Chemosensitivity Testing – What It Is and What It Isn’t

Several weeks ago I was consulted by a young man regarding the management of his heavily pre-treated, widely metastatic rectal carcinoma. Upon review of his records, it was evident that under the care of both community and academic oncologists he had already received most of the active drugs for his diagnosis. Although his liver involvement could easily provide tissue for analysis, I discouraged his pursuit of an assay. Despite this, he and his wife continued to pursue the option.

As I sat across from the patient, with his complicated treatment history in hand, I was forced to admit that he looked the picture of health. Wearing a pork pie hat rakishly tilted over his forehead, I could see few outward signs of the disease that ravaged his body. After a lengthy give and take, I offered to submit his CT scans to our gastrointestinal surgeon for his opinion on the ease with which a biopsy could be obtained. I then dropped a note to the patient’s local oncologist, an accomplished physician who I respected and admired for his practicality and patient advocacy.

A week later, I received a call from the patient’s physician. Though cordial, he was puzzled by my willingness to pursue a biopsy on this heavily treated individual. I explained to him that I was actually not highly motivated to pursue this biopsy, but instead had responded to the patient’s urging me to consider the option. I agreed with the physician that the conventional therapy options were limited but noted that several available drugs might yet have a role in his management including signal transduction inhibitors.

I further explained that some patients develop a process of collateral sensitivity, whereby resistance to one class of drugs (platins, for example) can enhance the efficacy of other class of drugs (such as, antimetabolite) Furthermore, patients may fail a drug, then be treated with several other classes of agents, only then a year of two later, manifest sensitivity to the original drug.

Our conversation then took a surprising turn. First, he told me of his attendance at a dinner meeting, some 25 years earlier, where Dan Von Hoff, MD, had described his experiences with the clonogenic assay. He went on to tell me how that technique had been proven unsuccessful finding a very limited role in the elimination of “inactive” drugs with no capacity to identify “active “drugs. He finished by explaining that these shortcomings were the reason why our studies would be unlikely to provide useful information.

I found myself grasping for a handle on the moment. Here was a colleague, and collaborator, who had heard me speak on the topic a dozen times. I had personally intervened and identified active treatments for several of his patients, treatments that he would have never considered without me. He had invited me to speak at his medical center and spoke glowingly of my skills. And yet, he had no real understanding of what I do. It made me pause and wonder whether the patients and physicians with whom I interact on a daily basis understand the principles of our work. For clarity, in particular for those who may be new to my work, I provide a brief overview.

1.    Cancer patients are highly individual in their response to chemotherapies. This is why each patient must be tested to select the most effective drug regimen.

2.    Today we realize that cancer doesn’t grow too much it dies too little. This is why older growth-based assays didn’t work and why cell-death-based assays do.

3.    Cancer must be tested in their native state with the stromal, vascular and inflammatory elements intact. This is why we use microspheroids isolated directly from patients and do not grow or subculture our specimens.

4.    Predictions of response are not based on arbitrary drug concentrations but instead reflect the careful calibration of in vitro findings against patient outcomes – the all-important clinical database.

5.    We do not conduct drug resistance assays. We conduct drug sensitivity assays. These drug sensitivity assays have been shown statistically significantly to correlate with response, time to progression and survival.

6.    We do not conduct genomic analyses for there are no genomic platforms available today that are capable of reproducing the complexity, cross-talk, redundancy or promiscuity of human tumor biology.

7.    Tumors manifest plasticity that requires iterative studies. Large biopsies and sometimes multiple biopsies must be done to construct effective treatment programs.

8.    With chemotherapy, very often more is not better.

9.    New drugs are not always better drugs.

10.   And finally, cancer drugs do not know what diseases they were invented for.
While we could continue to enumerate the principles that guide our practice, one of the more important principles is humility. Medicine is a humbling experience and cancer medicine even more so. Patients often know more than their doctors give them credit for. Failing to incorporate a patient’s input, experience and wishes into the treatment programs that we design, limits our capacity to provide them the best outcome.

With regard to my colleague who seemed so utterly unfamiliar with these concepts, indeed for a large swath of the oncologic community as a whole, I am reminded of the saying “There’s none so blind as those who will not see.”

