Transcript of Live Chat, from June 17, 2001
Steven Brem M.D.
Moderator: Al Musella, DPM President, Musella Foundation
Location: Virtualtrials.com Auditorium
Musella "OK. We can get started..."
Musella "Welcome Dr. Brem.. Can you tell us about your background?"
DrBrem "I received my medical, surgical, neurosurgical, oncology training at Harvard and its teaching hosptials. I was on the faculty at McGill, Northwestern, and now at USF/Moffitt Cancer Center where I direct the brain tumor program, and am the Chief of Neurosurgery.I"
Musella "Tell us about the clinical trials that you are now involved in"
DrBrem "I am the P.I. at Moffitt for the NCI-sponsored NABTT clinical trials. These currently include Onyx-15 (gene therapy), COL-3, EMD 121974 (anti-angiogenesis), suramin (anti-angiogenesis), as well as a co-investigatgor on the Agouron 3340 trial (with Dr. Phuphanich) an anti-angiogenesis agent. We are also working with Proxima to study the ""Gliasite"" for metastatic carcinoma, as well as with Schering Plough to look at Temodar + Penicillamine for br"
DrBrem "A complete list of the NABTT clinical trials is available at the NABTT web site, www.nabtt.org."
Musella "Do you feel that there will be any major advances in brain tumor treatments in the next few years?"
Musella "IF So, which look the most promising?"
DrBrem "Certainly. I am heavily biased towards anti-angiogenesis therapies, a field in which I have been working for 30 years, since our initial studies of brain tumors in Boston with Judah Folkman. We predicted that if anti-angiogenesis was going to work, it woul work in patients with brian tumors."
Musella "Has antiangiogenisis ever helped in any type of human cancers?"
DrBrem "There are many exciting technologies of course. We are very interested in pursuing them all, from the farnesyl transferase inhibitors, to the signal transduction inhibitors, to slow-release polymers, etc., our patients really don't care which molecule is effective, so long as one is."
Musella "What is the connection between a low copper diet and antiangiogenisis?"
Musella "(Sorry -I am one question ahead:)"
DrBrem "To answer your first question, there are 35 clinical trials now underway for anti-angiogenesis. I would predict that there will be several agents approved by the FDA in the next few years. Don't ask me which one, because that is why we have the clinical trials. Right?"
DrBrem "The low copper diet and anti-angiogenesis is part of the completed NABTT clinical trial 9704. We are still awaiting the final results of the study, so hopefully there is merit in that approach. In preclinical studies, we found that we could reproducibly inhibit brain tumor growth, angiogenesis, and invasion using a low copper diet and a chelator of copper, penicillamine. We now know the mechanism to be interference with polypeptide growth fact"
Musella "Would it be wise for brain tumor patients to restrict the copper in their diets - no matter what treatment they are using?"
DrBrem "That is a difficult question to answer. We first need to be sure that in humans copper reduction will block angiogenesis, then determine what level. Copper is not necessarily ""bad"", but at a certain level of copper reduction, angiogenesis shuts down. If someone restricts copper without monitoring of serum copper, he/she might not be lowering it sufficiently or lowering it more than necessary. Like glucose, copper is found in every cell. It is "
Musella "Would an anti-angiogenesis approach theoretically be usefull for diffuse tumors or only more solid types of tumors?"
06/17/01 20:19:17 ROOMMSG
DrBrem 1Cust220.tnt3.tampa.fl.da.uu.net PRIVMSG #Auditorium "In my view, it should work for both types. The solid tumor depends on the continual recruitment of vessels to maintain its volume; tumors deprived of blood supply never become huge masses. On the other hand, many or most of the angiogenesis inhibitors also block invasion, because there are similar molecular/ cellular processes to tumor cell invasion and endothelial cell migration (angiogenesis). In fact, in the earlier copper reduction studies,"
DrBrem "A summary of the clinical trials on angiogenesis and the NABTT 9704 clinical trial can be found on the internet, by going to the Moffitt Cancer Control Journal, www.moffitt.usf.edu. If someone ...."
