Breakthroughs In Cancer?

Coco Chanel, the icon of 20th century fashion once said, “Only those with no memory insist on their originality.” I am reminded of this quote as I review recent discoveries in cancer, among them, the recognition that cancer represents a dysregulation of cellular metabolism.

The field of metabolomics (the systematic study of cellular energy production), explored by investigators over the last decade is little more than the rediscovery of enzymology (a branch of biochemistry that deals with the properties, activity, and significance of enzymes), biochemistry (the science dealing with the chemistry of living matter) and stoichiometry (the part of chemistry that studies amounts of substances that are involved in reactions), pioneered by investigators like Albert Lehninger, Hans Krebs, Otto Warburg, and Albert Szent-Gyorgyi. These innovators used crude tools to explore the basis of human metabolism as they crafted an understanding of bioenergetics (the study of the transformation of energy in living organisms) and oxidative phosphorylation (processes occurring in the cell’s mitochondrion that produce energy through the synthesis of ATP (energy carrier of the body).

More recently, scientists wedded to genomics have slowly come to recognize the limitations of their approach and have returned to the field of phenotypic (the observable physical or biochemical characteristics of an organism analysis.

While newcomers to the field claim to be the first to recognize the role of cellular biology in tumor biology, a cadre of dedicated investigators had already charted these waters decades earlier. Beginning with the earliest studies by Siminovitch, McCulloch and Till, subsequent investigations by Sydney Salmon and Anne Hamburger, developed the earliest iteration of cellular studies for the examination of cancer biology in primary culture.

Ovarian Cancer

Ovarian Cancer

The work of Black and Spear, published in the 1950s similarly explored the study of human cellular behavior for the study of cancer research. While Larry Weisenthal, Andrew Bosanquet and others established useful predictive methodologies to study cellular phenotype, their seminal contributions have gone largely unrecognized.

Today, start-up companies are examining cellular biology to predict cancer outcomes, each claiming to be the first to recognize the importance of cell death events in primary culture. The most recent and widely touted in the literature is the use of mouse avatars. Implanting biopsied explants of tissue from patients into nude mice, they grow the cancers to desired size and then inject the drugs of interest to show tumor shrinkage. To the discerning eye however, it obvious that this represents little more than an expensive, inefficient, and extremely slow way to achieve that, which can be done more easily, inexpensively, and quickly in a tissue culture environment.

When I read the promotional material of some of the new entrants to this field, I am reminded of another quote, that of Marie Antoinette, who said, “There is nothing new except what has been forgotten.”

Stand Up to Cancer Research! The Downside to Clinical Trials.

As the practice of medicine has moved from a profession to an industrial undertaking, this most human of experiences has fallen prey to the dictates of the American business model. Patients are no longer the purchasers of medical care and services, but instead, the consumers of those goods and services that meet the needs of the purveyors. Whether this is a governmental entity, academic institution, or pharmaceutical company, individuals have become cogs in the wheel of the medical-industrial complex.

Cancer from dictionaryThis has become glaringly apparent in the field of cancer research. Cancer patients were once, for better or worse, in charge of their own destinies. They could choose their surgeon, oncologist, and institution, even to some degree the treatments that they wished to undergo. As the HMO model came into play, patients were increasingly told what doctor, what treatment, and what hospital. The capacity of individuals to make decisions was eliminated in favor of standardized care, cost guidelines and treatment protocols. While much of the academic community described this as progress with adherence to standardized protocols, these protocols have not provided superior outcomes in most settings. Instead, they offer hospital administrators the opportunity to anticipate costs, allocate resources, codify drug administration and regulate care delivery.

Recent experience has brought several disturbing examples to the fore. Working in the laboratory, we have been able to select candidates for new combinations, sometimes years before these regimens became broadly available. We then identify centers with access to these drugs under protocol. Many of the drugs have well-established safety records from prior phase 1 and 2 clinical trials, but have not achieved full FDA approval. When several of our patients with lung cancer revealed sensitivity to a regimen that we had identified years earlier (Kollin, C et al Abs 2170, Proc AACR, 2005) we immediately explored sites offering this combination of an oral agent with an IV antibody. The closest we could find was in Colorado. The injection, a widely established monoclonal antibody, FDA approved for gastrointestinal cancer, was not yet approved for lung cancer while the pill had been administered safely in hundreds of patients. Indeed, the combination had also been safely administered to dozens of patients by the time we inquired. Nonetheless, to participate in this potentially life-saving treatment my patients were forced to commute from LA to Colorado every other week.

