Medicare facing cancer care cuts

Oncotech was an American laboratory providing individual chemoresponse testing as a service to patients and physicians since the mid-1980s. It was co-founded by Drs. Robert Nagourney and Larry Weisenthal. They each left the company in the early 1990s, over disagreements with the controlling investors (4 venture capital companies) over the management and directions of the company. Dr. Weisenthal remained supportive of the company, over the years, and played an important role in securing and, later, retaining reimbursement by Medicare for their services. Drs. Nagourney and Weisenthal each started their own small private laboratories to offer related cell culture testing services. Oncotech continued operations as a privately-held, venture-capital controlled company until February of 2008, when it was acquired by a Danish biotechnology company called Exiqon, Inc. for $45 million (US) in Exiqon securities. Exiqon replaced the Oncotech CEO and installed its own management team, continuing to operate Oncotech as a wholly-owned subsidiary, with a business model centered around providing chemoresponse assays on a (US) national basis — importantly to Medicare patients. In the case of Weisenthal Cancer Group, they opted out of Medicare, effective July 1, 2008, because the reimbursements received from Medicare did not cover our costs of providing our services (although they are still required to file a Medicare claim on your behalf). Exiqon Oncotech, however, depended on Medicare reimbursement to support its business model. In the USA, Medicare coverage decisions for many types of medical services are made at the regional level (Local Coverage Decision or LCD), by the private insurance companies with which Medicare contracts to administer services to Medicare beneficiaries. Previous Medicare contractors for California made the determination that chemoresponse assays qualified as a Medicare covered service. These included the TransAmerica and National Heritage Insurance (NHIC) companies. Most recently, an insurance company called Palmetto was awarded the contract to administer Medicare services for California. Palmetto made the decision to discontinue Medicare payment for chemoresponse assays in California. Last week, Exiqon Oncotech announced that it was discontinuing operations, because of the withdrawal of Medicare reimbursement for its services. This was an entirely understandable, if regrettable, decision. What was in no way understandable — or defendable, for that matter — was the way that they ceased operations. Exiqon Oncotech sent out notifications to its client physicians that it was ceasing operations, virtually immediately. On a single day this past week, they received two dozen specimens from human tumor biopsies via FedEx and other couriers. All of these specimens were simply sent back to the hospitals and clinics which sent the specimens. Physicians were told that there were no other laboratories who could perform the tests requested. While it is true that no other American laboratories have chosen to utilize Exiqon Oncotech’s non-proprietary technology for chemoresponse assays, it was well known to Exiqon Oncotech that there are a number of highly experienced, well qualified, well-published American laboratories which provide this service, utilizing different, but at least comparably valid, technologies (cell-death as opposed to cell-growth endpoints). There have been only two previous, investor-backed, clinical laboratory companies which provided chemoresponse assays as a service to patients, only to make the decision that their business models were no longer viable. These companies were Analytical Biosystems and NuOncology Laboratories. When these latter companies ceased operations they did so in an orderly fashion, giving their clients adequate advance warning and winding down operations at a pace which enabled them to provide testing for those patients and physicians who had already planned and depended upon receiving these services, and these companies were open and helpful in providing their former client physicians with contact information for other laboratories within the US which continued to provide chemoresponse assay services. In the case of Exiqon Oncotech’s two dozen tumor specimens simply marked “return to sender,” It can scarcely be imagined anything more irresponsible. In many of those cases, doubtless the physicians and/or surgeons discussed in advance with their patients the importance of sending their biopsies for cell culture analysis. In some cases, the surgical procedure may have been performed primarily for the purpose of this analysis. In other cases, the patients were doubtless comforted by knowing that this testing was to be performed. Business is business, but, at a certain point, business is also about people, and cancer business is, or should be, about cancer patients. Many are saddened by the shuttering of Oncotech’s doors, 25 years after its founding, and are ashamed at the way in which those doors were apparently shutterd. It should be noted that the Medicare contractor for the state of Pennsylvania continues to provide coverage for chemoresponse assays and that there is an experienced laboratory in Pennsylvania (Precision Therapeutics) which both provides the assays and accepts Medicare reimbursement as payment in full. California laboratories continuing to provide chemoresponse assays with functional profiling (without Medicare reimbursement, possibly requiring patient payment for services) include Rational Therapeutics, Anticancer, Inc., and Weisenthal Cancer Group.

