The AZURE Shade of Blue

BY MARK SCHOLZ, MD

Patients frequently ask their physicians, “Am I stage A, B, C or D,” without realizing that the original purpose of a lettering system was simply to guide urologists in the selection of candidates for surgery. While stage matters, a combination of PSA level and the Gleason grade is a better way to assess disease status. So rather than using stage, it’s best to incorporate all three factors together—PSA, Gleason and stage—to divide prostate cancer into five broad categories or Shades of Blue.

Using standard doctor terminology, the AZURE Shade of Blue is essentially the same thing as “High-Risk” prostate cancer. “Risk” refers to a higher probability of relapse after surgery or radiation compared to men in SKY or TEAL shades. Therefore, men in AZURE are usually treated with combination therapy consisting of IMRT, a seed implant and testosterone inactivating pharmaceuticals (TIP) for 18 months.

 

Here are the specific factors that define AZURE. 

1.     No previous treatment with surgery or radiation.

2.     Bone and body scans without metastasis.

3.     One or more of the following three factors:

a.     PSA above 20 and less than 100, or

b.    Gleason score above 7, or

c.     A prostate tumor felt by digital rectal exam extending across the midline of the gland or outside the capsule.

Men with two or three of these factors are still classified as AZURE. Men with spread to pelvic nodes are classified as INDIGO.  Men with metastasis that has spread to bones or to nodes outside the pelvis are ROYAL. Radiation—rather than surgery—is the preferred treatment for AZURE because of the risk for cancer infiltration outside the prostate. Safe surgical removal is next to impossible when the disease extends into surrounding organs.  Incomplete cancer removal means radiation will be required to “mop up” the residual cancer anyway. Therefore, most experts recommend radiation because the risk of needing both surgery and radiation is so much lower.

Within the AZURE category exist subcategories of men who have a relatively more advanced type of AZURE. For example, some men have larger tumors, higher PSA levels above 40 and Gleason grade 9 or 10.  Men in this situation might want to try to further enhance their cure rates by adding a more potent form of TIP such as Xtandi or Zytiga to their therapeutic plan.  Also, a short course of Taxotere chemotherapy can be considered.

My last blog (about TEAL) reviewed potential side effects from surgery and radiation.  The side effects of TIP become more severe when treatment duration is prolonged. The three most troublesome TIP-related problems are low libido, weight gain and fatigue. However, libido recovers after TIP is stopped.  Weight gain and fatigue can be reduced with diet and exercise. Yet as we all know, maintaining a consistently good diet and getting adequate exercise over long periods of time can be very challenging.  Obtaining professional support from a trainer or a physical therapist is one way to sustain a disciplined program on an ongoing basis. 

 

Other common TIP side effects can be controlled with medications.  Hot flashes regress with a low-dose estrogen patch. Calcium loss from the bones can be prevented with an injection of Prolia every six months, a Fosamax pill weekly or with an Actonel or Boniva pill monthly. Mood swings can be reduced with low-doses of an antidepressant called Effexor.  Effexor also has salutary effects on hot flashes. Breast growth can be prevented with an estrogen-blocking pill called Femara.  When libido is chronically low, men tend not to care about getting erections, so taking daily Cialis should be considered standard for men receiving TIP.

Unfortunately, many doctors have limited knowledge about how to prevent TIP side effects. Patients, therefore, need to protect themselves by getting as much education as possible. Certain side effects, such as breast growth, erectile atrophy and osteoporosis, are preventable with appropriate intervention.  However, once they are allowed to occur, these effects can be permanent.

While side effects are an important consideration, men in the AZURE group have a relatively more dangerous type of prostate cancer compared to men with SKY or TEAL.  The appropriate treatment stance, therefore, is to be aggressive—to get cured.

The good news is that the majority of men with the AZURE stage of prostate cancer will be cured with the treatment approach outlined above.  Studies have shown that the best results come from using IMRT, radioactive seed implantation and testosterone inactivating pharmaceuticals (TIP) in combination with each other. 

So if you do find yourself in the AZURE zone, don’t despair: There is good reason for hope.

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.