It would have been quite easy, once the patients were formally accrued, for them to return to California and receive the same drugs under our care. After all, we were the ones who identified them as candidates in the first place and we were very familiar with the trial. Despite this, the rigidity of the protocol forced these lung cancer patients to become frequent fliers. The good news was that the treatments worked.

More recently a patient, who had failed experimental therapy for advanced uterine carcinoma at a large academic center in Texas, returned to LA five years ago to seek my assistance. A lymph node biopsy at the time revealed exquisite sensitivity to a drug combination developed and published by our group and she achieved a prompt complete remission. She has since relapsed and required additional chemotherapy. My concern for her long-term bone marrow tolerance, with repeated exposure to cytotoxic drugs, led me to seek alternatives. Her EVA-PCD functional profile had revealed excellent activity for PARP inhibitors. Here, I thought, would be the solution to her problem. After all, the PARP inhibitors had been in development for years. Several had revealed compelling activity in clinical trials and they are well tolerated. Despite this, no PARP inhibitor has been FDA approved.

When we pursued opportunities to accrue the patient to one of the PARP inhibitor trials, however, she did not qualify. Having received low dose Carboplatin several months earlier she ran afoul of an exclusion criterion in the protocol that dictated no platinum exposure for six months. “Six months?” I exclaimed. Few cancer patients can wait six months to start treatment and virtually no cancer patients can wait six months once they have relapsed. I was flabbergasted.

What exactly were the protocol designers thinking when they demanded a six-month wash out, fully four, five or six times longer than any protocol I’d ever encountered?  The absurdity of this demand virtually eliminated patients-in-need from consideration. As I considered the dilemma it became increasingly clear. When one examines the thinking behind clinical protocols it becomes evident that they are not designed to help patients or cure cancer. Instead, they are created to answer specific questions. In so doing they further the careers of investigators, expand medical center market share, standardize treatments and simplify the activities of clinical research organizations. Patient outcomes, well-being and convenience are far down the ladder of expectations.

As I pondered the inconvenience, hardship and lost opportunities associated with clinical trial participation for many patients around the United States, I began to wonder whether patients should throw off the yoke of this oppressive system. After all, it is not the academic centers that own the process, it is the patients. It is those brave individuals willing to participate in these studies. It is the patients whose tax dollars support these institutions. It is the patients who purchase either directly or indirectly the drugs they receive and it is the patients that are necessary for the process to succeed.

Patients should demand more user-friendly, convenient, patient-centric therapy programs. Perhaps patients should simply refuse to participate. A ground swell of patient advocacy could re-orient the discussion away from the convenience and ease of the treating physicians and toward the good outcome and ease of the treated patient. While we applaud the investigators for their brilliance and prowess, we forget that no clinical investigator would receive accolades were it not for the hundreds or thousands of patients who martyr themselves at the altar of clinical research. Patients, not their doctors, are the heroes.  Perhaps it is time for cancer patients to stand up to cancer research.

Cancer Patients: Cure the Curable, Treat the Treatable and Avoid Futile Care

During my interview with Jeff Michaels on the March 28, 5:00 P.M. Fox News, we explored the themes of my current book, Outliving Cancer. One of the points that most interested my interviewer was the appropriate use of our laboratory platform for the selection of therapy. He asked, “Are there some patients for whom there is no cure?” I responded by explaining what it is, that our laboratory test is designed to do: “Cure the curable, treat the treatable, and avoid futile care.” Jeff Michaels stopped me and asked that I might repeat what I had just said. It seemed that my succinct description resonated.

However simple this distillation of our work may seem, I realized it was actually rather profound. After all, we are confronting an escalating crisis in medicine. How do we meet the needs of a growing population of cancer patients with shrinking resources? How do we allocate treatments to those most likely to respond and finally, how do we avoid the misadventures of toxic and ineffective therapies for those destined to fail chemotherapeutic intervention? On every level, laboratory models can assist us. For those patients with early stage breast cancer, ovarian cancer, small cell lung cancer, non-Hodgkin lymphoma and many leukemias, the expectation of a cure is well within our reach. These patients must receive the very best treatments from the start.

