More progress – Merry Christmas!

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Men who have metastatic prostate cancer at presentation are now quite rare. In the days before psa screening (which clearly works, but picks up way too many patients with low grade disease whom we don’t need to find…see multiple blogs elsewhere) we used to see 70 year old men come in with new bone pain, and then it turned out to be prostate cancer. In any case, since the discovery of the taxanes (docetaxel and cabazitaxel), the first drugs to prolong survival after castrate resistant disease sets in, we have all wondered if they were used earlier whether there would be an advantage. The earliest they could be used would be immediately after surgery – but the trial that attempted to study this was abandoned after 2 years because not enough men/doctors would sign their patients up. (see blogs on this elsewhere as well)

So… what about using taxanes at the time hormone therapy is first started? (This could be after surgery or radiation…many years…or when a rare patient first presented with metastatic disease. They HAD to have metastases, however, not just a rising psa. The study (which we called CHAARTED – and my colleagues at CU and I offered this trial to many patients and we treated quite a few who were willing) randomized to hormone treatment alone vs hormone treatment (ADT) combined with 6 cycles over 18 weeks of docetaxel. The trial has been reported now in preliminary form and shows significant improvement in survival in the men who received the docetaxel. This is really a trial between “early vs late” docetaxel, since I am relatively certain the men who got ADT alone would have eventually received docetaxel as well when they became castrate resistant. This is a BIG deal. It means that we have a shot at eliminating some of the cells that don’t fully die off from ADT alone right at the start. It also paves the way to go back and look at doing similar treatment right at the time of surgery or radiation, like we tried to do a decade ago. And if we add the newer hormonal agents (abiraterone, enzalutamide, Tak700, etc) up front, the results could be even better (please lobby the companies who make these agents to provide them for free to men willing to be treated in such trials)

Hats off to the men who agreed to this practice changing trial and to their physicians. And congratulations to my good friend Chris Sweeney who headed up the trial. (He and I have had some great times together over the years) Gentlemen, this is what our sisters did to advance breast cancer treatment 30 years ago! Don’t ever tell me it isn’t good to sign up for randomized trials, or that just doing what we always have done is adequate. Support research! Only 4% of U.S. cancer patients participate in clinical trials. Let’s work together to beat this disease. Happy holidays!

14 Comments

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14 responses to “More progress – Merry Christmas!

  1. As taxol treatment becomes more common, it will become important to make sure that patients about to undergo this treatment do not take the supplement quercetin, or perhaps better stated, that we keep close watch on the research as at this time we consider taxol and quercetin a bad mix. Alone quercetin may have value in slowing prostate cancer. Just not with taxol. “The flavonoid quercetin transiently inhibits the activity of taxol and nocodazole through interference with the cell cycle.” ‘although long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival, the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M’

    Nutr Cancer. 2010;62(8):1025-35.
    The flavonoid quercetin transiently inhibits the activity of taxol and nocodazole through interference with the cell cycle.
    Samuel T, Fadlalla K, Turner T, Yehualaeshet TE.
    Source
    Pathobiology Department, Tuskegee University, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee, Alabama 36088, USA. tsamuel@tuskegee.edu
    Abstract
    Quercetin is a flavonoid with anticancer properties. In this study, we examined the effects of quercetin on cell cycle, viability, and proliferation of cancer cells, either singly or in combination with the microtubule-targeting drugs taxol and nocodazole. Although quercetin induced cell death in a dose-dependent manner, 12.5-50 μM quercetin inhibited the activity of both taxol and nocodazole to induce G2/M arrest in various cell lines. Quercetin also partially restored drug-induced loss in viability of treated cells for up to 72 h. This antagonism of microtubule-targeting drugs was accompanied by a delay in cell cycle progression and inhibition of the buildup of cyclin-B1 at the microtubule organizing center of treated cells. However, quercetin did not inhibit the microtubule targeting of taxol or nocodazole. Despite the short-term protection of cells by quercetin, colony formation and clonogenicity of HCT116 cells were still suppressed by quercetin or quercetin-taxol combination. The status of cell adherence to growth matrix was critical in determining the sensitivity of HCT116 cells to quercetin. We conclude that although long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival, the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M.
    PMID: 21058190 [PubMed - indexed for MEDLINE] PMCID: PMC3021775 Free PMC Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021775/