The Death of Christopher Hitchens

Among the more colorful writers, orators and pundits in the later part of the 20th Century and the early part of the 21st was Christopher Hitchens. Born in England in 1949, he moved to the United States where he became famous for his deeply held political views. An outspoken critic of injustice, he called it as he saw it. While his political leanings were mostly liberal, he was willing to take on the establishment on both sides of the political isle when he saw injustice and political hypocrisy.

Christopher Hitches died at age 62 from cancer of the esophagus. Although unapologetic for his use of alcoholic beverages and tobacco products, his lifestyle may have contributed to his diagnosis. What saddens me most is the possibility that he could have done better. And didn’t.

Like so many celebrities when they are diagnosed with cancer, Hitchens entered a realm that I call, “social medicine.” Not to be confused with socialized medicine and related political issues, social medicine is the process whereby the rich and famous receive care from the “right” doctors. These luminaries, through their channels and connections, are hand carried to the most famous physicians in the country. Their prominent and widely published ivory tower investigators then provide the best care money can buy. Yet, more often than not it is exactly the same therapy that they would have received from their home-town oncologists, who read the same journals, attend the same meetings and adhere to the same NCCN guidelines as the “best and the brightest” academics. We then conveniently chalk these patient’s failures up to the biology of the disease and the patient’s drug resistance rather than examining the more discomforting reality that protocol therapy doesn’t work for famous patients any better than it does is for anyone else.

But what if these patients just got the wrong treatment? What if the drugs these doctors chose were the very best for many, but not right for them? What if the right treatment was just right around the corner, but these prominent academics couldn’t see it? What if these patients had submitted a tumor sample for an EVA-PCD® assay and knew which drug or combinations would kill their cancer cells?

It isn’t that Christopher Hitchens or Steven Jobs are more important than any other patient. Their collective suffering and the losses to their families are no greater than any other cancer patient who confronts this illness. It’s just that they are famous and we know about it from the beginning to the end. We watch as these patients suffer through the toxicities and side effects of randomly administered therapies. And, in the case of Hitchens we are provided a blow-by-blow description in his writings. Unlike other patients who seek their care outside of the limelight, these celebrities are above the fray, protected by their handlers, PR agents and managers – they are unapproachable. With Jobs or Hitchens I would have relished the opportunity to offer any assistance possible, and through contacts at Apple I actually tried, but to no avail.

These individuals suffer and die in the public eye. Like salt in a wound, investigators like my colleagues and myself who are engaged in the pursuit of better, more intelligently delivered therapies, suffer with them. No, they are not more important, but it just seems so when you watch it every day on television, online, or in the print media, you clearly see an “in your face” example of a failing paradigm of cancer therapeutics.

Paradigm Shifts

Scientific dogma in all disciplines is slow to change.

I am again reminded of this by the recent publication of a book by Dava Sobel, “A More Perfect Heaven: How Copernicus Revolutionized the Cosmos” about the life and times of Nicolaus Copernicus. I use the term “dogma” intentionally, for Copernicus lived in the tumultuous times of the Protestant religious movement. Thus, his revolutionary concept of a heliocentric (sun-centered) solar system clashed with both scientific and religious dogmas.

Copernicus himself, a polymath, was a linguist, astronomer and a physician. His original observations in 1514 so conflicted with existing thinking regarding the geocentric solar system, that his treatise on the topic wasn’t published until 1543 – just a year before he died.

Copernicus, Galileo and Giordano Bruno — who himself was burned at the stake in 1600 for having the temerity to suggest that there might be other solar systems in the universe — were all victims of prevailing thinking that would not and could not yield to the burgeoning new understanding contained within Copernicus’s carefully constructed view of the cosmos.

These experiences are instructive, for they shine the light of day upon dogma in contemporary science and medicine. Failed attempts to utilize human tissue for the study of tumor biology led to an entire generation of cancer researchers to erroneously dismiss this profoundly important field of endeavor. No amount of data or cogent scientific argument could dissuade these authorities from their “dogmatic” position that human tissue could not predict cancer response. When one colleague in the field compiled all of the existing data and showed in an analysis that patients who received assay-sensitive drugs responded statistically, significantly more often than those who received assay-resistant drugs (p= 0.00000001) it had absolutely no impact on the “experts” opinions.