The larger population of patients we confront are those with diseases like gastric, colon, non-small cell lung, recurrent breast, recurrent ovarian or sarcoma for whom cures are less likely and effective therapies must be tolerable so that they can provide benefit without undue toxicity. These are the patients for whom cancer can become a “chronic disease.”

Finally, we must all confront patients for whom treatments offer little likelihood of benefit, yet significant risks of toxicity. These heavily pretreated patients, or those who present with refractory malignancies like pancreatic, kidney cancer or melanoma – represent a special subset. Here the role of the physician is to decide that almost Shakespearean question, “To treat or not to treat.”

This is a particularly delicate circumstance as it forces the doctor, the patient and the family to confront the most difficult question of all, “Am I dying?” The answer is “maybe.” Without seeming flip, every patient no matter what diagnosis, has some chance of response to therapy. If we examine the performance characteristic of our laboratory analyses, they consistently double response rates. With this group however a doubling of response rate may still provide a rather low likelihood of meaningful benefit. If the laboratory finds drug resistance in this group, it is a near certainty that the patient will not respond.

However distressing this data may be, it may be comforting to know that the patient has left no stone unturned. For those patients where a treatment appears active, despite their diagnosis or treatment history, then the discussion surrounding tolerance, toxicity and realistic likelihood of benefit can be undertaken intelligently. This is the embodiment of rational therapeutics.

Beyond Our Borders

I recently returned from Brazil where I participated in a cancer symposium. During my visit I encountered many highly skilled physicians with expertise in breast, thoracic, gastrointestinal and orthopedic oncology. The degree of collegiality and enthusiasm was palpable. The most exciting aspect of my visit was the warm reception and extremely high level of interest in the clinical application of our laboratory platform. It was a refreshing reminder that the parochial thinking of the American oncology community is not the norm throughout the world.

Upon my return, I had the pleasure of meeting a charming 61-year-old woman from New Delhi, India. In review of her chart I recognized her name as a patient for whom we had conducted a study in February of 2012. Her husband, an accomplished businessman, had learned of our laboratory and worked diligently to obtain, process and transport a portion of his wife’s tumor from the surgical suite to our lab. Despite multiply recurrent disease and numerous prior treatments, this patient’s ovarian cancer cells revealed exquisite sensitivity to a drug combination in the laboratory. Her physicians at the Apollo Hospital of New Delhi delivered the treatment exactly as outlined by our lab, and here sitting across from me was the patient in complete remission six months later. The family had traveled from India to meet me and express their thanks.

Each of these experiences speaks volumes for the globalization of cancer care. Cancer patients, whether from Brazil, India or China are more alike than different. Each confronts a seemingly insurmountable adversary. Each in their own way seeks out the best information and advice. And each can be best managed with those treatments found uniquely effective for their tumor. Perhaps once we have conquered cancer in India and Brazil, the EVA-PCD® assay will be ultimately accepted in the United States of America.

Platinum Resistance is in the Eye of the Beholder

I was recently apprised of an online conversation surrounding the treatment of platinum refractory and platinum resistant ovarian cancer. To clarify our terminology, platinum refractory disease refers to cancer that progresses during platinum therapy. This would be considered the most platinum resistant of the ovarian patients. The term “platinum resistant” developed over the last two decades, by Markman and others, is used to describe patients who initially respond to platinum-based chemotherapy and then relapse within six months of treatment.

While platinum refractory seems intuitively obvious, it has been suggested that platinum resistance is somewhat more arbitrary.  That is, what if one relapses one month versus five months, or seven months after treatment. In fact, studies conducted by investigators at Memorial Sloane-Kettering under Dr. David Spriggs, suggest that platinum resistance is a continuum extending from six months continuing out to 24 months and beyond. The longer the “platinum-free interval” the better the chance of response to combinations like carboplatin plus Taxol. Within the scope of this discussion I am in general agreement. However, as I describe below, this is, by far, not the whole story.