    Clin Nutr. 2013 Sep 3. pii: S0261-5614(13)00235-5. doi: 10.1016/j.clnu.2013.08.011. [Epub ahead of print]
    Chemopreventive effect of quercetin, a natural dietary flavonoid on prostate cancer in in vivo model.
    Sharmila G, Bhat FA, Arunkumar R, Elumalai P, Raja Singh P, Senthilkumar K, Arunakaran J.
    Source
    Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, India.
    Abstract
    BACKGROUND & AIM:
    Prostate cancer is one of the frequently diagnosed cancers in men. Increased Growth factor IGF-1/IGF-1R axis activation mediated by both PI3K/Akt or RAF/MEK/ERK system and AR expression remains important in the development and progression of prostate cancer. Targeting such system by dietary agents quercetin in vivo model could aid its application in both treatment as well as prevention of prostate cancer.
    METHODS:
    In our study the rats were divided into four groups; Group I: control (propylene glycol-vehicle), Group II: cancer-induced (MNU and Testosterone treated) rats, Group III: cancer-induced + Quercetin (200 mg/kg body wt/orally) and Group IV: Quercetin (200 mg/kg body wt) thrice a week. After the treatment period rats were sacrificed and the ventral and dorsolateral prostate lobes were dissected.
    RESULTS:
    Antioxidant enzymes and apoptotic proteins were significantly decreased in cancer-induced animal and upon quercetin supplement its level was increased. The IGFIR, AKT, AR, cell proliferative and anti-apoptotic proteins were increased in cancer-induced group whereas supplement of quercetin decreased its expression.
    CONCLUSIONS:
    Quercetin down regulates the cell survival, proliferative and anti-apoptotic proteins thereby prevents prostate cancer, by acting as a chemopreventive agent in preclinical model.
    Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
    KEYWORDS:

    PLoS One. 2012;7(10):e47516. doi: 10.1371/journal.pone.0047516. Epub 2012 Oct 18.
    Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.
    Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X.
    Source
    Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.
    Abstract
    Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.
    PMID: 23094058 [PubMed - indexed for MEDLINE] PMCID: PMC3475699 Free PMC Article
    etc

  2. Dan

    Dr Glode, Thank You for the post. Very interesting results on the early use of docetaxol , DR Strum had suggested that years ago, when I was new to ADT, I did not do it. It also seems similar to what Servadio did in his studies of adding cyclophosphamide/ cytozan to orchiectomy and DES http://www.ncbi.nlm.nih.gov/pubmed/1532103. I noticed that you had some excellent results in a study of cyclophosphamide ,I was wondering how well it is tolerated. I am currently on a combo of xtandi and zytiga almost 8 years out after m1b dx as Gleason 10 and psa 148 and I am thinking that cyclophosphamide may be a next step for me, as it may allow me to continue with my active lifestyle of my work. currently I have been on the zytiga for 16 months and added xtandi three months ago , still responding nicely.
    Dan

    • Oral “metronomic” cyclophosphamide has been an interesting treatment as we first published several years ago. Others have been able to achieve similar results. Indeed, in a review article, other authors have called for more extensive exploration of this approach, which I would certainly support were there a national trial going on. To be “practice changing” as the study on adding docetaxel to up front hormonal treatment is, would require a large, randomized, phase III trial.

  3. Cindy Landsberg

    This news could not be more timely for us. We need to talk to you. Bill and Cindy Landsberg

  4. Marshall Freedman

    PCa is a wily villain and hard to outsmart. Adding firepower (to mix the metaphor) makes sense eo me.

  5. Paul Liao

    Sounds like it going on hormones early has a benefit. Maybe I should ask about this?

  6. Bob Lederer

    Great summation post. I saw this when the study first came out but did not appreciate how important it is. You always have a way to crystalize the thinking and to get it understandable for lay folks. Marry Christmas to you and Mimi.

  7. Dan

    Dr Glode, I see that the take home message is clearly that early taxotere is better than late, however you mention that using newer drugs like zytiga and xtandi up front may be a better approach with adt than starting with casodex switching to nilandron and getting the most of these drugs before moving on. Is this the new Paradigm in treatment of Men who have progressed beyond rp and radiation to the prostate bed. Thank you for all your research, and for taking time to educate us Patients who believe knowledge is power in our battle. This was a discussion at my support group

    • Just to clarify, the new data purport to show that using 6 cycles of docetaxel at the start of chemotherapy may be advantageous compared to waiting until CRPC ensues. These data don’t speak to when/how to use the newer antiandrogen drugs or whether one could use all of the above at the time when hormone therapy is first instituted. Still less, there are no data on whether such approach(es) would be best used in high risk patients at the time of initial surgery or radiation. All of the above will require the very long and arduous clinical trials before insurance/medicare will pay for them, but hopefully the pharmaceutical companies and NCI will get behind sponsoring such trials, and even more, the men who fit these trials AND THEIR UROLOGISTS will become more dedicated to participating!

  8. Pingback: The challenge of new drugs | prost8blog

  9. Pingback: Measles Virus – ’tis the season for sensational news | prost8blog

  10. Pingback: Practice changing results….chemotherapy up front. | prost8blog

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