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.