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?

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.

11 Responses to Ovarian Cancer Therapy

  1. It’s never been shown that adding paclitaxel (Taxol) to first line treatment of ovarian cancer improved survival. It’s been shown that paclitaxel + platinum is superior to paclitaxel + cyclophosphamide. It’s never been shown that paclitaxel + platinum is superior to single agent cisplatin or carboplatin.

    The findings in the GOG 132 study and the International Collaborative Ovarian Neoplasm study (ICON3) of equivalent effectiveness with the initial use of single-agent platin compared with platin-taxane doublets, the issue of whether the combination of platin and paclitaxel is superior to initial single-agent platin is still unresolved. First-line comparative studies have demonstrated equivalent effectiveness.

    Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 18:106-115, 2000

    The International Collaborative Ovarian Neoplasm (ICON) Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: The ICON3 randomised trial. Lancet 360:505-515, 2002

    Source: JCO, Vol 27, No. 9, March 20, 2009

  2. Linda S says:

    Dr. Nagourney — has there been any followup to this article which seems to indicate Taxol can cause increased metastases at least in breast cancer?

    http://www.umgcc.org/news/microtentacles.htm

    Is this true as well in ovarian cancer and if so, wouldn’t that in and of itself be a reason to avoid it front line, and to reconsider its growing popularity in the dose dense approach?

    Linda

    • It is an intriguing finding. The tau proteins are a subset of microtubules that are targeted by Taxanes. Cell line systems can offer interesting insights but have also been quite wrong in some circumstances. It is noteworthy, as Greg P points out that Carboplatin plus Taxol has not been proven superior to either single agent Carboplatin (ICON III) nor CAP(ICON II), the older 3 drug regimen. One can only speculate whether this reflects an unintended effect of Taxol.

      • Expression of the microtubule-binding protein Tau is not a reliable means of selecting breast cancer patients for adjuvant paclitaxel chemotherapy, according to research led by The University of Texas M. D. Anderson Cancer Center and presented at the December 2008 CRTC-AACR San Antonio Breast Cancer Symposium.

        The hypothesis was that patients whose tumors expressed low levels of Tau would benefit from the addition of paclitaxel. The researchers, using univariate and multivariate analyses, found Tau-positive status (high tau expression) was associated with better disease-free and overall survival. They found no significant correlation between high Tau expression (tau-positive status) and benefit from paclitaxel in the total population.

        What they did find was “low” Tau expression was actually associated with a relatively poor survival despite a higher sensitivity to chemotherapy. While patients with high levels of Tau expression, were not particularly sensitive to chemotherapy but had a significantly better survival.

    • Linda

      I would guess the question of whether this involves ovarian cancer is just a matter of time, because they answered it in lung cancer (Proc Natl Acad Sci U S A. 2001 September 25; 98(20): 11737–11742).

  3. Elaine L. says:

    Linda, I hope you get a response to your question.

  4. Cinahon says:

    MMM Did LInda get an answer? I’m not sure I understand Dr. Nagourney’s reply as it doesn’t seem he really addressed her question. Does it or does it not increased the potential metastases at least in breast cancer? I am getting ready to undergo chemotherapy for a second time from an ovarian cancer recurrance. I would like to know before I chose a regime.

    • Linda S says:

      Not that I can speak for Dr. N, but I think what he means is the research was based on cell line systems which sometimes do not provide reliable answers, thus the smoke may be there but not proven yet.
      I wish they would do dose dense platinum, that would be an attractive option.

  5. Linda S says:

    Dr. Nagourney– I wonder if you could comment on capecitabine which comes up sometimes in the RT assays as a treatment for ovarian cancer (in my case in combo with gemzar/cisplatin).

    I saw there is now a clinical trial testing it in combo with oxalplatin for those newly diagnosed. will be interested to see the results.

    My specific question regards folic acid or folate. From what I can gather, folic acid intake or higher folate baseline seem to make capecitabine more effective, albeit with greater side effects. Folate receptors are also apparently often overexpressed in ovarian cancer and are the target of several clinical trial drugs right now.

    What is the interaction of folate for ovarian cancer and the efficacy of capecitabine for treatment? Should dietary folate be avoided?

    thanks as always,

    Linda

    • This a bit of a different question from the other issue. FOLFOX or the closely related CAPEOX regimens are not unreasonable choices for ovarain cancer patients. FOLFOX provided a 29% objective response rate in previously treated ovarian cancer patients in a study conducted by Greek investigators (Pectasides, et al Gyn Onc, 2004), The second point being the interaction between Capecitabine (Xeloda) and folate. While high affinity folate receptors have been the subject of invetigation and a form of therapy in ovarian cancer, the interaction between 5FU (and related drugs) is different. This interaction is one of an enhancement of the effect of 5FU via a ternary complex (3 molecule ) between TS, 5FU and folate. This is the reason that 5FU is usually now given with Leucovorin (reduced foalte) to enhance its effect. This could also occur with Xeloda.

      • Linda S says:

        Thank you very much, Dr. Nagourney. When I recurred (platinum resistant) I was told by Hopkins my only choices were those on the NCCN compendium, or a clinical trial. I was also told the approximate time I had likely left to live, which made me think the clinical trial was their preferred option for me. For some reason, the FOLFOX regimen was never mentioned as an option for ovarian cancer. I wonder why?
        Does Rational Therapeutics ever receommend Leucovorin as part of its assay combos? It was not recommended as part of mine.

        thank you again
        Linda

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