Perhaps today, 500 years later, we can learn something from Copernicus and his experience with scientific dogma.

English Patients Denied Access to Ipilimumab

Among the more interesting discoveries in recent years have been two breakthroughs in the management of malignant melanoma. One drug, vemurafenib, a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation. The second drug ipilimumab, offered commercially from Bristol-Meyers Squibb as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While vemurafenib has a somewhat narrow target population, ipilimumab targets may extend to a broader range of melanoma patients and will likely find a role in other cancers.

The data supporting ipilimumab’s use in advanced melanoma was reported in a 2010 Phase III trial, which provided a superior median survival for those treated with the drug over those who received a placebo. Superior one and two-year survivals were also reported. Unfortunately, this did not rise to the level that met the standards of the English watchdog organization, National Institute for Health and Clinical Excellence (NICE). The chief executive of NICE did admit that the drug could “potentially be very effective for a small percentage of patients.” Unfortunately, under current NICE guidelines, that small percentage of patients will not have access to the drug.

This is not the first time that a drug, found effective for the treatment of a subpopulation of patients has been denied approval based upon cost efficacy and the comparatively limited population of patients who stand to gain.

The role of Avastin in breast cancer represents a similar dilemma for those patients who might benefit but cannot afford the out-of-pocket expenses. Indeed, NICE originally denied approval to bortezomib, a highly active drug for the treatment of multiple myeloma, based upon similar cost considerations.

What ipilimumab, Avastin and bortezomib have in common is that they are harbingers of the coming conflict between patients-in-need and society’s capacity to cover the increasing costs of cancer therapy. Cost efficacy questions will only be resolved when we have the capacity to identify likely responders prior to therapy, enabling us to use drugs only in those patients with the highest expectations of response. Marginal overall benefits that come at high price will continue to fail until we redouble our efforts to refine the process of drug selection for individual patients. Janet Woodcock, MD, from the FDA once said, that we need “a critical path” from bench to bedside to guide clinical decisions. The human tumor primary culture functional analyses that we employ can provide that critical path and we would hope limit the need for the broad-brush policy decisions that are being handed down by NICE and similar entities both here in the U.S. and abroad.

Faster than the Speed of Light

Last week, scientists at CERN, the European particle physics laboratory located outside Geneva, Switzerland, conducted an experiment, the results of which now challenge one of the most fundamental principles of modern physics. I speak of Albert Einstein’s 1905 declaration that the speed of light is an absolute and that nothing in the universe could travel faster.

E = MC2, the principle under which nuclear energy and weapons have been developed, as well as all of the corollaries of the theory of relativity were called into question when a series of sub atomic particles, known as neutrinos traveled from Switzerland to Italy at a speed that was 1/60 of a billionth of a second faster than the speed of light. What has followed has been a flurry of interest by departments of physics all over the world. Confronted with this new finding, these investigators will diligently seek to reproduce or refute the findings.

This was not the first time that someone challenged the primacy of Einstein’s 1905 theory. Indeed, during the 1930s, for largely political and anti-Semitic reasons, the Nazi party attempted to disprove Einstein. Yet, all of the political meanderings, personal vendettas and intellectual jealousy could not unseat Einstein’s guiding principle. That is, until objective evidence in the form of the CERN experiments came to the fore.

Science — however lofty — and scientists — however highly regarded — dwell in the same realm as all the rest of us mere mortals. Their biases and preconceived notions often cloud their vision. Comfortable with a given paradigm, they hold unyieldingly to its principles until they are forced, however unwillingly, to relinquish their belief systems in favor of a new understanding. I write of this in the context of laboratory-based therapeutics – a field of scientific investigation that has provided firm evidence of predictive validity. These technologies have improved response, time to progression and survival for patients with leukemia, ovarian, breast and lung cancers, as well as melanoma and other advanced malignancies. Thousands of peer-reviewed published experiences have established the merit of human tumor primary cultures for the prediction of response. Investigations into the newest classes of targeted therapies are providing new insights into their use and combinatorial potential.

Yet,  while the physicists of the world will now rise to the challenge of data, the medical oncologists and their academic counterparts refuse to accept the unimpeachable evidence that supports  the validity of assay-directed therapy. Perhaps if our patients were treated at CERN in Geneva,  their good outcomes would receive the attention they so richly deserve.