DrBrem "wants the exact address, you can send me a request at email@example.com, and I will get you the full article...."
Musella "Should brain tumor patients avoid sugar?"
DrBrem "I don't know of any scientific data one way or the other, but there is a lot of work...."
DrBrem "in general, that excess energy intake (i.e, overeating) will promote all forms of experimental..."
DrBrem "cancer, and the NCI and the AICR, organizations which study the
link between diet and cancer.."
DrBrem "do recommend a sound nutritional plan, avoid excesss sugar. The answer is ""probably, yes"".."
Musella "What are your thoughts on each of the following treatments for brain tumors (one at a time):"
DrBrem "Promising....await the NABTC trials...as you know, we are interested in studying Temodar +...."
DrBrem "Gleevac .Should only work on patients with PDGF-receptor in their tissues, its specificity is its strenght and potential weakness..."
DrBrem "We need to define which patients, if any, it would be effective."
DrBrem "Gliadel. We use that for recurrent malignant glioma, per FDA-indication, and for upfront use in metastatic carcinoma..."
DrBrem "We concluded a study with 5 centers, Matt Ewend was the lead investigator (UNC) and..."
DrBrem "there has been NO Recurrence in 25 patients with a mean follow-up of one year. We have been impressed with the use of Gliadel for patients with single mets + XRT to avoid recurrence, as we have treated more patients off study."
Musella "That sounds great...."
Musella "How about Celebrex?"
DrBrem "It is likely that Gliadel will be increasingly used for newly diagnosed GBM, based on the results of the European study."
DrBrem "Celebrex. Interesting. There is a lot about Cox-2 in angiogenesis. The science is good. It seems to be effective in colon carcionogenesis. I am not aware of much work in human brain tumors. It certainly is readily available."
DrBrem "We use a lot of temodar. It is effective for AA, of course. For GBM, it is a good alternative. We use a lot of T&T (Temodar + thalidomide) for the difficult gliomas.e"
DrBrem "We participated in the NABTT CPT-11 trials. The results were not impressive. The theory is good."
DrBrem "It is available as an anti-angiogenic agent. We have seen a few responses. The drowsiness limits its application for our brain tumor patients."
DrBrem "Widely available as an anti-angiogenic agent. Very mild. Little data on efficacy. Can be used as part of a combination cocktail."
Musella "Gene therapy?"
DrBrem "Very promising in the lab, but frustrating in the clinic because of problems of delivery, dosage, etc."
Musella "How about the new forms of radiation delivery, such as:..."
DrBrem "Gliasite is interesting. The data is good from the early NABTT trial. With all forms of focal radiotherapy, there is a selection bias. For selected patients, it may be a good approach. We are pursuing it at Moffitt."
Musella "Monoclonal antibody / I 131?"
DrBrem "I don't have personal experience with it, but it is an interesting and promising approach. The data presented at ASCO looked good."
Musella "Cotara? (which is a Tumor necrosis factor antibody/ I 131)"
Musella "Getting back to gleevec.. can a patient have their samples tested for the receptor?"
DrBrem "We are planning to do this at Moffitt. I don't know of other sites. It should be possible."
Musella "Radiation again: there are many new forms of radiosurgery and shaped beam radiation, IMRT, fractionated stereotactic radiosurgery, proton beam.. is there really a difference, if so - which ones are the best?"
DrBrem "With advances in computer software, the ability to give conformal therapy continues to improve..."
DrBrem "we are impressed with the Cyberknife, and are also looking at the Novalis system. There are advantages to the latest technology."
Musella "In surgery - we see advertisments for intra-operative MRI. Does it really make much of a difference in outcome compared to what is more commonly available?"
DrBrem "Controversial! No difference according to Pat Kelley who has been the ""guru"" of computer-assisted surgery. However, my friends in Boston are quite excited about intra-op MR. We use Image-Guided surgery. In one two percent of cases, usually with low-grade gliomas, we could have gotton a 100%% resection rather than a 90%% resection with intra-op MR. .."
