Sartor, Oliver MD – Bone Targeted Therapies: Radiopharmaceuticals Dr. Sartor is the Director of the Stanley S. Scott Cancer Center of the Louisiana State University Health Sciences Center in New Orleans, LA. He is also the Strong Professor of Oncology and Chief of the Hematology/Oncology service at LSU. This lecture reviewed the State-of-the-Art of treatment of bone metastases with those radio pharmaceutical drugs that have proven to have some effectiveness in palliative care. None of the approaches discussed by Dr. Sartor were “curative” did have supporting data that showed their effectiveness in palliation of bone pain caused my metastatic lesions. In contrast to Dr. Scholz’s presentation, Dr. Sartor spoke about the ratio of bone to soft tissue metastasis in PCa. The former’s presentation implied that mets in PCa only occurred in bone whereas Dr. Sartor more than implied that soft tissue also is the site for PCa mets. Bone mets are the generally the only ones detected radiographically in PCa. PCa is also notorious as an osteoblastic type of tumor. He presented a list of the radiopharmaceuticals (RPs) shown to have some effectiveness in metastatic HRPC: phosphorous 32, Strontium 89, Samarium 153 (EDTMP), Rhenium 186, Tin 117, and Radium 223. Of this list only three are commercially available : strontium 89, phosphorous 32 and samarium 153. One can find literature describing the effectiveness of these RPs in treating metastatic bone lesions of HRPC. Strontium 89 tracks the deposition of calcium and therefore goes to the bone sites where new formation is occurring after osteoclastic lesions have formed. Samarium 153 is complexed with EDTMP which adds a phosphonic acid group to it in a chelated form and this complex goes to the sites where newly deposited bone tissue has formed. The phosphorous 32 follows phosphorous metabolism in the body and finds its way to bone sites. Of the three listed above, both strontium 89 and samarium 153 are in regular use medically today. The differences in the radiological properties of these elements are significant: for example, the half-life of Sr89 is 50.5 days whereas that of Sm153 is only 1.9 days. The beta ray energy from the former is 0.58, whereas that of the Sm 153 is 0.22. So in one case the radioactive source is much longer lived and more intense than in the latter case. Also the reported depth of penetration is 2.4 mm in Sr89 and only 0.55 in Sm 153. All of these differences obviously will impact the nature of the side effects and overall effectiveness of these RPs in treating bone mets from PCa. Because these RPs can and do have myelosuppressive effects in bone tissue, there are contra-indications to their use: “predominant soft-tissue involvement, unifocal bone lesions, lack of bone scan RPs uptake,” and “….severe myelosupprssion”. In the case of Sr89, Dr. Sartor showed data from the literature that reflected how the Sr89 worked: it did not reduce the pain of the mets but did reduce the number of new sites of metastases formed after defined time periods. The data he showed was taken from a “TransCanada Strontium Study published in 1995. For the first three to four months after administration of the RP, there was a pronounced difference in the number of new met sites between the placebo curve and the Sr89 curve. At three months the data showed differences in “Mean New Pain Sites” of approx. 1.3 vs 0.5. Further along the time axis the two sets of pain site data came closer together. This implies that the effectiveness of the Sr89 is transitory. Dr. Sartor also showed data comparing palliative local field radiotherapy with Sr89 treatment. Data was published in 2003. The local field radiotherapy is called “spot welding” in the trade because the radiation is focused as closely as possible onto a single lesion at a time. These data showed an overall advantage in survival for the “spot welding” technique. Both curves dropped rapidly for the initial two years of the study with only an approximately 10% indicated survival benefit for the spot technique patients. ( ED Note: when a patient is dealing with multiple met sites on his bones, the local radiation approach becomes less useful than the generalized one of Sr89 wherein the radioactive element goes to the multiple sites.) He showed images from bone scans that illustrated how Samarium 153 goes to the same sites as the radioactive Technetium used in bone scan imaging. In both cases, the isotope was complexed in a chelate form with the phosphonic acid group attached. The sites of mets was clearly visible on these scan films. Dr. Sartor reviewed a clinical trial he ran testing Sm 153 vs placebo for palliation. The trial design provided for measuring the use of analgesics by the patients attempting to alleviate their bone pain. He found about a 15% reduction in the use of opiods after 4 weeks use of the Sm153 compared to a placebo. He also showed the effect of the RP on the white cell counts and platelet counts. Both dropped over the 4 weeks of the program but recovered to nearly the starting levels after 12 weeks had elapsed. This impact on the functioning of the marrow is a limiting factor in the use of RPs for bone pain palliation. He discussed another clinical trial in which chemotherapy drugs were used in conjunction with the RPs. This is work reported in Lancet: Tu, et. al., Lancet 357 336-41. In this trial, the authors reported a significant survival advantage for the trial arm in which the RPs were used in conjunction with doxorubicin. After 24 months, the combination arm showed approx. 