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Chemotherapy Recommendations Based on Published Reports of Clinical Trials
By gdpawel at 2013-01-28 10:47
Chemotherapy Recommendations Based on Published Reports of Clinical Trials

The American Society of Clinical Oncologists (ASCO) says oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences.

How about published reports of clinical trials?

More chemotherapy is given for breast cancer than for any other form of cancer and there have been more published reports of clinical trials for breast cancer than for any other form of cancer.

According to NCI’s official cancer information website on state of the art chemotherapy for recurrent or metastatic breast cancer, it is unclear whether single-agent chemotherapy or combination chemotherapy is preferable for first-line treatment. At this time, no data support the superiority of any particular regimen. So, it would appear that published reports of clinical trials provide precious little in the way of guidance (1).

In the total absence of guidance from published reports of clinical trials then, what basis are treatment regimens selected instead? ASCO says that this should be further based on a patient’s health status and patient treatment preferences.

So what is being done?

Published in the journal Health Affairs is a joint Harvard/Michigan study entitled, Does reimbursement influence chemotherapy treatment for cancer patients? The authors documented a clear association between reimbursement to the oncologists for the chemotherapy of breast, lung, and colorectal cancer and the regimens which the oncologists selected for the patients. In other words, oncologists tended to base their treatment decisions on which regimen provided the greatest financial remuneration to the oncologist (2).

A March 8, 2006 New York Times article described the study. One of the more interesting aspects of the story was a comment from an executive with ASCO, Dr. Joseph S. Bailes, who disputed the study’s findings, saying that cancer doctors select treatments only on the basis of clinical evidence (3).

So ASCO’s Dr. Bailes maintains that drugs are chosen only on the basis of clinical evidence. Yet, Dr. Neil Love reported in a survey of breast cancer oncologists based in academic medical centers and community based, private practice medical oncologists. The former oncologists do not derive personal profit from the administration of infusion chemotherapy, the latter oncologists do derive personal profit from infusion chemotherapy, while deriving no profit from prescribing oral-dosed chemotherapy.

The results of the survey could not have been more clear-cut. For first line chemotherapy of metastatic breast cancer, 84-88% of the academic center-based oncologists (who are motivated to keep off-protocol patients out of their chemotherapy infusion rooms to reserve these rooms for on-protocol patients) 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 commuity-based oncologists, only 18% prescribed the non-remunerative oral-dose drug (capecitabine), while 75% prescribed remunerative infusion drugs, and about 40% prescribed the expensive, highly remunerative drug docetaxel (4).

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. While being faced with a large number of choices of otherwise equally acceptable therapies, oncologists select the treatments which generate the most income for private practices or generate the least inconvenience for the clinical research institutions.

What needs to be done is to remove the profit incentive from the choice of chemotherapy treatments. Medical oncologists should be taken out of the retail pharmacy business and let them be doctors again.

Sources:

(1) http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page8#Section 297

(2) http://content.healthaffairs.org/cgi/content/abstract/25/2/437

(3) http://www.nytimes.com/2006/03/08/health/08docs.html?ex=1145160000en=584b5c2aa35995a3ei=5070

(4) http://patternsofcare.com/2005/1/editor.htm (figure 37, volume 2, issue 1, 2005)



8 comments | 2617 reads

by gdpawel on Mon, 2013-01-28 11:02
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.

Two scientific studies giving us a dose of reality that once a decision to give chemotherapy is taken, oncologists receiving more-generous reimbursements used more-costly treatment regimens.

It’s not that all oncologists are bad people, it’s the SYSTEM which is rotten. Some oncologists prescribe chemotherapy drugs with equal efficacies and toxicities. I would imagine that some are influenced by the whole state of affairs, possibly without even entirely admitting it. There are so many ways for humans to rationalize their behavior. The solution is to take medical oncologists out of the retail pharmacy business and forece them be doctors again.

A good benchmark assessment of the efficacy of cancer drugs that come out of clinical trials, could be functional cytometric profiling (Cell Function Analysis).

At present, clinical trials are highly empirical, they test drugs on general populations and then look for a clincial response and a treatment effect that is not likely to be a chance result. However, the side effect of this is inflexibility, some patients may unnecessarily be exposed to inferior experimental therapies.

A problem with the empirical approach is it yields information about how large populations are likely to respond to a treatment. Doctors don't treat populations, they treat individual patients. Because of this, doctors give treatments knowing full well that only a certain percentage of patients will receive a benefit from any given medicine. The empirical approach doesn't tell doctors how to personalize their care to individual patients.

The number of possible treatment options supported by completed randomized clinical trials becomes increasingly vague for guiding physicians. Even the National Cancer Institute's official cancer information website states that no data support the superiority of more than 20 different regimens in the case of metastatic breast cancer, a disease in which probably more clinical trials have been done than any other type of cancer.

More clinical trials have not produced more clear-cut guidance, but more confusion in this situation. It is more difficult to carry out clinical trials in early stage breast cancer, because larger numbers of patients are needed, as well as longer follow-up periods. But it is likely that more trials would lead to the identification of more equivalent chemotherapy choices for the average patient in early stage breast cancer and in virtually all forms of cancer as well.

