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.

Best Chance for Colon Cancer Survival – Don’t Let It Start

Two papers in the February 23, 2012, New England Journal of Medicine reported important findings in the fight against colon cancer. The first paper (Zuber, AG et al; Colonoscopic Polypectomy and Long-Term Prevention of Colorectal Cancer Deaths) conducted by American investigators establishes the benefit of polyp removal in the prevention of death from colorectal cancer. The study conducted upon 2,602 patients who had adenomas removed reveals a 53 percent reduction in mortality from colon cancer compared with the expected death rate from the disease in this population.

To put this into perspective – virtually no intervention in the advanced disease setting provides a survival advantage. The best we can usually do once the disease is established is an improvement in time to progression. When we do observe a true survival advantage it is usually in the range of a few percentage points and never of this magnitude. How might we explain this astonishingly positive result?

One way to view this finding is to reexamine the biology of cancer. One of the leading experts in the field, Bert Vogelstein, MD, from Johns Hopkins, explained colon carcinogenesis as a pattern of gene perturbations starting at atypia, progressing to carcinoma in situ and ending with invasive, metastatic disease. According to Dr. Vogelstein, the average colon cancer found in a patient at the time of colonoscopy has been present in that person’s colon for 27 years. From there it is only a hop, skip and a jump from one-centimeter adenomatous polyp to metastatic (lethal) disease, all playing out over the last three years in the natural history of the disease. Thus, cancer truly is a disease that doesn’t grow too much, but dies too little and interrupting this process while it is still slumbering can, it would seem, lead to cures.

What I find surprising is the success of the strategy. Since it is now well established that cancer can metastasize when it has achieved the rather diminutive proportions of 0.125 cubic centimeters or less and the average polyp can only be detected at one or more cubic centimeters, it is our good fortune that so many cancers chose not to (or could not) metastasize prior to detection. Reading between the lines, those 12 patients who died of colon cancer as opposed to the expected 25.4 are presumably those with early metastasizing disease. The next frontier will be the detection of these cancers when they are teenagers and not 20-somethings. It may be that proteomic analyses will provide an avenue for earlier detection in the future.

The second article is a European study (Quintero, E et al; Colonoscopy versus Fecal Immunohistochemical Testing in Colorectal-Cancer Screening) that compared colonoscopy with fecal blood testing in a large cohort of patients. While the rates of detection for colorectal cancer were similar, the rates of detecting both advanced and early adenomas, favored colonoscopy (p < .001). This study represents an interesting adjunct to the American study described above. Specifically, if the early detection (and removal) of adenomas can confer a survival advantage then it could be argued that colonoscopy by its virtue of it’s higher detection rate of these precancerous adenomas, is the preferred “screening” modality. With over 50,000 deaths attributed to colorectal cancer in the U.S. each year, the public health benefit of colonoscopies becomes an intersecting point of discussion. Until now, fecal occult blood testing yearly or sigmoidoscopies every several years has been considered equivalent to colonoscopies every 10 years starting at age 50. Do we need to move colonoscopies to the front of the line?

What is most interesting about both these reports is the low-tech nature of the study modalities – and the astonishing efficacy of their application. Colonoscopies have been conducted for decades. They are comparatively simple, do not require affymetrix chips, and yet provide demonstrable benefit that appears to exceed anything offered, to date, by the “genomic revolution.” Perhaps we should all keep an open mind about other comparatively low-tech methodologies that can provide survival advantages.

Cancer Survivorship

Some of you may have read the January report from the American Cancer Society (ACS) that described a decline in U.S. cancer death rates by 1.8 percent per year in men and 1.6 percent per year in women during the period between 2004 to 2008.

These encouraging results have been touted as evidence of success in the war on cancer. The war on cancer itself began in December 1971, when then president Richard Nixon established a national priority to conquer this disease. Since that time, we have dedicated more than $200,000,000,000 to this effort and published literally millions of articles on the topic. Despite these efforts and tremendous resource allocations, the focus of this research effort, i.e. treatment of advanced malignancies, has provided limited successes.

If we drill down onto the ACS statistics we find that most of the survival changes reflect earlier detection and the successful application of cancer screening. Mammograms, colonoscopies, the use of PSA and the growing application of screening CT scans for lung cancer detection have, and will continue to have, a favorable impact on cancer statistics.

This is the good news. The bad news is that our success in treating advanced disease is almost non-existent. While there have been slow migrations in a favorable direction for the five-year survival rates in some malignancies, the big killers like lung and GI, have shown extremely limited progress. There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase our rate of success.