The cell-based assay utilized by the recently defunct Oncotech was the EDR (extreme drug resistance) assay, a soft agarose tritiated thymidine assay, which is a direct descendent of the old original Salmon/Von Hoff Human Tumor Stem Cell or clonogenic assay of the late '70s/early '80s. This is the assay ASCO talks about in their infamous 2004 tech assessment of CSRAs (chemo senstivity and resistance assays). Over twenty year old material that had been discredited twenty years ago.

The so-called ASCO expert panel who did this tech assessment included only three investigators who had ever worked in the field of cell culture assay technology: Dan Von Hoff, Anne Hamburger and a German named Hanauske who worked with Von Hoff in San Antonio. All three were old-line "Human Tumor Stem Cell" (clonogenic) assay workers, who (along with Salmon) convinced the oncologic community that clonogenic assays were the only valid approach to chemosensitivity testing (no one had ever heard of apoptosis back then).

The newer studies of apoptosis occurred during the heyday of the oncogene discovery period in cancer research, where oncogene products were frequently found to be associated with cell growth and where cancer was most prominently considered to be a disease of disordered cell growth. In contrast, the concept of apoptosis (programmed cell death) had yet to become widely recognized. Also unrecognized were the concepts that cancer may be a disease of disordered apoptosis/cell death and that the mechanisms of action of most if not all available anticancer drugs may be mediated through apoptosis.

When problems with proliferation-based assays emerged, there was little enthusiasm for studying cell death as an alternative endpoint. These factors explain the abandonment of research into cell culture assays by American universities and cancer centers by the mid-80s. However, clinical laboratories began to offer cell culture assay with cell-death endpoints as a service to patients in the USA by the late 1980s, and studies of cell culture assays continued in Europe and Asia.

The clonogenic assay failed and it dragged down the whole field of inquiry along with it. So basically, the panel consisted of various oncologists who knew nothing about the technology and data, along with three proponents of a long-ago discredited approach which had nothing to do with the technologies (assays with cell-death endpoints), and with no one at all who understands anything at all about the newer technologies and published data pertaining to them.

In the tech assessments, the authors invented a brand new criterion for validating a laboratory test. The existing standard had always been the "accuracy" of the test. This is true for every single test used in cancer medicine, from estrogen receptors to bacterial culture and sensitivity testing to panels of immunohistochemical stains to diagnose and classify tumor to Her2/neu and CA-125 to MRI scans, CT scans, PET scans and on and on. Yet they never even attempted to review the voluminous literature which defined the "accuracy" of cell death assays, and instead restricted their analysis to a consideration of papers which tried to address the issue of whether the use of the assays actually improved patient outcomes. They lumped together the old and long abandoned technologies (clonogenic assay, subrenal capsule assay, etc.) with the cell death assays. And yet, even in their own review, there were five studies with cell death assays and patient outcomes that were improved in four of the five studies and one negative study wasn't even relevant, because the authors did their tests on subcultured cells (as opposed to "fresh" tumor cultures) and tested the cells in monolayers (as opposed to three dimensional cell clusters). They ignored all studies having to do with "accuracy," the criteria used in tech assessments of all previous laboratory and radiographic tests, and only included studies dealing with "efficacy," a standard never met by any laboratory or radiographic test.

Were they to have reviewed studies showing that the use of estrogen receptor improved treatment outcomes, they would have found no publications at all. Were they to have reviewed papers showing that the use of panels of immunohistochemical stains to subclassify tumors improved treatment outcomes, they would have found no publications at all. Were they to have reviewed studies showing that treatment outcomes were improved through the use of MRI scans or PET scans or CT scans to monitor growth and shrinkage of tumors (for the purpose of influencing the decision to continue the same chemotherapy or to change chemotherapy), as opposed to simply following patients with history, physical, simple plain radiographs, and simple lab tests, they would have found no publications at all.