So, it would appear that published reports of clinical trials provide precious little in the way of "gold standard" guidance. Almost any combination therapy is acceptable in the treatment of cancer these days. Physicians are confronted on nearly a daily basis by decisions that have not been addressed by randomized clinical trial evaluation.

The needed change in the "war on cancer" will not be on the types of drugs being developed, but on the understanding of the drugs we have. The system is overloaded with drugs and underloaded with the wisdom and expertise for using them.

Patient tumors with the same histology do not necessarily respond identically to the same agent or dose schedule of multiple agents. Laboratory screening of samples from a patient's tumor can help select the appropriate treatment to administer, avoiding ineffective drugs and sparing patients the side effects normally associated with these agents.

It can provide predictive information to help physicians choose between chemotherapy drugs, eliminate potentially ineffective drugs from treatment regimens and assist in the formulation of an optimal therapy choice for each patient (not average populations). This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free survival.

Identifying patients with resistant neoplasms may not only spare them toxicity but may prolong their lives, by sparing them from the life shortening effects of ineffective chemotherapy.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with empiric chemotherapy.

With the absence of effective laboratory tests to guide physicians, many patients do not even get a second chance at treatment when their disease progresses. Spending six to eight weeks to diagnose treatment failure often consumes a substantial portion of a patient's remaining survival, not to mention toxicities and mutagenic effects.

Good review papers exist and are increasingly appreciated, understood, and applied by private sector and European clinicians and scientists. This literature is not understood by many NCI investigators and by NCI-funded university investigators. NCI studies never determine if fresh tumor assays worked. All of the considerable literature which supports the use of these assays in patient management has been based on true fresh tumor (non-passaged) cell assays.

The NCI used "cell lines" because the major expertise of the investigators who carried out any study was in the creation of cancer cell lines, and they wanted to see if they could perform assays on these cell lines to use in patient therapy. The results were that they were able to test successfully only 22% of specimens received, including only 7% of primary lesions. This contrasts with a 75% overall success rate reported by earlier investigators who used the same assay system in fresh tumors and a routinely obtained > 95% success rate using improved methods available today.

Cell culture analysis using the functional profiling method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell "population" level (rather than at the "single cell" level), measuring the interaction of the entire genome.

I believe that improving cancer patient treatment through cellular-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different. 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.

In cases where there are several equivalent treatments available, patients can benefit from these assay-testing results as a supplement to other clinical data when deciding on a treatment option. There may be some resistance to this approach from some oncologists, but no one has ever shown that harm could result from the use of these technologies.

Why Community Oncology Can Benefit From Cell Function Analysis

[url]http://cancerfocus.org/forum/showthread.php?t=574

World renowned Oncologists are challenging the cancer industry to recognize a Chemo-Screening test (CSRA) that takes the "guesswork" out of drug selection. One of the reasons medical oncologists don’t like in vitro chemosensitivity tests is that it may be in direct competition with the randomized controlled clinical trial paradigm.

[url]http://vimeo.com/72389724

by gdpawel on Sun, 2013-02-03 07:06
Silvana Martino, M.D.

In the August 10, 2012 issue of the Journal of Clinical Oncology, Dr. John Marshall and Dr. Otto Ruech from Georgetown University in Washington, DC, raised the question of how they choose the approved and recommended dose for each chemotherapy drug as well as some of the newer non-chemotherapy drugs.

For each drug there is a recommended dose which is generally multiplied by an individual’s meter-squared number. A person’s meter-square (m2) number is a mathematical relationship of their height and weight.

For example, in the Adriamycin + Cytoxan regimen, the dose of Adriamycin is 60 mg per m2. Therefore, if you are 1.5 m2, one multiplies 60 times 1.5 to calculate a total dose of 90 mg for that individual.

How is that first number arrived at, the Adriamycin number? That number, which is different for every drug, is arrived at experimentally. When a drug is first studied in people, one begins at a low dose calculated from studies done in animals.

As several individuals are treated at the low dose, one observes and records side effects. If there are no intolerable side effects, the dose is increased and a new group of people are treated with the higher dose.

Again, if no intolerable side effects are noted, the dose is further increased for administration to another group. This process continues with increasing doses being used until a dose is reached where the toxicity is considered too high.

The dose just below this toxic level is then chosen as the maximum tolerated dose and recommended for use. This schema which has been used for many years is based on the concept that more is better and if we could only manage to give a higher dose, we would be more effective against a tumor.

What may appear to be a logical conclusion may not actually be a correct biological conclusion. It is not clear that anything in nature really works this way.

For example, if you give a plant too little water, it will not do well. Likewise, if you give it too much water it will also not do well. There is a level in the middle of the two extremes that works best. It is likely, that drug dosing also works in the same manner.

The authors of this article question the method by which they have chosen drug dosing in the past, and suggest that other ways should be considered. Ideally, there should be some aspect of how a drug interacts with its target in a cell that should guide us as to what dose achieves the desired effect in a cell.

Though presently this is difficult to do with most drugs, it must be the ultimate goal. The concept of using toxicity to guide dose calculations cannot be the best solution.

Reference: Maximum-Tolerated Dose, Optimum Biologic Dose, or Optimum Clinical Value: Dosing Determination of Cancer Therapies, Marshall JL, and Ruech OJ, the Journal of Clinical Oncology, Vol 30, No 23, August 10, 2012: pp2815-2816

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