I am composing this particular blog in response to a comment that I encountered in a recent chat room discussion. The individual took an extremely strong stance stipulating that no medical oncologist should re-challenge a patient with a platinum-based regimen if they fall within the category of platinum refractory or platinum resistant. This statement is absolutely, positively WRONG.

Platinum resistance is mediated by DNA repair enzymes. These enzymes recognize and respond to platinum adducts and excise the DNA residues, replacing them with the appropriate base pairs. While this confers resistance to single agent platins, a degree of resistance which is largely is unaffected by the addition of taxanes, platinum resistance actually opens up an Achilles heel for treatment of these patients. Drugs like the antimetabolites (Gemcitabine, 5-FU), as well as the topoisomerase inhibitors become collaterally more active in those tumors with the most active DNA repair capacities. This is the reason why we have consistently observed responses in both platinum resistant and platinum refractory patients utilizing the combination of cisplatin and gemcitabine, as we reported in the original paper describing this combination in 2003 (Nagourney, R et al, Gyn Onc, 2003). Our response rate of 50 percent in heavily pre-treated and platinum resistant patients was confirmed by investigators in Ohio who reported similarly good results in patients with p-glycoprotein positive/platinum resistant disease (Rose, P, Gyn Onc 2003).  To formally test this hypothesis we conducted a national clinical trial with the GOG, which treated platinum resistant and platinum refractory patients with the combination of cisplatin plus gemcitabine. This trial provided the longest-time-to-progression for this population (six months) in the history of the GOG (Brewer et al, Gyn Onc 2006). These observations were subsequently reported in our textbook (Deoxynucleoside Analogs in Cancer Therapy, GPeters [ed] Humana Press 2006).

Similar results have been reported for Folfox in recurrent ovarian patients by Greek investigators (Pectasides, D et al, Gyn Onc 2004). To examine this phenomenon, one of the great investigators of antimetabolite chemistry, William Plunkett, conducted an instructive series of experiments in which they showed that platinum resistant ovarian cell lines expressed high levels of the DNA repair enzyme ERCC1. When these investigators blocked the ERCC1 expression with siRNA, the cell lines became resistant to the cisplatin plus gemcitabine combination, indicating beyond a shadow of a doubt, that it is the cells’ own DNA repair capacity that makes it sensitive to this drug doublet.

I write this blog because it is critically important for patients and doctors alike, to understand the chemistry of these agents and their interactions. While platinum resistance may indeed confer clinical resistance to platinum, carboplatin plus Taxol and related combinations, platinum resistant tumors may actually be more sensitive to intelligently administered drug combinations. Using our laboratory platform to measure the chemosensitivity and synergy for drug combinations we have identified numerous platinum resistant and platinum refractory patients who have had dramatic and durable response to re-challenge with platinum based therapies that employ these synergistic combinations. This is why we are extremely interested to study platinum resistant patients. After all, platinum resistance is in the eye of the beholder.

Ovarian Cancer Therapy

For many years I have been interested in the ovarian cancer literature. After all, it was our group that originally developed the platinum plus gemcitabine doublet and tested it through a Phase II trial conducted by the Gynecologic Oncology Group (GOG). The study’s results were reported in Gynecologic Oncology in 2006.

I then watched with interest as the GOG 182 five-arm clinical trial unfolded. This international study of over 4,000 patients randomly mixed and matched drug combinations but provided no evidence of superiority of one arm over another. The final conclusion of the manuscript that reported these results (Bookman, MA., Brady, MF, McGuire, WP, et al. J Clin Oncol 27: 1419-1425, 2009), stipulated that carboplatin plus taxol remained the “gold standard” for advanced epithelial ovarian carcinoma. A study of over 900 patients that compared carboplatin plus gemcitabine to carboplatin plus paclitaxel induction (Gordon A, Teneriello M, Lim, P, et al Clinical Ovarian Cancer, 2, 2:99-105, 2009) again provided comparable outcomes between arms yet carboplatin plus taxol remains the “gold standard.”

