The co-authors of Invasion of the Prostate Snatchers, blog alternate posts weekly. We invite you to post your comments.

Tuesday, November 19, 2013

The ROYAL Shade of Blue


Men in the ROYAL shade have metastatic prostate cancer that has spread to bone, or, to lymph nodes outside the pelvis, or, they have a PSA over 100, or, they have a rising PSA with a low testosterone level. Metastases are typically detected by doing a body scan or a bone scan.

Men with advanced prostate cancer tend to live longer than men with other types of cancer. One major reason is because prostate cancer doesn’t usually spread to critical organs like the brain, the liver or lungs.  Another reason is the availability of so many effective treatments. Standard hormonal treatment with Lupron and Casodex, for example, can induce long remissions. And just recently, the FDA approved two new types of hormone therapy—Xtandi and Zytiga. These medications are so powerful they can induce remissions in men who have become resistant to Lupron and Casodex. In addition to Xtandi and Zytiga, two non-hormonal treatments—Provenge and Xofigo—have also been recently approved by the FDA.

Since so many effective treatments are available, wasting time on a treatment that has stopped working is a terrible crime. Therefore, after initiating a new treatment close monitoring of disease status is essential. Monthly blood tests and PET scans with sodium fluoride or carbon 11 acetate help to determine when a specific treatment stops working. Ineffective treatment should be stopped as soon as disease progression occurs so that a more effective therapy can be started in a timely fashion.

Treatment for ROYAL
Men in the ROYAL category who have never had hormone therapy should start testosterone inactivating pharmaceuticals (TIP).  The standard approach is to begin with Lupron and Casodex in combination.

Men who have become resistant to Lupron, but have fewer metastases and a slower PSA doubling time, should take Provenge to boost their immune system. Studies show that Provenge works better when treatment is started earlier. Preliminary research has also suggested that Provenge might be more potent if it is combined with spot radiation directed at a site of metastatic cancer. Studies to evaluate this possibility are ongoing.

With or without Provenge, radiation to cancer metastases has historically been reserved for controlling bone pain, a use for which it is quite effective. However, newer thinking suggests that radiation directed to all known sites of metastases—when the numbers of metastases is relatively small, say less than five—may occasionally lead to longer remissions.

Potent medications to strengthen the bones—Xgeva and Zometa—are routinely recommended when bone metastases are present. These medications have three potential benefits: They inhibit cancer growth in the bones; they reduce bone pain; and they help counteract calcium loss that hormonal therapies commonly cause.

If men in ROYAL have the type of prostate cancer that progress quickly while on Lupron and Casodex, the first step should be to stop Casodex and start one of the following three options:

1.    Second-line TIP such as Zytiga or Xtandi

2.    Chemotherapy with Taxotere or Jevtana

3.     Xofigo, a form of injectable radiation

Three additional treatment options can be considered if these first three options are no longer effective in controlling the disease:

1.       Combination chemotherapy using Carboplatin or Xeloda with a Taxane or the combination of both Revlimid and Avastin added to a Taxane. 

2.       The “off-label” use of Cabozantinib (XL-184), a medication being researched for prostate cancer but already FDA-approved to treat thyroid cancer

3.       Other investigational medications

Investigational trials represent an opportunity for patients to get medications prior to FDA approval.  A patient’s enthusiasm for embarking on a study that uses an investigational medication, however, needs to be tempered by what is actually known about the effectiveness of the specific medication.  Some medications are so new that even the investigators performing the trial don’t know if they are going to work or not.
While on treatment men need to have their blood monitored monthly by checking PSA, PAP, ALP and CTC levels. Medication side effects and cancer-related problems also need to be screened for with monthly blood tests such as CBC, a metabolic panel and a hepatic panel.  A periodic bone scan and body scan should be performed to track the disease status.  Two to three months after starting a new treatment, if the blood markers are not improving, a change in therapy needs to be considered.    
Reducing the Side Effects of Treatment
Fatigue is one of the biggest challenges faced by men in ROYAL. First, both chemotherapy and radiation can cause tiredness. Second, muscle loss is a frequent occurrence from TIP-induced, low testosterone.  Stimulants such as Provigil or Nuvigil may be helpful, but the most important priority is to counteract muscle loss with consistent, diligent exercise. Resistance training with weight lifting is only known effective method for restoring muscle mass.

Xgeva and Zometa cause gum recession and infections of the jaw bone, a condition called osteonecrosis.  This phenomenon is much more likely to occur after a tooth extraction so men on this therapy are advised to avoid extractions as much as possible.  Osteonecrosis, when it occurs, generally resolves, albeit slowly, after Xgeva or Zometa are stopped.

A variety of different medications can be useful for reducing side effects from hormone therapy. Low-dose estrogen skin patches can control hot flashes. Excessive mood swings can be stabilized with low doses of antidepressant pills. Breast enlargement can be prevented with Femara. 

Final Thoughts
In this blog I have outlined a traditional, sequential approach to treatment selection.  Strong consideration, however, should be given to using these active new agents in combination and at an early stage.  Men in ROYAL have a potentially life-threatening type of prostate cancer. An aggressive and imaginative treatment plan should be designed that has the specific goal of attaining and maintaining a complete remission, i.e. a PSA less than 0.1. In my opinion, the standard “one treatment at a time” approach that is so popular at academic centers, it is a grave disservice to the men fighting aggressive prostate cancer. 


Bill Vercammen said...

Dr Scholz,
In your "Royal Shade of Blue" commentary, you mention the off-label use of cabozantinib in late-stage refractory disease. Today is 9/3/14, and over the holiday weekend Comet-1 reported failed top-line data preview...which is to say, the primary endpoint of statsig overall survival was not met. Will this change your outlook wrt Cabo prescription? Any commentary wrt cabozantinib or Comet-1 greatly appreciated. Thanks in advance,
Bill V

Prostate Oncology Specialists said...

While XL-184 did not meet the formal survival endpoint in comparison with Placebo, there was a trend to improved survival. This means that the drug has activity in some men, just not with sufficient frequency to move the overall survival needle. We still consider XL-184 in men who have limited other options, for example, those who have failed Taxotere and Jevtana. In the dozen or so men we have treated with XL-184 at Prostate Oncology, I recall two that had a meaningful clinical benefit.
Mark Scholz, MD