Research roundup: Docs' views of industry gifts; Chemotherapy payments; Health law an

[News]

How Medicare's Payment Cuts For Cancer Chemotherapy Drugs Changed Patterns Of Treatment -- This study examines the impact that Medicare payment cuts for chemotherapy drugs had on treatment for Medicare beneficiaries with newly diagnosed lung cancer, before and after implementation of the June 2005 new payment system, focusing on five chemotherapy drugs "in common use singly or jointly for lung cancer..."

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[Rich66]

The authors write: "Contrary to concerns about access, we found that the changes actually increased the likelihood that lung cancer patients received chemotherapy. The type of chemotherapy agents administered also changed. Physicians switched from dispensing the drugs that experienced the largest cuts in profitability ... We do not know what the effect was on cancer patients, but these changes may have offset some of the savings projected from passage of the legislation. The ultimate message is that payment reforms have real consequences and should be undertaken with caution" (Jacobson et al., 6/17).

[gdpawel]

The findings of this paper add to the survey done by Dr. Neil Love, entitled "Patterns of Care" http://patternsofcare.com/2005/1/editor.htm

In Jacobson and colleagues' study, physicians switched from dispensing the drugs that experienced the largest cuts in profitability, carboplatin and paclitaxel, to other high-margin drugs, like docetaxel.

One of the results of Dr. Love's survey shows that for first-line chemotherapy of metastatic breast cancer, 84-88% of the academic center- based oncologists (who do not derive personal profit from infusion chemotherapy) 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 community-based oncologists (who do derive personal profit from infusion chemotherapy), only 18% prescribed the oral dose drug (capecitabine), while 75% prescribed infusion drugs, and 29% prescribed the expensive, highly remunerative drug docetaxel. (Patterns of Care: 2005,Vol 2,Issue 1).

While Newhouse and Earle's previous Michigan/Harvard study, "Does reimbursement influence chemotherapy treatment for cancer patients?" [Health Affairs 25, no. 2 (2006)] showed results before the new Medicare reform, Love's "Patterns of Care" study showed results that the Medicare reforms were still not working. This new study adds another "smoking gun" about the chemotherapy concession issue.

I believe that all of these studies showed results that the Medicare reforms are still not working. An impossible conflict of interest still exists. And 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. It is way past time to take medical oncologists out of the retail pharmacy business and let them be doctors again.

The current issue of Oncology News International (June 2010, V 19, No 6) quotes a Duke University study of the use of high-tech cancer imaging, with one representative finding being that the average Medicare lung cancer patient receives 11 radiographs, 6 CT scans, a PET scan, and MRI, two echocardiograms, and an ultrasound, all within two years of diagnosis. A study co-author (Dr. Kevan Schulman) asks: "Are all these imaging studies essential? Are they all of value? Is the information really meaningful? What is changing as a result of all this imaging?"

Why is it that oncologists are so accepting of high tech, expensive imaging studies, yet so reluctant to consider the use of cell culture diagnostic tests? For one thing, clinical trials virtually always have time to disease progression as a primary endpoint. Without the imaging studies, one can't get accurate time to progression data. So these are tests performed for the benefit of drug companies seeking new drug approval, for clinical investigators seeking contracts and publications, and for clinicians seeking an easy way to make clinical decisions (and, occasionally, seeking income enhancement).

In the absence of information provided by cell culture testing, oncologists have complete freedom to choose between a myriad of drug regimens. The proven basis on which they make these selections, by and large, is on the benefit a given regimen provides to the oncologist (or academic institution). Cell culture testing threatens this freedom of choice. There's absolutely nothing in it for the oncologist or academic medical center (unlike, for example, imaging studies).

[Rich66]

How is it that Academic oncologists have different reimbursements than community clinics?

Unfortunately, cell based assays don't seem to test for sensitivity to most endocrine therapies which are at the lower end of the cost curve.
Cell based analysis could be a great way to check for off label benefits.
Of course, repeated biopsies for test tissue isn't always possible.
Another issue is the possible need to keep the infusion rooms full.
Let's hope the repeatedly delayed Medicare reimbursement cuts (21%) don't ever happen. That could increase the influence of drug choice incentives.