75% alive compared to the non-randomized control group of approx 33%. ED NOTE: Men dealing with metastatic PC disease that is also HRPC should consult this paper by Tu, et. al. and determine whether they might benefit from it. In yet another combination trial using Sm153EDTMP and Docetaxel he reported significant reductions in PSA i.e., 5/6 had >50% PSA drop for >6months and 4/6 pts had a >80% drop in PSA. With other encouraging results similar to these, other trials are being designed to test efficacy of different chemo drugs in combination with RPs like Sm153 EDTMP. Interested parties are urged to contact Dr. Sartor’s office at LSU to obtain exact status of these trials. Mitchell Gross, MD – Future: What’s In The Lab Dr Gross is the Assistant Director of Research of the Warschaw Prostate Center at Cedars-Sinai Hospital in Los Angeles. In addition to his MD degree, he holds a PhD in molecular biology from UCLA. At the WPC he is responsible for treating patients clinically and for supervising the many clinical trials conducted at the Center. Dr. Gross’s talk was intended to review the newest approaches as presented at the ASCO meeting in Orlando, Florida in May of this year. Because of the great number of presentations dealing with prostate cancer at this meeting, he selected a few to discuss during his lecture. [ ED NOTE: The key Internet link for this ASCO meeting can be found by entering “ASCO 2005” in Google. This will pull up the key link allowing the reader to browse for him or her self through the many presentations made there. Based on experience many of these presentations will subsequently and quietly fade from interest. Ongoing research will uncover either overall lack of efficacy, poor toxicity profiles, long development periods before clinical trial results can appear, or other factors that prevent reaching meaningful conclusions. Therefore, the Editor will simply identify the ones selected by Dr. Gross for his lecture. He strongly recommends that each interested individual scan through the ASCO lectures to identify those of particular interest and read them him/her self.] He talked about mTOR, short for “mammalian target of rapamycin”. Rapamycin is a drug routinely used to prevent organ rejection in transplant surgery. Work with rapamycin began in 1975. It derives from soil on, of all places, Easter Island. The mechanism whereby rapamycin is thought to influence cancer cells is to interfere with a particular protein that makes the cell think its dying so it ceases to replicate itself. The connection to rapidly growing and multiplying cancer cells is obvious. Trials are being developed to test this substance in vivo. Another drug he described is Avastin ™ (bevacizumab)as a possible sensitizer for chemo drugs. He referred to some studies of this drug in breast cancer tx. Taxol with and w/o Avastin. He reported an early trial that showed a PSA>50% reduction when it was used in conjunction with Taxol. See CALGB B9100 for more details. Cilengitide was another new drug candidate he discussed. It is in Phase I trials and is intended to stop blood flow to solid tumors. Another one with a unique mechanism of action is Pertuzumab ™ which is intended to “prevent dimerization of the HER receptors on cells. It’s believed by the Genentech Company that this could be an effective anti-cancer mechanism. Still a long way off before real efficacy can be demonstrated. Another one he mentioned was Sorafenib ™ . This is a potential anti-cancer drug that works by inhibiting a particular signaling pathway (s) involved in cell multiplication. Gross also referred to Zometa as an effective new drug in PCa (already discussed in more detail earlier). Prostasol was mentioned as a useful drug along the lines of the original PC-SPES product that was ultimately banned by the FDA when contamination with selected active drugs such as DES and Warfarin was discovered. He also mentioned a commercial product called Prostasol ™. This is similar in composition to the previously mentioned PC-SPES but without the DES and Warfarin additives. Prostasol contains a blend of selected Chinese mushrooms and certain phytoestrogens (plant derived compounds with estrogenic-like properties). Many men with PCa are using this and similar products to reduce their PSA levels but definitive studies of effectiveness are lacking. NPC Program Review, 6/05 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.