The ROYAL Shade of Blue

BY MARK SCHOLZ, MD

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. 

Osteoporosis Basics for Men

BY MARK SCHOLZ, MD

Osteoporosis is the medical term for “weakened bones” resulting from the slow leaching of calcium over time. Osteoporosis is incorrectly thought to happen only in females. However, one-third of hip fractures occur in men and are associated with higher mortality rates in men with prostate cancer. Calcium loss is a silent process until a fracture suddenly occurs. Common fracture sites are spine, rib, wrist, and hip. Compression fractures of the spine can be quite painful and result in loss of height with forward curvature of the spine.  

Cause of Osteoporosis
Just as there is a link between lack of estrogen and osteoporosis in women, studies show that there is also a relationship between a lack of testosterone and osteoporosis in men. Other causes of osteoporosis are thyroid or parathyroid hyperactivity, excessive alcohol, cortisone, lack of exercise, low vitamin D and low calcium intake. Osteoporotic fractures also occur more frequently in men taking testosterone inactivating pharmaceuticals (TIP).

Detecting Osteoporosis
Osteoporosis, when it is diagnosed at an early stage, is easier to treat. Unfortunately, the most common scanning technique for diagnosing osteoporosis, the DEXA scan—grossly underestimates the degree of bone mineral loss from the spine in men. Why? Because almost all men over fifty have calcium deposition in the ligaments surrounding the spine. When the DEXA is used to measure bone density, the excess calcium in the ligaments causes an incorrectly “normal” bone density reading.

Fortunately there is a better technique called QCT that measures bone mineral density in the center of the vertebral column. Awareness of the DEXA scans' limitations in men is under appreciated by many physicians even though these limitations have been well documented in a study from Massachusetts General Hospital. In this study 41 men underwent both DEXA and QCT scanning. QCT detected osteoporosis in 26 of the men (63%) but DEXA only diagnosed it in two (5%).

Preventing Osteoporosis
Osteoporosis treatment begins with an exercise program. Supplementation with calcium and vitamin D should also be considered routine. We recommend 500 mg of calcium at bedtime and a starting dose of 1,000 units of Vitamin D. Blood levels of vitamin D should be checked and oral intake of vitamin D adjusted accordingly.  Studies show that using TIP intermittently (compared to continuous TIP) results in less bone loss. Treatment with bisphosphonates or denosumab (see below) can prevent TIP-induced bone loss.

Osteoporosis Medications
Osteoporosis can be reversed with bisphosphonates or denosumab. Normal bone metabolism is a balance between the rate of bone breakdown and the formation of new bone. Osteoporosis occurs when the formation of new bone lags behind the rate of bone breakdown. Bisphosphonates and denosumab function by slowing the rate of bone breakdown, allowing the osteoblasts, the cells that form new bone, to increase the net amount of bone matrix.

Oral Medications: Boniva, Actonel and Fosamax
Bisphosphonates come in both oral and intravenous forms. Absorption into the blood of oral forms is enhanced when they are administered with an empty stomach. The most common side effect from oral bisphosphonates is stomach or esophageal irritation which can be minimized by maintaining an erect position for an hour after taking the drug.

Intravenous Bisphosphonates: Zometa (zolendric acid)
Intravenous administration of Zometa has the advantage of bypassing the stomach thus avoiding concerns about stomach irritation. Also with the intravenous approach 100% of the drug gets into the system as compared to the oral preparations that are only 1-2% absorbed. The most common side effect from Zometa is a brief flu-like muscle soreness lasting a day or so. These symptoms do not usually recur on subsequent infusions. For the treatment of osteoporosis the infusions are repeated every three to six months.

Denosumab Injections: Prolia and Xgeva
Like Zometa, denosumab inhibits the osteoclasts, but by a different mechanism.  Denosumab is marketed in two strengths for injection. A half-dose shot called Prolia is administered every 6 months for osteoporosis.  A full dose shot called Xgeva is given monthly for cancer metastasis to the bone.

Medication Induced Jaw Problems: Osteonecrosis
Zometa and denosumab and to a much lesser degree, oral bisphosphonates can rarely induce damage to the jaw, a condition termed osteonecrosis.  The risk of developing osteonecrosis is much higher when a tooth is extracted. When osteonecrosis occurs, the gum tissue recedes leaving exposed bone which is susceptible to recurrent infections. The risk of osteonecrosis becomes higher as the lifelong cumulative medication dosage increases. In my experience, osteonecrosis almost always reverses, albeit slowly, after the medication is stopped.

 

Bone Metastases

Zometa and denosumab are also FDA approved to treat cancer that has metastasized to bone. Their anticancer effect is believed to occur because by inhibiting bone breakdown, cancer cell access to the growth factors and cytokines that are normally locked up in the bone matrix is blocked. So these medications that inhibit bone turnover by stopping osteoclast activity not only help osteoporosis but also help to prevent bone metastases from progressing.

Final thoughts

Eventually some degree of osteoporosis occurs in most men as they age.  Regular exercise, calcium and vitamin D help delay bone loss.  Bone density screening in men should probably begin when they are in their 60s, so the condition can be detected early.  Bone density augmentation with denosumab or bisphosphonates seems to be more effective when osteoporosis is not too severe at the start of therapy.