First, we need to incorporate systems biology into cancer research. As opposed to analyte-based approaches like genomics that unravel one finding at a time, the field of biosystematics examines human cancer through the lens of interacting networks.

Second, we need to redouble our efforts in the study of basic metabolism and the growing field of metabolomics.

Third, we need to revamp the clinical trial process. Were investigators incentivized to achieve greater clinical successes, there were be fewer failed Phase II and Phase III trials. Contrary to the business world where success is rewarded, academic physicians today receive the same compensation for every patient treated, whether the intervention is successful or not. This has the unintended consequence of encouraging physicians to accrue patients to clinical trials with no focus on effective therapies. While it may be gratifying to the trialists to have successes, they receive the same compensation for their failures. Clinical investigators need skin in the game.

Finally, the regulatory environment is currently over-restrictive. The process should allow investigator-initiated efforts with more lenient review processes. The current environment that punishes dedicated physicians for stepping out of the established guideline therapies is thwarting progress and frightening dedicated investigators out of the field. Good faith efforts on the part of physicians using new drugs and combinations that document successes and failures, could unleash an army of clever physicians to utilize novel approaches to advance new therapies with little additional cost.

Lethal diseases, like advanced cancer, pose hurdles that require novel trial designs and less stringent controls. Patients confronting these illnesses should be allowed to receive therapies and should be granted the dignity to determine their own risk-benefit ratios when they confront life and death decisions. Simple consent forms could make available effective treatments while pharmaceutical corporations should be encouraged to provide drugs under the auspices of these patient-driven developmental trials.

While we applaud the discoveries of our colleagues in the field of genomics, and their analyte-driven platforms, we forget at our peril that medicine and most of its discoveries have been observational.

A Day at CHORI (Children’s Hospital of Oakland Research Institute)

As a hematology fellow at the Scripps Clinic in the 1980s, my friend and colleague Sheldon Hendler, MD, PHD, recommended that I read an article in Science magazine. The manuscript entitled “Cancer and Diet,” by Bruce Ames, PhD, described the mutagens and carcinogens to which we are exposed on a daily basis that are found in a normal diet. His paper then examined the defenses that we have developed as a species.

Dr. Ames has distinguished himself as a pioneer in the study of aging, degenerative disease and cancer and I have read many of his papers since then. You can imagine my delight when I received a phone call some months ago and found that my interlocutor was none other than Bruce Ames, inviting me to speak at his research institute.

On Tuesday, January 31, I traveled to Oakland to present a symposium. Dr. Ames arranged for me to meet many of his colleagues. The topics ranged from neuraminic acid residues expressed as neoantigens on dividing cancer cells, to antifungal agents as anti-cancer drugs. One discussion of particular interest surrounded sphingomyelin metabolism as an important mediator of tumor cell progression. A subject about which I knew little prior to this discussion but will certainly now examine with interest.

It is my hope that I might forge collaborations with some of these investigators. But, there is little that could have prepared me for the pleasure I experienced when sitting across the table from Dr. Ames, while sipping a freshly brewed espresso (deftly prepared by Dr. Ames himself), while we discussed Bruce’s six decades of extraordinary discoveries. Everywhere I looked was an award or a textbook that he had authored. Despite his many accomplishments he was humble, engaging and very witty.

My symposium that afternoon introduced the attendees to human tumor primary culture studies as predictors of response to cancer therapy. I then moved through the accumulated data supporting the clinical outcomes and finally examined our developmental work, finishing with our published collaboration with investigators at NYU and Cornell on the study of a novel class of Wnt inhibitors. Lively discussion ensued.

Among the attendees was Bengt Mannervik, who asked several good questions. I note his presence for he is one of the leading experts in the field of glutathione metabolism and a scientist who I had met several times before. As one of the fathers of glutathione s-transferase chemistry, Bengt’s work had influenced my earlier studies. It was an unexpected honor to have him in the audience, as a visiting professor on sabbatical from Uppsala.

As I have noted before, the reception from the scientists in these fora improves as they examine the data on its own merit, unaffected by the clinical dogma and politicking that contaminates so much discourse in medical oncology today. There was no agenda, just scientific interest and open discussion. It was a refreshing departure and a welcome opportunity to interact with open-minded investigators.