Is Rationed or Rational Medical Care In Our Future?

We are witness to a sea change in medicine. Doctors and nurses are being replaced by “healthcare providers;” medical judgment is being phased out in favor of therapeutic algorithms; and the considered selection of treatments is giving way to rigid therapy guidelines. All the while, the regulatory environment increasingly precludes the use of “off label” drugs. It is understandable why insurers, governmental entities and hospital chains might welcome these changes. After all, once therapies have been reduced to standardized formulae, one can predict costs, resource allocations and financial exposures to the twentieth decimal place. For many medical conditions, these approaches will provide adequate care for the majority of patients.

But, what of the outliers? What of those complicated disease entities like cancer, whose complexity and variability challenge even the best minds? How do we bang the round peg of cancer therapy into the square hole of formulaic care?

There are several answers. The first is the least attractive: In this scenario, predicated upon cancer’s incidence in an older population, at the end or beyond their productive (and reproductive) years, we simply don’t allocate resources. Most civilized modern societies haven’t the stomach for such draconian measures and will seek less blunt instruments.

The second is a middle of the road approach. In this scenario, standardized guidelines that provide the same treatment to every patient with a given diagnosis are developed. Every medical oncologist knows the drill: FOLFOX for every colon cancer, Cytoxan plus Docetaxel for every breast cancer and carboplatin plus paclitaxel for ovarian cancer. The treatments work adequately well, the schedules are well established, the toxicities are well known and no one is cured. The beauty of this approach is that the average patient has an average outcome with the average treatment. By encompassing these regimens into standardized algorithms, we may soon be able to eliminate physicians entirely — first, with nurse practitioners and physician’s assistants and, ultimately, with computers. What is perhaps most surprising about this scenario has been the willingness of the medical oncology community to embrace it, a sort of professional self-induced extinction. At the time of this writing, this is the predominant model and is becoming increasingly entrenched under the auspices of NCCN and related guidelines. The operative term being guidelines, in as much as these “guidelines” are rapidly becoming “dictates.”

The final approach, and the one I find most appealing, is that which utilizes the clinical, scientific, laboratory and technical acumen of the physician to the maximum. Combining diagnostic skill with scientific insight, the physician becomes the captain of the ship, who must assume control from the autopilot once the vessel has entered the tempest and use his/her experience and training to guide the patient to a soft landing. This requires the capacity to think and demands an up-to-date knowledge of many disciplines. The judicious application of laboratory-directed approaches can further enhance the skillset, introducing objective data that is then used to guide drug and treatment selections. Predicated upon an understanding of the patient’s tumor biology, cancer therapy becomes an intellectual exercise that draws upon literature, and a knowledge of pharmacology and physiology. Adding the wealth of newly developed signal inhibitors to the mix only enhances the odds of a good outcome.

This approach improves responses and eliminates futile care. It provides patients the opportunity to participate in their own management. Correctly delivered, it would make available to every patient any FDA-approved drug. While it would seem to some that this would open the floodgates of drug use, I would strenuously disagree. It would instead limit drug administration to those patients most likely to respond, a goal currently pursed by virtually every major institution, yet accomplished by none. While a handful of targeted approaches have come to fruition in the last few years — erlotinib for EGFR mutation, and sunitinib in kidney cancers — most of the molecular profiling being done today doesn’t aid in the selection of therapy but instead provides negative information (e.g. RAS in colon cancer, ERCC1 over expression in lung) enjoining the physician against the use of a given agent but then leaving the unfortunate patient to fend for themselves amidst a panoply of randomly chosen options.

This is the approach that I have chosen to adopt in my own care of cancer patients. Our rapidly growing successes in ovarian, breast, lung, melanoma, leukemias and other diseases could and should serve as a model for others.

Targeted Therapies for Cancer Confronts Hurdles

The September 1 issue of the ASCO Post, a periodical published by the American Society of Clinical Oncology, features an article entitled “Research in Combining Targeted Agents Faces Numerous Challenges.” Contributors to the article by Margo J. Fromer, participated in a conference sponsored by the Institute of Medicine. These scientists representing both public and private institutions examined the obstacles that confront researchers in their efforts to develop effective combinations of targeted agents.