To this collection of published experiences, we now add the report by Sandro Pignata and co-investigators from the MITO-2 Phase III trial (Pignata, S., Scambia, G., Ferrandina, G., et al. J Clin Oncol 29: 3628-3635, 2011). This clinical trial conducted by Italian investigators compared carboplatin plus taxol to carboplatin plus pegylated liposomal doxorubicin (PLD) known in the U.S. as Doxil. Four hundred and ten patients were randomized to each arm of the trial. The results revealed numerical superiority for the carboplatin plus PLD arm in terms of median progression-free survival (19 months vs. 16.8 months) and numerical superiority for overall survival for the carboplatin plus PLD over the carboplatin plus taxol arm (61.6 vs. 53.2 months). However, these results did not achieve statistical significance. Therefore, the authors conclude that carboplatin plus taxol “remains the standard first-line chemotherapy for ovarian cancer.” While they do grant that, based on toxicity, carboplatin plus PLD could be considered as an alternative therapy.

With the GOG 182 study, the Gordon study (comparing carboplatin plus gemcitabine) and the most recent Pignata study comparing carboplatin plus PLD all establishing activity for several first-line regimens, why is it that the gynecologic oncologists continually return to carboplatin plus taxol as the “gold standard?”

Is there not ample evidence that several regimens provide similar results and survivals? Is there not evidence that the toxicities differ? Why can’t the gynecologic oncologists get off the dime? Why can’t they admit that several treatment regimens are appropriate and indicated for the malignancy? Why can’t they admit that some patients may, in fact, do better with one treatment over another?

And, finally, why can’t they admit that using laboratory analyses to determine a patient’s functional profile has the potential to select amongst these regimes to provide the best outcomes for the majority of patients?

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.

Why Some Patients Refuse Chemotherapy – And Why Some of Them Shouldn’t

In the June 13, 2011, issue of Time magazine, Ruth Davis Konigsberg described cancer patients who refuse to take potentially lifesaving therapy. Her article, titled “The Refuseniks – why some cancer patients reject their doctor’s advice,” examined the rationale applied by patients who decline chemotherapy. Many of these patients are rational, articulate, intelligent and capable individuals. While there are those who by virtue of religious belief, underlying depression, or loss of loved ones, decline interventions, many of these patients make compelling arguments in favor of their decisions.

When we examine the basis of these patients’ therapeutic nihilism, much of it reflects the uncertainty of benefit combined with the certainty of toxicity. What these patients articulate is the fundamental dilemma confronted by cancer patients, what we might describe as their logical assessment of “return on investment.”

Everything in life is based on probabilities. Will your husband or wife be true? Will you have a boy or a girl? Will you live to see retirement? Will your nest egg be adequate? Cancer medicine is no different.

Will the treatment I’m being offered extend my life long enough to be worth the short- and medium-term toxicities that I will certainly suffer?

While I cannot address this question with regard to surgery or radiation, I feel uniquely qualified to do so in the context of chemotherapy. What, after all, is a chemosensitivity assay? When correctly performed, it is a laboratory test that dichotomizes groups of patients with average likelihoods of response (e.g. 20%, 30%, 40%, etc.) into those who are more or less likely to respond based on the results. On average, a patient found sensitive in vitro has a twofold improvement in response, while those found resistant have a demonstrably lower likelihood of benefit. We have now shown this to be true in breast, ovarian, and non-small cell lung cancers, as well as melanoma, childhood and adult leukemias, and other diseases.

To address the misgivings of the Refuseniks, we might ask the following question: Would you take a treatment that provided a 30 percent likelihood of benefit? How about a 40 percent? 50 percent? 60 percent? 70 percent? Or 80 percent? While many might decline the pleasure of chemotherapy at a 20-30 percent response rate, a much larger number would look favorably upon a 70 percent response rate. On the flipside, a patient offered a treatment with a 50 percent likelihood of benefit (on average), who by virtue of a lab study realizes that their true response rate is closer to 19 percent (based on resistance in vitro), might very logically (and defensibly) decline treatment. These real life examples reflect the established performance characteristics of our laboratory tests (Nagourney, RA. Ex vivo programmed cell death and the prediction of response to chemotherapy. Current Treatment Options in Oncology 2006, 7:103-110.).

Rather than bemoan the uncertainties of treatment outcome, shouldn’t we, as clinical oncologists, be addressing these patients’ very real misgivings with data and objective information? I, for one, believe so.

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.