DrBrem "In those cases, we have gone back for a second procedure to attempt a ""cure"". I suspect intraop MR is the wave of the future, but the current models have technical problems that offset the theoretical pluses."
Musella "What would be your preferred treatment plan for a young, (otherwise) healthy patient with a newly diagnosed gbm?"
Musella "your last message didn't come through.."
DrBrem "Gross total resection by a skilled neurosurgon, followed by radiation therapy and a good clinical protocol."
Musella "Do you beleive in a ""cocktail"" approach - being aggressive with a few treatments at once, or to take it one step at a time - one treatment alone. (From a patient's point of view - not a researcher's:)"
DrBrem "The ""molecule of the month"" is oxaliplatin."
Musella "There are over 100 different trials. How could someone go about selecting a trial?"
DrBrem "Tough question. I wouldgo one step at a time, because of the hazards of mixing unproven treatments."
Musella "What would be the drug of choice for an anaplatic oligodendroglioma?"
DrBrem "Establish a trusting relationship with an expert, staying abreast with the knowledge (internet), that is the best approach."
DrBrem "For AO, either Temodar or PCV."
Musella "For an acoustic neuroma: would you favor radiosurgery or surgery?"
DrBrem "I am biased to microneurosurgery, but the data on radiosurgery is looking good."
Musella "Same question with meningioma: surgery or radiosurgery?"
DrBrem "Surgery, wherever possible. When not resectable, then radiosurgery."
Musella "With radiosurgery for an acoustic neuroma: what is better, gamma knife or fractionated stereotactic radiosurgery?"
DrBrem "I do not know of any trial or data to show superiority of one method over the other."
Musella "Which trial is your favorite now?"
DrBrem "I try not to have a ""favorite"", we like them all, we will love the one that works the best."
Musella "Do you think that the drug companies try to infulence the outcome of trials by trying to sway researchers with a lot of money?"
DrBrem "Whew!!!! A researcher at Moffitt noted that 50%% of NCI clinical trials that are published have positive conclusions, and 95%% of pharmacuetical-supported trials conclude with postive results. It is important to remain objective."
Musella "Coincidence! Do you think we will ever find a cure - or at least turn brain tumors into a chronic manageble condition?"
DrBrem I am an eternal optimist. I have seen great strides in the past few years."
Musella "How fast can a gbm double in size?"
DrBrem "we have been on the ""verge' of a blockbuster breakthrough for many years, hopefully soon the brain tumor community will celebrate. The success with STI-571 should give us all hope that the science will deliver."
Musella "How long does a gbm tumor cell live, and how long does a normal glial cell live?"
DrBrem "A GBM can sometimes double in size as fast as two weeks, but usually it is a 4-6 weeks. It can double fast!"
DrBrem "The glial cell is normally in a Go phase, it lives a long, long time, but does not proliferate. The tumor cell has a shorter lifespan but is dividing as well asundergoing apoptosis ..."
DrBrem "(programmed cell death)."
Musella "What are your thoughts on the new formulation of bcnu that is injected stereotacticlly into the tumor bed? (I forget the name:)"
DrBrem "DTI-015. We have the protocol ""up and running"" at Moffitt. It is an interesting approach."
Musella "We have time for 1 last question: Any new treatments for radiation necrosis?"
Musella "(ie. hyperbaric oxygen?)"
DrBrem "Unfortunately, no. Hyperbaric oxygen....perhaps...that is not new....A very tough problem!"
Musella "Wait.. 1 more:)"
Musella "Any new treatments for edema?"
DrBrem "Dr. Grossman's group at Johns Hopkins is working on an interesting approach in the laboratory, should go to clinical trials soon..."
Musella "what is it called?"
DrBrem "It is a COX-2 inhibitor....preliminary work was presented at ASCO ..."
Musella "Like Celerex?"
DrBrem "Not exactly, perhaps similar. (Celebrex), it is of the same family, but a different molecule."
Musella "That concludes this chat. Thank you Dr. Brem!"