One of the participants, Jane Perlmutter, PhD, of the Gemini Group, pointed out that advances in genomics have provided sophisticated target therapies, but noted, “cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.”

James Doroshow, MD, deputy director for clinical and translational research at the NCI, said, “the mechanism of actions for a growing number of targeted agents that are available for trials, are not completely understood.” He went on to say that the “lack of the right assays or imaging tools means inability to assess the target effect of many agents.” He added that “we need to investigate the molecular effects . . .  in surrogate tissues,” and concluded “this is a huge undertaking.”

Michael T. Barrett, PhD, of TGen,  pointed out that “each patient’s cancer could require it’s own specific therapy.” This was followed by Kurt Bachman of GlaxoSmithKline, who opined, “the challenge is to identify the tumor types most likely to respond, to find biomarkers that predict response, and to define the relationship of the predictors to biology of the inhibitors.”

When I read this article I dashed to my phone and waited breathlessly for these august investigators to contact me for guidance. It was obvious that they were describing precisely the work that my colleagues and I have been doing for the past two decades. Obviously, there had been an epiphany. The complexities and redundancies of human tumor biology had finally dawned on these investigators, who had previously clung unwaiveringly to their analyte-based molecular platforms.

Eureka! Our day of vindication was at hand. The molecular biologists humbled by the manifest complexity of human tumor biology had finally recognized that they were outgunned and would, no doubt, be contacting me presently. Whole-cell experimental models had gained the hegemony they so rightly deserved. The NCI and big pharma would be beating a path to my door.

But the call never came. Perhaps they lost my number. Yes, that must be it. So let me provide it: 562.989.6455. Remember I’m on Pacific Daylight Time.

The False Economy of Genomic Analyses

We are witness to a revolution in cancer therapeutics. Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients we have a long way to go before these tests will have meaningful clinical applications.

So, let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva®) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori®) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order ALK gene rearrangement     $1,500
•    And EGFR mutation analysis     $1,900
•    The costs associated $1,500 + $1,900 x 100 people =    $340,000
Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.
Resulting in a cost per correctly identified patient =     $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order an EVA-PCD analysis    $4,000
•    The costs associated: $4,000 x 100 people =    $400,000
•    With 65 percent of patients responding, this
constitutes a cost per correctly identified patient =     $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques.

No wonder we call our group Rational Therapeutics.

Ovarian Cancer National Alliance 2011

The July meeting of the OCNA included a lecture by John Hays, MD, from the National Cancer Institute (NCI), entitled “Decision time: what is the right choice of chemotherapeutic agent(s)? Dr. Hays, part of the molecular signaling section at the NCI, reviewed literature on the topic. He described the need for prospective clinical trials to validate retrospective and in vitro results.

He then examined data from three technologies, the Oncotech extreme drug resistance test, Precision Therapeutics ChemoFX test and the ATP-based chemosensitivity test.

I found it odd that Dr. Dr. Hays spent time examining the EDR technology of Oncotech in as much as it is no longer offered and reflects proliferation-based studies, which have since largely been discredited.

The ATP assay was reviewed using the results of a study published by Dr. Ian Cree in which 180 patients received either assay-directed (ATP) or physician choice. This study actually provided an improvement for patients who received the ATP-based treatment but failed to achieve significance. Thus, it failed largely because it was underpowered.

But this reflected a more concerning aspect of the study.  It seems that the “physician choice” arm increasingly applied the best drug regimens developed in Dr. Cree’s own laboratory. As the trial continued to accrue, an increasing proportion of patients received Gemcitabine-based doublets (which were very new at the time) based upon Dr. Cree’s observation of activity for these novel combinations. This had the uncomfortable effect of forcing Dr. Cree to compete with himself. Had Dr. Hays been truly interested in examining this study as I have, he might have noticed the good control group response rate partly reflected the application of Dr. Cree’s’ own observations.

Indeed, when during my many attempts to conduct a prospective study with the GOG, I was at the very last moment confronted with a study design similar to Dr. Cree’s, (e.g. they could incorporate any treatment they chose, including those that I developed), my statistician demanded that I forego the pleasure, as he could see only too well that the trial had become impossible to power. You see, there was no true control arm for statistical comparison.