In the audience was Dr. Ames’ wife, Giovanna, a former professor of biochemistry at Berkeley, and a scientist whose work included the earliest discovery of the ABC transporters, now recognized as the basis for the human p-glycoprotein drug resistance mechanisms. At the end of the lecture, Giovanna Ames, impressed by the data, raised her hand and asked, “If what you need is a small portion of each patient’s tumor to conduct these studies, what do we have to do to be sure that every doctor sends you a piece of tumor?” While I’m not sure I that have the answer to her question, I am very sure that I like the way she thinks.

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.

Cancer Gets Personal

Early in the morning of Nov 21, I suffered the loss of my father. However prepared one might be for this eventuality, there is nothing that can really prepare you.

At 95 years of age, he had lived longer than many. I had cared for my father as a patient since 1974, when he was first diagnosed with inoperable prostate cancer. I remember the day I received notification of the diagnosis. I felt a sense of deep sorrow that my father at 74 would soon die of high-grade locally advanced prostate carcinoma. As a member of the generation that forgot to have children, I was saddened that my father would not live to see grandchildren.

I remember traveling to Connecticut for his initial evaluation and then scouring the literature for the best possible options. Fortunately, despite the aggressiveness of the disease it had not metastasized.

I arranged for my father to travel to California where I then oversaw his care in collaboration with Dr. A.M. Nisar Syed in radiation oncology. There is a well-known dictum in medicine that only doctors and their families suffer unexpected complications. In my father’s case it certainly rang true. First, the radiation implants did not penetrate the tumor and needed to be removed and replaced. As a result of this double procedure, he then developed bleeding that required emergency hospitalization several days later.

Despite these hiccups, the combination of implant and external beam radiation provided excellent control. With a full recovery my father returned to his normal activities.

As so often happens in medicine a personal experience provides a focused interest. I delved into the prostate cancer literature and became increasingly interested in the biology of this disease. One area of particular interest was the role of hormonal therapy. When? How much? How long?

When my father’s PSA began to rise the second year, I had a unique opportunity to examine these questions at a very personal level. Would the early institution of androgen blockade induce the hormone refractory state? Was there a “trigger” value of the PSA that dictated the institution of the therapy? I remember discussing these questions with a prostate cancer expert and chairman of the ECOG committee, Dr. Basil Kasimis, whom I had had the pleasure of working with several years earlier. I agonized over starting hormonal therapy as my father’s PSA rose from 4 to 10, to 25, to 54, and up to 150. Despite these frightening PSA values, there was no evidence of metastatic disease on serial bone scans, which I performed religiously every six to 12 months.

Almost a decade passed but there was still no metastatic disease. And then my father developed severe coronary artery disease in his early 80s. Coronary artery bypass graft was the only option. To avoid the possibility of seeding the sternal wound, I bit the bullet and treated him with hormonal suppression – immediately driving the PSA to nearly 0.

With his coronary artery bypass surgery a success, he came off hormonal therapy and I let his PSA drift upward again.

As he had returned to Connecticut, his urologist became increasingly concerned by the rising PSA, and, without my knowledge, decided to rechallenge him with hormonal ablation. While I understood the motivation for this intervention, I didn’t agree and took him off all hormones for a prolonged period of time. Over the subsequent years, I would intervene occasionally to shepherd my father through pneumonia, a broken hip, a bleeding ulcer, and a variety of other maladies so common in patients who transition from their 80s to their 90s. On several occasions, we gave brief courses of hormonal ablation to suppress the PSA, when the steepness of the rise gave concern. Twenty-one years after his diagnosis my father died of natural causes, with no evidence of metastatic prostate cancer.

The experience was instructive on many levels. First, I realized how important it is to treat all patients as if they are a member of your own family. Second, it takes a lot of guts to step outside the normal guidelines and to do what you believe to be best. Third, I realize that in medical oncology it is the most “aggressive” physician who has the courage not to treat.

So often in this field doctors institute treatment, not because it is needed, nor because it will work, but because by doing so they have “done their job,” the rest is no longer their responsibility.

But “doing your job” as a physician, particularly in medical oncology may demand that you step outside of the NCCN guidelines, however uncomfortable it may make you, to do the right thing. Virtually every urologist or oncologist in America would have treated my father for his rising PSA 20 years ago. While I cannot say with certainty, I feel fairly confident that he lived the past 21 years in part because I didn’t treat him. Every patient needs an advocate. I feel a sense of personal satisfaction that I was there to be my father’s. He lived a long and productive life, I hope and believe that I helped him to do so.

