Lack of Meaningful Clinical Trials

gdpawel

We have produced an entire generation of investigators in clinical oncology who believe that the only valid form of clinical research is to perform well-designed, prospective, randomized trials in which patients are randomized to receive one empiric drug combination versus another empiric drug combination.

What passes for a successful experiment in clinical oncology? Henderson, et al, entered 3,100 breast cancer patients in a prospective, randomized study to compare cyclophosphamide with doxorubicin alone versus cyclophosphamide/doxorubicin plus Taxol (in the adjuvant, pre-metastatic setting). The results were microscopically positive, at best, and cannot begin to justify the enormous financial and human resources expended (while making no effort at all to test and improve methods to individualize treatment).

But these results changed the face of the adjuvant chemotherapy of breast cancer. Cyclophosphamide+Doxorubicin+Taxol became standard of care. Taxol recently went off patent. Now the thrust is to identify on-patent therapy which is microscopically better in clinical trials of one-size-fits-all treatment. Already, the community-based oncologists are migrating to Cyclophosphamide+Doxorubicin+Docetaxel (expensive/remunerative) so what was the purpose of doing that 3,100 patient prospective, randomized Henderson study?

Some academic oncology groups have as their major ovarian cancer project, clinical trials to show that Taxotere (Docetaxel) can now be the new "standard" therapy. Patients are treated with Taxol plus Carboplatin. If (or when) Taxol plus Carboplatin doesn't work, they'll be crossed over to Taxotere, a drug which is mostly (if not completely) cross resistant with Taxol, for which the cancer clinic will collect several thousand dollars per patient from the large pharmaceutical company if and when they are treated with this drug (delaying the patient's treatment and possibly subjecting them to a horrible death).

There were a couple of recent clinical trials, one dealt with breast cancer and the other dealt with lung cancer; both of them had the drug Taxotere (Docetaxel) in their repective studies. These kind of chemotherapy studies have never yielded any kind of meaningful advance. It's being done simply because Taxotere (Docetaxel) is an on-patent drug which has a Big Pharma sponsor willing to spread around a lot of money to identify and expand indications.

We are getting an expanding list of treatments which are partially effective in a minority of patients, ineffective in a majority, remarkably effective in a few, while being enormously expensive. The fastest way to improve things is to match treatment to the patient.

All the rigorous clinical trials identified are the best treatments for the average patient. But cancer is not an average disease. Cancer is far more heterogeneous in response to various individual drugs than are bacterial infections.

The tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient's cancer. There are over 100 different therapeutic drug regimens which any one or in combination can help cancer patients. The system is overloaded with drugs and underloaded with wisdom and expertise for using them.

In clinical trials, many patients are excluded because they could not complete the rather arduous treatment. So randomized comparisons are of healthier treated patients against all the controls, rendering a lot of trials invalid. 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 present system exists to serve the clinical investigators and the clinical oncologists, but not to serve the best interests of the cancer patients.

One of the main problems in providing effective chemotherapy is the situation that every patient is unique. Tumors grow and spread in different ways and their response to treatment depends on these characteristics. The amount of chemotherapy that each patient can tolerate varies considerably from patient to patient. Therapeutic protocols currently in use are limited in their effectiveness because they are based on the results of clinical trials conducted on a general patient population, yet no two patients are alike.

Recent NCI data showed that U.S. cancer mortality rates have increased and age-adjusted cancer mortality rates in response to treatment have not improved in several decades, despite the introduction of many new drugs. There is a mind-set of cancer culture that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that rewards academic achievement and publication over all else. Tumor shrinkage should not be the criteria for approving cancer drugs.

A patient responds to therapy when their tumor shrinks, but apparently this has nothing to do with survival. A tumor responds, that is, shrinks a little, then quickly grows and spreads. The cancer comes back with a vengeance and the cancer patient is given a death sentence by his/her oncologist who will wash his hands of it.

Experimenting on cancer patients is permissible behavior for medical oncologists. They have been allowed free access to their bodies with no accountability. After a cancer patient dies, there are no repercussions. The oncologist's compensation, reputation, position, career prospects and opportunities for advancement have no relationship to whether or not his patients live or die.

gdpawel · Posted: Wed Aug 10, 2005 6:25 pm Post subject: GOG Clinical Trial

The Gynecologic Oncology Group (GOG) has decided to move forward with a study in platinum-resistant ovarian cancer, utilizing the Oncotech "EDR" assay to direct chemotherapy. The design is one that is bound to fail.

This assay is specifically designed to identify "inactive" drugs and Oncotech reports even state that the assay results should "not" be used to identify "active" drugs. A prior paper by Oncotech already established that the EDR assay can only identify a small percentage of patients who will "not respond" but then when the results were used to select an non-EDR alternative, it did not provide responses. In this light, the EDR assay has the advantage of telling you who will "not respond" but cannot in any way change the negative outcome by selecting an "active" alternative.