A "valid" tech review would have started with the published "accuracy" of the tests, and would have included in excess of 2,000 published correlations, in all types of neoplasms from acute leukemia to breast cancer to ovarian cancer to colon cancer and so forth, every single one of which showed that patients treated with drugs "active" in the assays had significantly higher response rates than patients treated with drugs which were "inactive" in the assays. They would have noted a half dozen papers which also showed that patients treated with drugs "active" in the assays also enjoyed significantly longer survivals. They would have made note of the preliminary studies which supported the concept that the use of the assays influenced treatment decisions which resulted in superior outcomes. A "valid" technology assessment would have concluded that the weight of the available evidence supports the decisions of individual oncologists to make at least selective use of these assays in their clinical practices.

What is it that ASCO was saying? Cell culture assays should not be used outside the confines of a clinical trial setting. The same people who maintain that assay-directed therapy should not be used until proven in prospective randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical companies (that, plus fees from speeches they give for these companies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting?

Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis. It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all "relevant" parties that the decisions have been unfavorable.

Opponents of cell culture assays are insesently confused with the old "clonogenic" chemosensitivity assays, the one that Dan Von Hoff had been discredited long ago. When most academic oncologists refer to "chemosensitivity testing," they are virtually always referring to and thinking about the "human tumor stem cell" assay or "clonogenic" assay. Yet this technology hasn't been used by any private sector laboratory for more than twenty years. Nor has it ever been advocated the clonogenic assay as the best cell culture assay. But Von Hoff had tried to sell it, not within the confines of a clinical trial, but as a service to patients.

A study of Von Hoff and associates of the Phoenix-based Translational Genomics Research Institute was presented at the American Association of Cancer Research meeting in Denver, Colorado. Sixty-six patients were treated at nine different U.S. medical centers. All of the patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy. However, after molecular profiling identified precise targets, new treatments were administered that resulted in patients experiencing significant periods of time when there was no progression of their cancer. This clinical trial was unique because patients acted as their own control. They compared each patient's progression-free survival, following treatment based on molecular profiling, to how their tumors progressed under their prior treatment regimens, before molecular profiling. The molecular profiling for this research study was performed by Caris Diagnostics in Phoenix. Patients eligible had to have (1) clear disease progression on prior therapy and (2) received at least two prior lines of systemic chemotherapy. "Success" was defined as a time to progression (TTP) or progression-free survival (PFS) of at least 30% longer than the TTP/PFS of the most immediate prior therapy. A total of 18 patients (of 66) achieved this 30% improvement in time to progression. An interesting question is what percentage of cancer patients in general have increased times to progression with subsequent cycles of empiric chemotherapy, compared to the prior empiric therapy. An additional issue is the precision with which time to progression (TTP/PFS) with prior therapy was measured. With prospective clinical trials, using TTP/PFS as the primary endpoint, there is generally a protocol to standardize follow-up, with physical examination, laboratory tests, and radiographic tests being performed as standardized intervals, so that comparisons of TTP/PFS are meaningful. There would appear to be a problem with utilizing "historical" TTP/PFS on patients enrolled from the general oncology community, in which there is no standardization regarding the methodology for determining disease progression or the intervals at which these measurements are taking place. Additionally, it was not known from what was presented in the abstract, whether or not there was "blinded" assessment of TTP/PFS by outside auditors, or whether "historical" TTP/PFS was assessed and reported by the referring oncologists who enrolled the patients onto the trial. Using the patient as his/her own control using TTP/PFS as endpoint is a useful study design that could be used to assess predictive tests for drug selection when it is not possible to do a randomized trial or to provide a basis to start one. TTP/PFS inversion, ie longer TTP/PFS on treatment selected by test than the standard empirical treatment given just before would be a justified endpoint provided that TTP/PFS is accurately measured. There may be some labs doing drug resistance testing in vitro that have sufficiently long experience and reasonably a large number of patient cases (considerably more than Von Hoff's 66) that has been treated with assay-based therapy after progression on empirical standard. A proposal to show the effect of test selected therapy, i.e. a prospective trial in a number of tumor types at very high costs would be the ultimate proof of efficacy but will probably never be done. In other words, the objective response rate was 10%. Median overall survival for the 66 patients treated with assay-directed therapy was 9.7 months versus the overall survival for all 106 patients of 5 months (but this included the patients who had progressive disease and deteriorated before any treatment at all could be given). The reason patients did not proceed to therapy was disease progression in 75%. Only 62% of all the accrued patients were treated. The drop out of 40 patients may have served to cull the most vigorous from the herd, introducing a bias for survival regardless of intervention.