[gdpawel]

Office chemotherapy has served as an incentive to overtreat with infusion chemotherapy and to encourage the patient to receive 2nd, 3rd, and 4th line chemotherapy, regardless of the likelihood of meaningful benefit. This kind of system creates hopeless conflicts of interest, in that certain forms of therapy are much more remunerative than others. Of course, ASCO has never felt the need to perform clinical trials to determine whether or not treatment outcomes and patient satisfaction are altered by profit incentives.

On the other hand, large academic cancer institutions that are soulfully involved in clinical trials may feel a subtle pull towards getting patients involved in those trials. Some researchers may discourage patient empowerment so they can call the shots through these trials. They've even broaden their appeal by encompassing community hospital oncology practices. These researchers seem to have a readiness to believe that the clinical trial is more reasonable for the patient and that other options do not offer an advantage. Many of these academic researchers, supported by specialty medical societies and other fraternal organizations, are often paid phenomenal amounts of money for enrolling patients in clinical trials, making financial gain the key motivation.

Functional profiling assays can test for sensitivity to hormonal therapies like tamoxifen. It can include anti-vascular drugs, such as Avastin, Sutent, Nexavar, Tarceva, Iressa, Tykerb, both as single agents and in combination with each other and with traditional cytotoxic agents and hormonal therapies. It can simultaneously test for direct anti-tumor activity and for antivascular activity against the microvascular present within the three dimensional tumor cell clusters. High-dose tamoxifen can potentiate chemotherapy through inhibition of p-glycoprotein and/or inhibition of protein kinase c.

[Rich66]

I guess I don't understand why Academic oncs don't get the same payback from chemos that community oncs do.
I can definitely understand involvement in a trial might influence patient management. If there is a kickback for enrollment, that doesn't seem good. Likewise, if there is incentive to select patients who are perceived to be more likely to do well/produce positive results, similarly questionable.

I don't doubt that cellular assays could test for any myriad of agents, it's just that when I contact them, endocrine testing seems very limited..I'm only aware of occassional Tamoxifen testing. I haven't encountered Faslodex, Femara, Arimidex or Aromasin as options.

[gdpawel]

Well, high-dose tamoxifen can potentiate chemotherapy. Perhaps the same cannot be said for Faslodex, Femara, Arimidex or Aromasin?

[Rich66]

To my mind, the starting point is that even in viscerally metastatic settings, endocrine monotherapy can be effective. Even combinations of endocrine agents (AI+SERM) may be effective. And there is a fair amount out there to support certain chemo/endocrine and biological/endocrine therapies as synergistic.
I have heard that endocrine therapies by themselves may take longer than chemos to show measurable effect. So perhaps cell assays are too brief to emulate that scenario.
But if it were possible to know in advance the likelihood that (generally) lower toxicity endocrine therapy could give benefit, that would be a big help to many.

[gdpawel]

The immunohistochemical (IHC) assay is supposed to accurately define responders to endocrine therapy.

The estrogen receptor (ER) assay is used to determine a number of very important things. Which patients with early breast cancer should receive adjuvant chemotherapy. Whether or not chemotherapy should include hormonal therapy. In the advanced setting, whether chemotherapy should be given versus hormonal therapy. These are all very important decisions. The stakes are high with the ER assay, in terms of potentially harming the patient.

The ER assay is broadly accepted to be the number one prognostic test in all of clinical oncology, from the standpoint of drug selection. The test is used to make gravely important treatment decisions, generally between cytotoxic chemotherapy on one hand or hormonal therapy on the other hand or the combination of chemotherapy and hormonal therapy. In some situations, this test is used to determine if patients are to receive any drug treatment at all. In contrast, cell culture assays are simply used to select between treatment regimens with otherwise equal efficacy in patient populations -- situations in which the choice could be made by a coin toss or, more commonly, on the basis of remuneration to the treating physician, with equivalent results on a population basis, though certainly not at the level of the individual patient. So, if anything, the "bar" should be higher for the ER assay than for cell culture assays. So what data exist to "validate" the most important predictive laboratory test in clinical oncology?