A pilot study, in which two GOG investigators used the Oncotech EDR assay to identify the "best" treatment regimens for platinum-resistant ovarian cancer was negative, with both assay directed and non-assay directed patients having the same median survival.

Proposals for a head to head comparison of the Oncotech EDR assay with the DISC (cell death assay) and the ATP (another cell death) assay have been submitted to GOG since 1992. They have refused to do the study and have, in the ensuing 13 years, received copious financial support from Oncotech, which seems to be the only relevant criterion motivating the GOG to perform clinical trials of assay-directed therapy.

I believe that a separate study, a front-line randomized trial with the primary endpoint being "time to disease progression," secondary endpoint being "overal, long-term survival," and third endpoint being "correlation between assay-directed and physician's choice therapy, would be more in keeping with positive results.

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." Cell-death assays (DISC, MTT, ATP and Caspase 3/7) correlate very well with each other on direct comparisions of different methods.

Different methods of Chemotherapy Sensitivity and Resistance Assays (CSRA) results should be applied in choosing a particular drug regimen to be used in treating an individual patient's cancer. CSRAs will sort the different reasonable treatment regimens into the different groups (above-average, avereage, below-average and very below-average), which would direct attention away from regimens "less" likely to provide benefit and toward regimens which are "more" likely to provide benefit.

I am increasingly convinced, along with many others, that the best trial is a first-line study, no prior therapy, assay versus a control. However, the same people who maintain that assay directed therapy should not be used until "proven" in prospective randomized trials are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards, and these people have, through the years, refused, denied, and rejected any and all efforts made to get these trials off the ground.

All the while, at the same time vigorously defending a system in which chemotherapy gets selected more on the basis of remuneration and convenience to the oncologist than on the basis of the biology of the cancer.

mikes · Senior User Joined: 25 Jul 2005 Posts: 143

[quote]
for which the cancer clinic will collect several thousand dollars per patient from the large pharmaceutical company if and when they are treated with this drug
[/quote]

Very interesting. How does this work?

I noticed from looking at our insurance statements that a typical visit for chemo costs over $3000.00.

gdpawel

In an academic oncology setting, this experiment in clinical oncology is to identify an "on-patent" therapy which is microscopically (1%) better in at least one clinical trial so that platinum/Taxotere can now be the new standard therapy (instead of a platinum with Taxol, which is now "off-patent"). It's being done simply because Taxotere (Docetaxel) is an on-patent drug (and more renumerative), which has a Pharma sponsor willing to spread around a lot of money to identify and expand indications (they're even looking at using Taxol to coat stents in cardio stent procedures). As noted above, if (or when) Taxol plus Carboplatin doesn't work, they'll be crossed over to Taxotere, and be renumerated for their efforst. The system exists to serve the clinical investigators and the clinical oncologists, but not to serve the best interests of the cancer patients.

The largest ever international clinical trial of treatments for ovarian cancer, had concluded that standard chemotherapy drug treatments (like single agent Carboplatin) for women with ovarian cancer are equally as effective adding the drug paclitaxel (Taxol) to those treatments, and also cause fewer side effects. The surpise finding was published in the August 17, 2002 edition of The Lancet.

The 2074 women, from 130 clinical centers in eight countries that participated in the trial were randomly assigned to be treated with standard drugs - carboplatin or a combination of cisplatin, doxorubicin and cyclophosphamide - or a combination of paclitaxel and carboplatin. The study's results suggest that standard treatments such as carboplatin may be considered the preferred treatment as they have fewer side effects.

Basically, oncologists prescribe patients one standard empiric chemotherapy regimen after another, until they find one that works. This is also called "physician's choice" therapy. This often can expose patients to the side effects of chemotherapy, without showing any cancer-killing results. Guesswork can be done in a laboratory instead. The process of targeting treatment directly to the tumor cells, can spare healthy cells the worst of chemothrapy's damage. A push in oncology toward protecting patients against drugs and treatments is exploding.

The tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of tumor tissue, apply different chemotherapy treatments to it and examine the results to see which drug or combination of drugs do the best job killing the tumor cells.

The problem with standard empiric chemotherapy is that it's like taking a machine gun and shooting everything in the way and hoping you get the cancer cells along with that. If you target the therapy, meaning you're only treating patients who will benefit from the treatments, you'll eliminate patients from having undue chemotherapy side-effects without any benefit.

There are many cancer drug regimens (over 100), all of which have approximately the same probability of working (there are over 400 drugs in the pipeline). The tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient's cancer.

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