Chemotherapy and other treatments for metastatic prostate cancer. As we have talked about previously, almost all chemotherapy drugs have been designed to keep cells from dividing. Cancer cells tend to divide more rapidly than normal cells, and therefore they are more likely to die from treatment. Normal cells in the body, like cells in hair follicles, white blood cells that fight infection, and the lining of the colon are also dividing and that is why the main side effects fo chemotherapy are hair loss, infections risk, and nausea and diarrhea. There are two broad classes of chemotherapy drugs, agents that interfere with replication of DNA and agents that interfere with cell division by blocking mitosis. The commonly utilized chemotheraphies for prostate cancer are Docetaxel or Taxotere and cabazitaxel or Jevtana. They both interfere with mitosis. An older drug that is occasionally still used in the treatment of metastatic prostate cancer is Mitoxantrone or Novantrone. This interferes with DNA replication. To divide, cells use microtubules. Microtubules provide the infrastructure to pull the chromosome of dividing cells into two daughter cells. Both docetaxel and cabazitaxel are drugs that block microtubules and stop the cells from dividing, when the cells are stopped from dividing they basically panic and undergo program cell death or epitosis. How effective is chemotherapy? Well, docetaxel is used as first-line chemotherapy, after patients fail castration therapy. It is generally used after the second-line hormone agent abiraterone and enzalutamide fail. Is generally given every three weeks, on average it adds approximately three months to overall survival. Some patients get much more benefit. Cabazitaxel is approved as a second-line chemotherapy after patients fail castration therapy, and it's generally given after docetaxel fails. It's, again, given generally every three weeks, and on average, adds approximately two to three months to overall survival. This does not sound like much but some patients get much more benefit. What are the possible side effects of chemotherapy? Well, chemo drugs again attack cells that are dividing quickly, which is why they work against cancer cells. But other cells in the body, such as those in the bone marrow, or the lining of the mouth and intestines, and the hair follicles also divide quickly. These cells also can be affected by chemo which leads to side effects. You can predict the common side effects. They include hair loss, loss of appetite or nausea, fatigue, increase the susceptibility to infection. Peripheral neuropathy, numbness and tingling in fingers and toes as a result of nerve damage. Diarrhea which is a more common with cabazitaxel, and sometimes allergic reactions to the chemotherapy or what the chemotherapy is mixed in. These are very rare. There are other treatments that are approved for Castrate-Resistant Prostate Cancer. These include Sipuleucel-T, Provenge and Radium-223 or Xofigo. Sipuleucel-T or Provenge is a cancer vaccine. Unlike traditional vaccines which boost the body's immune system to help prevent infections, this vaccine boosts the immune system to help it attack prostate cancer cells. It is used in men with castrate-resisting prostate cancer with few or no symptoms. It is made specifically for each man. To make it, white blood cells are removed from the blood over a few hours with a procedure called apheresis. The cells are then sent to a lab Where they are exposed to a protein from prostate cancer cells called prostatic acid phosphatase (PAP) and an immune stimulant (GM-CSF) which is a colony stimulating factor. The cells are then sent back to the hospital and re-infused into the patient. This process is repeated two more times, two weeks apart, for a total of three doses. It is thought that the cells help other immune system cells attack the prostrate cancer. The vaccine hasn't been shown to stop prostrate cancer cells from growing, but it seems to help men live an average of several months longer. Of note, it does not change PSA and it is very well tolerated with few side effects. Here, you can see the recombinant fusion protein consisting of the GM-CSF and PAP binding to a dendritic cell. This dendritic cell is then turned on to recognize prostate cancer cells as foreign. When it's reinfused into a patient, it activates T cells, which specifically then search out prostate tumor cells and try to kill them. What about Radium-223 or Xofigo? This is a systemic radionuclide. It is an alpha-emitting particle that is calcium-avid and is attracted to where bone is being remodeled. It is injected through the vein every four weeks, generally for up to six doses. It improves average survival by several months and it decreases pain. So how do we put all these various treatments together? I've presented to you here a 59-year-old with Metastatic Castration-resistant Prostate Cancer to bone. He's already received an LHRH analog. How will we approach his treatment? Well, if he doesn't have very many symptoms or he has bone-only disease, we would consider giving him Sipuleucel-T or Provenge as a one time therapy. He could then get Abiraterone or Zytiga. When that's stop working, if it's AR-V7 negative, he could get in enzalutamide. Keep in mind could have started with enzalutamide first. If after that he has bone pain, we could give him Radium-223 or we could give him docetaxel. After he's had docetaxel and that doesn't work anymore he could get cabazitaxel. And after cabazitaxel isn't working, he could get mitoxantrone. Through all of these steps he's eligible for clinical trials. We would also be treating him concurrently with anti-osteoclast medicines. Medicines to strengthen his bones like denosumab and zometa. We'll talk about those in Lecture 5. Many men now are also biopsied very early to look for driver mutations in their tumor to help us better take care of these patients as well inform us about what clinical trials the patients might be eligible for.