The history of the ER test is that it was originally developed as a complicated biochemical test, generically called the "radioligand binding assay" (RLB assay). The RLB assay was "validated" in the 1970s and very early 1980s by means of retrospective correlations with clinical outcomes for patients treated with hormonal therapy. Overall, in retrospective correlations with hundreds (not thousands) of patients, the RLB assay was found to be about 60% accurate in predicting for treatment activity and 90% accurate in predicting for treatment non-activity. In other words, an RLB assay "positive" tumor had a 60% chance of responding to hormonal treatment. An RLB "negative" tumor had a 10% chance of responding to hormonal treatment and were more likely to recur after "curative" surgery. There were never any prospective randomized Phase 3 trials to prove that either performing or not performing the test made a difference in treatment outcomes. There were just retrospective studies correlating assay results with clinical response to treatment.

In the early 1980s, the technology was changed from the complicated RLB assay, which could be done only in a few highly specialized laboratories to a much more simple immunohistochemical (microscope slide) assay, which could be done in most pathology labs. This newer assay was initially validated by comparison of the RLB assay in the specialized labs. The IHC assay was validated in studies in which archival specimens were batch processed in the same time frame by a single team of laboratory workers. There were not real world conditions, in which specimens are accessioned, processed, stained, and read by different people, at different times, using different reagents. Various studies have shown that there is often a broad variation of results between different laboratories, in formal proficiency testing studies. And yet, hundreds of thousands of cancer patients have had life and death treatment decisions based on these tests (the IHC test for Her2/neu is an even more egregious example, and the IHC test for EGFR is more egregious still).

The new assay correlated reasonably well with the older assay and it replaced the older assay. No one ever did a prospective or even retrospective study to show how the newer assay correlated with and predicted for response to treatment. It was just "the old assay works and the new assay correlates (in a few, highly specialized laboratories) with the old assay; so the new assay is OK to use."

In 2006, there was finally a study (in a highly sophisticated laboratory) showing how well the new assay predicts. A study on the ability of the IHC ER assay to predict for clinical reponse to hormonal therapy (Yamashita, et al. Breast Cancer 13:74-83, 2006). In a very small study, which was retrospective, meaning they could draw the best possible cut off lines after the fact, in a total of 75 patients studied, they found that ER positive patients had a 56% response rate, while ER negative patients had a 20% response rate. And these were data from a laboratory which certainly had above-average expertise in performing the test. Correlations which are vastly inferior to those obtained in much bigger and better studies with cell culture assays.

Here we have the most universally admired and utilized predictive test for treatment selection in all of clinical oncology, and it is validated only by the most retrospective and limited of data, and, even then, the predictive accuracy of the test is vastly inferior to that of the cell culture assays being performed. What in the world is the justification for claiming that the "bar" should be higher for using the cell culture assays to choose between docetaxel and 5FU (or capecitabine) in breast cancer, than to use the ER IHC test to select between tamoxifen and paclitaxel/cyclophosphamide in breast cancer?

If a highly sophisticated lab gets such lousy correlations, then you can imagine the accuracy of tests done in community hospitals. And yet every patient with breast cancer gets this test and in almost every patient the information is used to make much more critical decisions than in the cases of both the Her2/neu assay and also the cell culture assay.

Questions regarding the best methodology of HER2 testing as well as the clinical applications of such testing remain. Ultimately, the most useful test will be the one that correlates best with HER2-mediated cellular biology and clinical outcome. The comparison of HER2 detection with clinical end points will allow clarification of the predictive value of a particular method.

The degree of tumor reduction in size achieved by conventional chemotherapy vs endocrine therapy may well reflect the sensitivity of micrometastases to systemic chemotherapy and this could be a highly significant prognostic feature in patients with breast cancer.

[Rich66]

Ok...all of that further supports the notion that competent cell based sensitivity testing for various endocrine agents is needed.
I'm just saying that even the companies that do sensitivity testing seem to leave endocrine considerations underinvestigated.
The question in my mind is why. Are the available procedures not capable? They seem focused on traditional chemos and targeted biologicals.

[gdpawel]

There is a very strong bias in the U.S. medical community towards chemotherapy/targeted therapy over hormonal therapy. I understand Europeans are more inclined to treat patients with hormonal therapy that American oncologists would treat with chemo. Another factor has been the lucrative reimbursement policies that U.S. oncologists get for using chemotherapy/targeted therapy as opposed to hormonal treatment or even to give no drug treatment. Will physicians and their patients consider Oncotype Dx or MammaPrint to forgo both chemotherapy/targeted therapy and hormonal therapy? Sometimes you're forced to go with the flow.