The final portion of Dr. Hays’ presentation was the ChemoFX assay. This technology propagates tissue biopsies to confluence and then conducts measurement of drug-induced cell death. With substantial funding largely provided by venture capital, Precision Therapeutics has leapt into the GOG with a series of trials. Should this hybrid technology fail to provide prospective results that meet significance, it will be a damaging blow to this unfairly maligned area of investigation. While I wish the ChemoFX investigators luck, a failure on their part could be harmful to the field. Their reliance on propagated, sub-cultured tissues grown to monoculture has been a concern to me since they first arose in the last few years as participants in the field. We await the results of their trials with great anticipation.

What is interesting in Dr. Hays’ review is not so much what he said, but what he didn’t say.

First, he did not mention the seminal work of Dr. Larry Weisenthal, a pioneer in the field.

Second, he did not describe the nearly 2,000 retrospective, yet statistically significant correlations in the literature in a wide variety of diseases. He neglected to mention that one of the most widely used regimens for breast and ovarian cancer was developed using the same human tumor culture analyses that he decries. If he actually treats patients, he no doubt uses the cisplatin gemcitabine doublets developed using one of these platforms.

Finally, Dr. Hays has failed evidence-based medicine 101. He has forgotten that in life-threatening illnesses where prospective clinical trial data is not available, in accordance with the dictates of evidence-based medicine, one should use the best available data to guide treatments.

There is a wealth of data supporting laboratory based drug selection.  Presentations like that described do not add to the discourse.

Lots of Heat No Light – ASCO Technology Assessment Update 2011

“Once more unto the breach, dear friends.”

This famous line from Shakespeare’s Henry V, describes the Battle of Agincourt and England’s unexpected victory over the French. Not unlike Henry V a small coterie of relatively underfunded and embattled investigators around the world continue to fight an entrenched medical community who refuse to relinquish their grip on the clinical trial process.

Their re-review updated from 2004, sheds no new light on the field, as the authors conclude that their 2004 recommendations stand without modification.

The authors, to their credit, have updated their database to include cell death endpoints. They cite the ovarian cancer study by Dr. Ian Cree, that assigned 180 patients, (of which 147 were evaluable), with recurrent disease, and reported a response rate of 40.5 percent for assay directed versus 31.3 percent for physician choice, yet failed to achieve significance. The reasons for this trial’s failure however were obvious, as it was underpowered and more importantly allowed the physician’s choice arm to include Dr. Cree’s own drug combinations as the trial accrued. This left Dr. Cree in the uncomfortable position of having to compete with himself.

More disturbing is their dismissal of a paper by Selma Ugurel, MD, from Clinical Cancer Research 2006 in which, patients with metastatic melanoma received assay-directed treatment for this otherwise chemo resistant and lethal disease. Patients found drug sensitive in the laboratory had a response rate of 36.4 percent, while those found drug resistant had a response rate of only 16.1 percent (a two-fold improvement). The overall survivals were similarly improved with assay-directed patients 14.6 months vs. drug resistant patients of 7.4 months. Again a doubling. Furthermore these results achieved statistical significance.

The ASCO group concludes with the comment, “However, the investigator did not compare the two interventions.” As I know this paper well, and was extremely impressed that some of the responders went out to 30 months, I find the ASCO group’s insouciance surprising.

This reminds me of an old joke by the comedian Jerry Seinfeld. It seems that he had watched a television program where a man caught bullets shot from a gun with his bare teeth. Seinfeld went on to say, that despite being immensely impressed by this man’s prowess, he just couldn’t seem remember his name. “What do you got to do to impress people”?

As I am familiar with the Ugurel paper, I have been very impressed with these investigators completing a study by dint of their dedication to the field. Stranded without funding or cooperative group support, laboratory-based therapeutics remains unconfirmed, not by the unwillingness of the investigators but by the unwillingness of the cooperative and funding agencies to test the hypotheses.

While we squander billions of dollars on genomic analyses that are increasingly leading us nowhere, these ASCO study groups and their colleagues continue to refuse to formally evaluate human tissue studies. In light of the lack of improvement in survival for most cancers over the past 50 years, despite the expenditure of hundreds of billions of dollars on research, perhaps assay-directed therapy is just the solution that medical oncology needs.