Metastases originate from the prostate and spread to another part of the body, most commonly the lymph nodes and bones, and less often to the liver or lungs. Early metastases are usually without symptoms. When cancer becomes widespread, a “whole-body” treatment plan with systemic therapy is necessary. The backbone of treatment is hormonal therapy with testosterone inactivating pharmaceuticals (TIP), also known as androgen deprivation therapy or ADT (Chapters 26 and 29). Deprived of testosterone, prostate cancer cells are unable to replicate and eventually die. The most important predictor of how long TIP will remain effective is determined by the degree of PSA decline after starting TIP, the PSA nadir, which is the PSA level when it arrives at its lowest point. A nadir of less than 0.1 is ideal. When the nadir is above 0.1, hormone resistance and progressive disease is likely to develop quickly. 

When selecting therapy, doctors strike a balance between a treatment’s potency and its side effects. If the PSA rises, or new lesions appear on bone or body scans, a change in therapy is necessary. Provenge’s convenience and lack of toxicity make it a logical first step when men become resistant to Lupron. Provenge requires three visits, one every two weeks, at which time leukapheresis, a process sort of like dialysis, is performed to filter out white blood cells (dendritic cells) from the bloodstream. The dendritic cells are then incubated and “trained” to recognize prostate cancer. Three days later, these “primed” dendritic cells are reinfused back into the patient at the doctor’s office. Dendritic cells activate the killer T cells of the immune system to attack the cancer cells directly. In general, side effects are mild, though occasionally patients will have transient fever, fatigue, nausea, headache, and flulike symptoms. 

The FDA’s approval of Provenge came in 2010 after a prospective, randomized trial demonstrated improved survival compared with placebo. Provenge achieved this in men with relatively advanced disease. Their average PSA was over 50. Further studies in earlier-stage disease have shown a larger survival benefit. For example, Provenge improved survival by 13 months in men with a PSA levels under 22.

Immunotherapy with Provenge is a completely new realm of therapeutic technology. Unlike other types of therapy, PSA levels don’t usually decline. Critics claim this is a sign that Provenge is ineffective. Such criticism is ironic, however, considering that the FDA refuses to use PSA changes as an indicator of a drug’s efficacy. Instead, the FDA demands proof of extended survival in prospective, placebo-controlled trials. Two such trials confirm that Provenge prolongs survival. Even so, some may wonder, “How can life be extended without PSA dropping?” One plausible explanation is that immune enhancement impedes the growth of new cancer cells without causing immediate mortality of the existing cells.

Additional hormonal agents can be added or substituted when Lupron becomes ineffective. For a seasoned prostate cancer road warrior like myself, 2011 marked the start of the “Golden Age” of prostate cancer therapeutics, when a new oral medication called abiraterone (Zytiga) was first approved by the FDA. Zytiga works by counteracting the autologous production of testosterone that commonly occur inside cancer cells that have developed Lupron resistance.  

In a landmark trial, Zytiga was compared head-to-head with placebo in TIP-resistant men who had already tried chemotherapy. The study was stopped early because Zytiga was so effective. In addition to extending life, Zytiga decreased PSA and improved quality of life. Subsequently, in a second study, Zytiga was again compared to placebo, but in patients with earlier stage disease. Zytiga’s anticancer benefits were even more substantial. 

Generally, Zytiga is extremely well tolerated. The most common side effects, if any, are high blood pressure, low potassium, leg swelling, and liver inflammation. Therefore, during the first few months of starting treatment regular lab monitoring is required. Another oral medication called prednisone is also used in small doses to maintain normal potassium levels in the blood. Rarely, prednisone can increase blood sugar, so diabetics need monitoring of their glucose. 

In 2012, another landmark event occurred. The FDA approved another highly-effective oral medication called enzalutamide (Xtandi). In a clinical trial evaluating Xtandi after chemotherapy, Xtandi prolonged survival as well as delaying the onset of pain, bone cancer progression and PSA progression. In addition, quality of life was improved. The most common side effects were hot flashes and fatigue. There was also a risk of seizure, though under 1 percent. In 2014, a second clinical trial evaluating Xtandi prior to chemotherapy showed an even greater improvement in survival, and delayed the need for chemotherapy by 17 months, along with other benefits. In this study, there was no increase in the incidence of seizures. 

In making comparisons between Zytiga and Xtandi, there doesn't seem to be a major advantage of one over the other. Each patient should compare the pros and cons. With Zytiga, the requirement for an additional drug (prednisone) to be prescribed is a disadvantage. Zytiga also requires blood monitoring to check for potassium or liver problems, whereas Xtandi does not. On the other hand, Xtandi is associated with a small risk of seizures. It can also cause fatigue more frequently. 

In 2013, the FDA approved a totally new anticancer technology called Xofigo, a type of “smart radiation” that targets bone metastases. Previous attempts to achieve bone targeted radiation were ineffective and toxic. Xofigo uses alpha emitting radiation derived from Radium-223. Alpha radiation is much more effective and causes far fewer side effects than older radionucleotides which utilized beta radiation. When tested in a randomized clinical trial, Xofigo showed a survival advantage when compared with “best clinical care” which consisted of treatment with Casodex, ketoconazole and spot radiation. Xofigo consists of a simple one-minute injection given monthly for a total of six months. Potential side effects are occasional nausea, vomiting, diarrhea or low blood counts. Although Xofigo extends survival, PSA levels often continue to rise. This “disconnect” between PSA and survival can be disconcerting to doctors and patients alike. Experts hypothesize that Xofigo’s survival benefits work by slowing the rate of cancer cell growth rather than causing precipitous cell death. 

After a patient has been treated with Provenge and Xofigo, and if Xtandi and Zytiga stop working, starting treatment with Taxotere or Cabazitaxel (Jevtana) is usually considered next. Taxotere and Jevtana are chemotherapy and have characteristics that are quite similar to each other. Most of the information provided here about Taxotere is also true for Jevtana. 

Taxotere has two basic roles to play. Taxotere (or Jevtana) is usually reserved for men with progressive metastatic disease after the development of Lupron resistance as well as resistance to Xtandi and Zytiga. Now, however, new studies show that Taxotere’s anticancer effects can be enhanced by using it at an earlier stage, before the onset of Lupron resistance. In one important study, four months of Taxotere added to TIP improved survival by 18 months in men with metastatic, hormone-sensitive disease. Jevtana was initially FDA approved by demonstrating a survival advantage in men who had already taken Taxotere. A more recent study comparing Taxotere with Jevtana showed that Jevtana was equally effective but caused fewer side effects.   

Two “bone-targeted” medications, Xgeva and Zometa, strengthen bone and reduce fractures. Xgeva arrests cancer growth in the bone. Neither, however, impacts survival. With these medications, a severe problem called osteonecrosis can occur. Osteonecrosis consists of a breakdown of gum tissue allowing the exposed bone to become susceptible to recurrent infections. The risk of osteonecrosis is increased when treatment is continued at higher doses and for longer periods. Dental extractions also increase the risk. 

 


ABOUT THE AUTHOR

Richard Lam, MD is a board-certified internist and oncologist, and has specialized full time in the treatment of prostate cancer since 2001. He is director of clinical research at Prostate Oncology Specialists, Inc. Dr. Lam has written numerous articles based on his research. Dr. Lam received his undergraduate degree in biology, magna cum laude, at UCLA. He then went on to earn his medical degree at UCLA School of Medicine before completing his residency training in the specialty of internal medicine at UCLA Center of Health Sciences. He completed his oncology and hematology fellowship at Harbor-UCLA Medical Center.

 

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