Every experience, even traumatic ones, can have a silver lining. My father’s diagnosis lead me to develop a combined modality approach for locally advanced prostate cancer that has provided among the best biochemical relapse-free survival rates ever observed in this disease. Had I known then what I know today, I would have certainly treated my father with this approach.

Secondly, my interest in prostate cancer lead me to examine the lifestyle, nutritional, and micro-nutritional aspects of this disease – knowledge that I apply to this day. This lead to my analysis of an herbal remedy for prostate cancer that unfortunately uncovered the adulteration of an herbal mixture as we reported. (Herbal Composition PC-SPES for Management of Prostate Cancer: Identification of Active Principles: Journal of National Center Institute, Vol. 94, No. 17, September 4, 2002.) Despite our disappointment at the discovery, it lead me to reexamine the use of estrogenic substances as therapies in this disease, insights that have provided benefit to many of my patients ever since.

In retrospect, it may have been my father’s natural inquisitiveness (that he imparted to me) that leads to my pursuit of these lines of investigation. And for that I will always be grateful.

To read more about Alphonse Nagourney, click here.

Looking Beyond the Academic Walls for Cancer Care

At the recent Society for Integrative Oncology meeting in Cleveland, Ohio, I had the opportunity as an invited lecturer, to sit in on many informative presentations. As I listened to these investigators, who have developed clinical therapy programs combining traditional chemotherapies with dietary, lifestyle and herbal remedies, I felt a sense of shared frustration. Here, after all, were dedicated therapists using available non-toxic interventions to improve outcomes, yet the major academic centers continue to turn a blind eye to their contributions. Instead they are required to meet stringent research criteria that those within conventional therapy might be unable to meet.

I then realized that cancer patients must step outside the confines of usual and customary referral patterns and treatment programs to obtain the best outcome for themselves. I was favorably impressed by the dedication of the many investigators and feel convinced that the application of natural products, supportive measures, dietary and lifestyle modifications, and the judicious use of chemotherapeutics will indeed lead the way to a better future in oncology.

As I often say to my patients, “No one is more interested in saving your life than you.”

An Ounce of Prevention

Colorectal cancer is among the leading causes of cancer death in the United States. While most patients develop this disease over a period of decades, associated with an accumulation of genetic mutations (elegantly described by Burt Vogelstein, PhD at Johns Hopkins), a small percentage of patients have a genetic predisposition for this cancer. Among these are those people that carry the familial adenomatous polyp syndrome (FAPS) and those who carry mismatch repair mutations know as Lynch syndrome.

It is the latter group who are the subject of a report in the October issue of the English journal Lancet. In this study, known as the CAPP2 trial, patients with Lynch syndrome received either placebo or 600mg of aspirin per day (the equivalent of two tablets). The results reveal a statistically significant reduction of colon cancer that clearly favored the aspirin group.

To put this in perspective, this dramatic improvement in the highest risk population didn’t come about as the result of a new signal transduction inhibitor or a monoclonal antibody. Instead, it came from the simple administration of one of mankind’s earliest medicinal substances. I applaud these English investigators in conducting this study of 861 patients.

What is most laudatory is that the intervention, while highly effective, is so inexpensive. In an era of proprietary medications and the promotion of expensive new interventions, it is indeed refreshing to read the results of a well-conducted study using an intervention available to all.

Data generated more than two decades ago established the benefit of non-steroidal anti-inflammatory drugs like aspirin for the prevention of colorectal cancer. It is gratifying that this simple intervention has additional scientific support both for those with high-risk predisposition, as well as other patients at risk for this relatively common, yet potentially lethal, malignancy.

What Exactly are the Targets of Targeted Therapy?

The term “targeted therapy” has entered common parlance. Like personalized medicine, targeted therapy is a generic description of drugs and combinations that inhibit specific cancer-related pathways. I am impressed by how quickly esoteric phenomena like the downstream signal in the insulin factor pathway have entered the lexicon of medical oncologists. With the advent of temsirolimus and everolimus, both rapamycin derivatives that target mTOR, we now have at our disposal agents that are every bit a part of the therapy repertoire. Unlike erlotinib that targets a specific tyrosine kinase, mTOR is a complex and multifaceted target.

There are actually two separate forms of mTOR, TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy. One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, we have utilized the primary culture platform. It enables us to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach we can partner with collaborators to define the specific operative pathways in each disease entity.

Biological complexity is the hallmark of life. We ignore it at our peril.

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?