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.

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.

5 Responses to Platinum Resistance is in the Eye of the Beholder

  1. Liz Mane says:

    Dr. N.

    I am the one who opined on a chat room that most oncologists won’t redeploy carbo to platinum refractory patients right after unsuccessful front line platinum therapy. However, whoever alerted this comment to you omitted a crucial qualifying aspect of my argument.

    I was responding to the person who was advocating IMMEDIATE redeployment of carbo to a platinum refractory patient with NO platinum free interval as long as it is paired with Gemzar, which is supposed to be synergistic. I am a so called platinum resistant patient (remission lasting less then 6 months), and I have done a lot of independent research on this subject (I have a Ph.D. in research science though not in bio medical field). My conclusion was, yes, indeed, I can use platinum drugs again, but it’s best if I create a meaningful platinum free interval. None of the doctors I consulted (and I have consulted a few in world renowned cancer centers) would recommend IMMEDIATE redeployment of carboplatain for me when I recurred, though they agreed that with a sufficient interval, they would definitely consider redeploying it

    What are your thoughts? Would you recommend immediate redeployment of carboplatain right after a patient is declared platinum refractory during their front line therapy? Especially when there are so many options given the likelihood that they are still chemosensitive to a variety of other drugs?

    I have another related question for you. Do you believe that any drug which stopped working for a patient can be redeployed later with a sufficient interval? My recurrence treatment started with Gemzar which worked well enough to wipe out tumors, but it stopped working and CA125 has been rising consistently last two months (still a clean scan though). Will I be able to use Gemzar/platinum combo some time down the road? I eagerly await your feedback.

    Sincerely

    • We and other investigators have shown that the combination of platins with gemcitabine can be very active in patients who fail Carboplatin plus Taxol, even when administered immediately following. The specific mode of action of Gemcitabine renders this agent an ideal salvage regimen EVEN IN THE PLATINUM REFRACTORY state. While it does not work for every patient, it can be used effectively in many.

      As to patients responding to the the drugs again, this is well established in many diseases. Cancers do not retain resistance to all classess of drugs forever. After some period of time, in the absence of a selective pressure (drug exposure), cancer cells can evolve out of the resistance that characterized their intial response and subsequent resistance and become sensitive again. This is one of the reasons why assay-directed theapy can be helpful, in encouraging phsyican to re-challenge a patient if a profile of re-sensitivity has been identified ex vivo.

      • Liz Mane says:

        Dr. N,

        thanks for the reply. As a platinum resistant patient who also failed in another therapy, this is very encouraging. Can you cite some studies that demonstrated success cases of immediate redeployment of so called “failed” drugs in combination of synergistic drugs?

        Another question that is still outstanding is, even if the failed drugs can be redeployed immediately, wouldn’t it make sense to create some “interval” so that the cancer cells have a chance to evolve out of that particular drug? Following your own logic (your own quote above: After some period of time, in the absence of a selective pressure (drug exposure), cancer cells can evolve out of the resistance that characterized their intial response and subsequent resistance and become sensitive again), it would make sense to provide some interval before redeployment of the same drug that failed. Wouldn’t you agree?

  2. Elaine L. says:

    Although I recurred between 5-6 mos after completing first line treatment with carboplatin and taxol, my oncologist did not consider me to be platinum resistant. He actually felt that I had a very good response. I completed carboplatin and gemzar, nine weeks, ago, and I am hoping for a longer remission.

    • “Platinum resistance” is a continuum from platinum refractory (no response to initial therapy) to responses with re-challenge after some duration of platinum-free interval. As we reported in this blog, the combination of platins with Gemcitabine, is somewhat different than simply re-challenging with single agent Carboplatin (or Cisplatin) or Carboplatin plus Taxol. Your treatment sounds appropriate and we wish you success with this course.

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