always used to evaluate medical tests is the "accuracy" of the tests and not the "efficacy" of the tests. There is no single test (laboratory or radiographic or anything else) used in cancer which has been proven to be "efficacious" in prospective randomized trials, where patients are managed with and without the benefit of the information provided by the tests, and treatment outcomes compared. The only information which has ever been obtain is how accurate the tests are, and the accuracy of the cell culture assays compares favorably with that of other similar tests used in cancer medicine. Critics of the testing are demanding a standard of proof which is truly unprecedented, and which has not been met by all of the other tests used in cancer medicine.

Most of the cancer treatments used have not met the standard of proof demanded of a cell culture assay, which is a test and not a treatment. The degree to which "standard" cancer chemotherapy has been "proven" to be more efficacious than other forms of treatment has been overstated, overassumed, and over-sold.

Having some foreknowledge of a given chemo agent's expected result before its administration would benefit the individual patient. The cost of drugs is enormous. Patients are followed with serial CT scans, MRI's and even Pet Scans, just to see if a tumor is growing or shrinking. Not to mention the hospitalizations for toxicity, bone marrow tranfusions, etc. The point is, the cost of ineffective therapy is truly enormous and all cell culture assays are particularly good at identifying ineffective therapy, and some are good at identifying effective therapy. The biggest criticism of cell culture assays is its standard for proving its value - improving overall survival.

[gpawelski]

Medicare Contractor Establishes Reimbursement Coverage Policy for Cell Culture Assay Tests

National Heritage Insurance Company (NHIC), the contractor that administers Medicare programs in California, has established a positive coverage policy for Cell Culture Assay Tests known as Chemosensitivity (Resistance) Testing or Oncologic In Vitro Chemoresponse Assays for a tumor specimen from a Medicare patient obtained anywhere within the United States, but submitted for testing by one of the approved laboratories located within Southern California. Medicare bills for this testing are billed through NHIC because the test is conducted by the approved laboratories in California.

This pre-test can help see what treatments have the best opportunity of being successful for "high" risk cancer patients. The test measures the response of "live" tumor cells to drug exposure. Following this exposure, the assays measure both cell metabolism and cell morphology (Functional Profiling). The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. Assays based on "cell-death" occur in the entire population of tumor cells.

This cell culture assay technology has been clinically validated for the selection of optimal chemotherapy regimens for individual patients. It is a laboratory analysis based on tumor tissue profiling that uses "fresh" human tumor biopsy or surgical specimen to determine which drugs or combinations of chemotherapeutic agents have the highest likelihood of response for individual cancer patients.

Following the collection of "fresh" tumor cells obtained from surgery or tru-cut needle biopsies, 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. Tissue, blood, bone marrow, and ascites and pleural effusions are possibilities, providing tumor cells are present. At least one gram of fresh tissue is needed to perform the tests, and a special kit is obtained in advance from the lab. The treatment program developed through this approach is known as assay-directed therapy.

Individualized assay-directed therapy is based on the premise that each patient's cancer cells are unique and therefore will respond differently to a given treatment. This is in stark contrast to standard or empiric therapy, which chemotherapy for a specific patient is based on average population studies from prior clinical trials.

The decision had been made that the assay is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. What is of particular significance is that they abandoned the artificial distinction between "resistance" testing and "sensitivity" testing and are providing coverage for the whole FDA-approved kit. Drug "sensitivity" testing is merely a point a little farther along on the very same continuum which "resistance" testing resides.

Cell cuture assay tests based on "cell-death" have proven very effective in identifying novel treatment combinations for a variety of cancers. The value of cell-death assays is that they can and do accurately predict clinical outcomes and define novel chemotherapeutic synergies. It 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.

The payment provided will be sufficiently realistic that all Medicare patients for whom this testing is indicated will be able to get it with only the routine 20% co-payment, as Medi-gap insurance secondaries are mandated to provide payment for co-pays for Medicare-approved services.

The coverage became effective for claims for services performed on or after February 19, 2007. The decision is posted at:

http://www.medicarenhic.com/cal_prov/ar ... t_0107.htm

NHIC Medicare Services reimburses qualified laboratories in Southern California for cell culture assay tests on a Medicare patient anywhere in the United States.

Likewise, Highmark Medicare Services reimburses a qualified laboratory in Pennsylvania for cell culture assay tests on a Medicare patient anywhere in the United States.

NHIC has jurisdiction over Southern California, so that is who gets billed when the laboratory is located in California.

Highmark has jurisdiction over laboratories in Pennsylvania, so that is who gets billed when the laboratory is located in Pennsylvania.

The coverage decision is posted at:

http://www.highmarkmedicareservices.com ... 32007.html

[gpawelski]

Medicare's National Coverage Decision specifically notes noncoverage on two distinct types of assays: a. human tumor stem cell assay, and b. clonogenic assay. These are what most academic oncologists still mistakenly refer to as chemosensitivity testing.

In October 2003, CMS notified all contractors that the NCD was very specific to those tests and does not include tumor cell sensitivity or resistance testing on any other class of cells other than tumor stem cells. In 2006, Medicare officially recognized cancer chemosensitivity tests as a special test category in Federal Regulations (42 CFR 414.510((3), 71 FR 69705, 12/01/2006).

Two Medicare contractors (NHIC Medicare Services and Highmark Medicare Services) established reimbursement coverage policies for cell culture assay tests, the same way that the Oncotype DX assay is being covered. Medicare bills for Chemosensitivity (Resistance) Testing, from any Medicare patients, anywhere in the United States, are billed through NHIC and Highmark Medicare Services because the test is conducted by approved laboratories in Southern California and one in Pennsylvania. As far as payments for this test, it is just as good as having a NCD. Numerous private payors pay for the tests also.

As with any other laboratory tests in cancer medicine, the determination of the efficacy of cell culture assays is based on clinical correlations (comparisions of laboratory results with patient response). The "standard" of retrospective correlations between treatment outcomes and laboratory results is sufficient in the case of ALL laboratory tests. It is what established FDA-approval for the test kit.

[gpawelski]

It amazes me not only that some private insurance carriers don't like to pay for cell culture assay tests but that they don't emphatically mandate it as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments.

The validation standard that private insurance companies is accepting from "molecular" profiling tests is "accuracy" and not "efficacy." The "bar" has been instantly lowered. No longer will it be essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these "molecular" profiling tests is prove that the test has a useful degree of "accuracy." However, at the same time, the validation standard they want for "cell-based" profiling tests is "efficacy."

The "cell-based" profiling tests have the same entitlement to be judged by the same validation standard as "molecular" profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the "profile" at the whole cell level. It must be noted that both types of dignostic tests are just that, "tests" and not treatment.

Profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the test, which is to identify efficacious therapies irrespective of drug mark-up rates.

The evidence in support of these assays is more than sufficient to justify the funding of validation trials, if any more truly are needed, as claimed - speciously and self-servingly - by the medical establishment.

Everyone is scared to death - and rightly so - at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class, such as Sutent, Tarceva, Iressa, and Nexavar.

The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.

It explains the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies. The pressure, in fact, is so great that the companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

I think that in both of these areas - private insurance carriers and the FDA - there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately.

Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments - everybody wants that - but also, in the "here and now," using currently-available cell culture assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.