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.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

12 Responses to Lots of Heat No Light – ASCO Technology Assessment Update 2011

  1. Gary Brutsch says:

    Well stated

    Instead of a gun, perhaps a cannon strike will get the attention of the politically sensitive medical community. With out political will to change, the resistant head wind will be difficult to penetrate.

    in the mean time your patients are experiencing a extended life. This accomplishment is a gift that you and your staff share with us. Miracles are not definded by length of time to achieve a result. Miracles are definded by outcome

    • Thanks for your comment. We delight in the good outcomes of our patients and are always very happy to be apprised of them. We hope that we can convince the clinical trial organizations to formally test our hypotheses.

      Thanks

  2. Elaine L. says:

    There are many supporters of Assay testing on the Ovarian Cancer National Alliance who are requesting Assay testing. The patient interest is there. It’s finding the physician who is willing to embrace the concept and try the recommended protocol that is the difficulty. The ASCO platform certainly doesn’t help.

    I had an Assay done a year, ago through RT and I was shown to be highly platinum sensitive. The recommended protocol was carbo/gemzar which were synergistic. My oncologist was pleased to see that I was platinum sensitive and proceeded to use Carbo/Taxol. My CA125, which was at nearly 4000 dropped like a stone. However, after five months it’s looking like I might be recurring. In my mind I question if it was the omission of the Gemzar and if the Taxol did more harm than good.

    • It is very difficult to know how your case might have proceeded with an alternative platinum based regimen. We were the first to use platinum plus gemcitabine in ovary (Nagourney, RA et al Gyn Onc 2003) and continue to regard it as a very important regimen in this disease.

      Several years ago I approached the authors of the GOG 182 clinical trial that used 5 different treatment combinations in first-line therapy randomly selected. Our request was to add a 6th “assay-directed” arm that would give patients the “best” regimen” chosen from the same treatments that they were already using albeit “randomly” selected. They turned down the request and proceeded to accrue 4312 patients only to find no difference between arms. Had we had the chance to particpate, we might have provided them a successful trial (the assay directed arm) and at the same time tested this important hypothesis in a randomized clincial trial. It remains a bitter disappointment that they did not allow that to go forward particularly in light of the subject of this blog and the “cry” for randomized clinical trials. I think the phrase is something like “put up or shut up”.

      As to your current situation, you might indeed consider using a gemcitabine plus platinum. The rationale for that change can be found in our textbook on the subject (KroepJR, Peters GJ and Nagourney RA, in Deoxynucleoside Analogs in Cancer Therapy. GJ Peters (ed) Humana Press, 2006). We can provide you physician information if needed.

      We wish you every success.

      Thanks for your comment.

  3. With Taxol increasing the production of cellular communication molecule (IL-8) that initiates growth of new blood vessels to feed a growing cancer, Taxol is worse off than anyone has ever realized (highly resistant, initiates cancer blood vessel growth, increases circulating tumor cells, and not the least, very toxic).

    • We reported our findings on the lack of synergy between taxanes and platins in ovarian cancers at the SGO meeting in 2007 (Brewer C, et al Soc Gyn Oncol Plenary session, 2007). Your comment is an interesting one and raises questions as to why carbo & taxol has not been shown superior to single agent caroplatin when formally tested in the ICON 3.

      Thanks

  4. Pat M says:

    Medical Oncology doesnt need this solution: fifty years worth of dead patients do!

    More and more, today’s patients can think for themselves. Given the evidence for assay directed therapy vs the archaic approach of blindly throwing chemo at a patient in the hope that something sticks, patients will, of course choose the former. Unless, of course, their deeply entrenched Oncologists bully them out of it.

    Dr. Nagourney and all like-minded investigators, please carry the gratitude of all the patients you have helped while “unto the breach”‘ you go. You have kept many of us from going “unto the grave” too soon, if not at all.

  5. Denise M says:

    In the cancer world today, patients cannot “Hope for change”. These two words are not synonymous. Patients have to take their disease and treatment options into their own hands and insist that their Oncologist run the Assay test before anything else is started. Treatment protocols given to patients blindly quickly kill. We have the statistics to prove it.

    • Elaine L. says:

      Denise I totally agree.

      Unfortunately, some patients aren’t financially able to afford to pay for an assay. My insurance would not reimburse me. Also, once an assay is done, it can be challenging to find an oncologist who is willing to administer the protocol, especially when it’s for first line treatment.

  6. A woman on the Inspire ovarian cancer board had the same problem with her insurance company not reimbursing her for her assay. They told her it was “not medically necessary for the treatment of ovarian cancer.” She took the bull by the horns and appealed the decision. She appeared in person and stated her case using her own story and information put together on live cell assays. She was contacted by a representative of the insurance company within an hour of leaving the hearing to tell her they had decided to reimburse her for the cost of the procedure. She said the representative mentioned to her that the group of twelve, including a lawyer, doctor and company accountant had been “blown away” by her presentation and that they had all learned so much from her, they hope this procedure can become commonplace for cancer patients because it is cost effective and better for the patient. This woman is a hero to cancer patients who research the disease they’re inflicted with and do what is practical for their own individual cancer treatment.

  7. Elaine L. says:

    Dr. Nagourney, If a patient tests sensitive for carbo/gemzar combination and the oncologist proceeds with Carbo/Taxol, which was only an intermediate response, does the cancer mutate when it comes back rendering the previous assay useless?

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