Xofigo—A Wonderful New Treatment for Men with Advanced Prostate Cancer

BY MARK SCHOLZ, MD

It’s a special event when the FDA approves a new treatment.  Xofigo, otherwise known as Radium 223 or Alpharadin, is now commercially available.  The FDA approved Xofigo based on the results of a large, prospective, placebo-controlled trial that demonstrated significantly greater survival in Xofigo-treated men compared to placebo-treated men.  The trial also shows a very low incidence of side effects and good relief of bone pain. The treatment is easy to administer, consisting of monthly intravenous injections.

How Xofigo Works
Cancer treatment falls into four major categories. Chemotherapy selectively targets fast growing cells. Unfortunately, since chemotherapy works as a nonspecific cell poison, it frequently causes prominent side effects. Hormonal and targeted agents work by blocking the internal mechanisms of the cancer cell, thus forestalling growth. These treatments tend to have fewer side effects than chemotherapy.

However, by nature cancers are genetically variable, so resistant clones eventually appear. Immunotherapy stimulates the patient’s immune system. New forms of immunotherapy are promising and development is progressing very rapidly but this area of study is still in its infancy. Lastly, radiation consists of high energy particles that blast cellular DNA. A cancer cell with disabled DNA can’t reproduce.

Radiation needs to be given in a dosage sufficiently large enough to be effective. However, it also has to be targeted accurately to spare the surrounding healthy tissue. Xofigo addresses both of these demands elegantly. In terms of power, just one of the alpha particles emitted by radium 223 can cause irreversible cell damage because alpha particles are large enough to sever double-stranded DNA (typical beam radiation with photons requires multiple hits on DNA because it only damages one of the two DNA strands).

Xofigo Targets the Bone Metastasis
When cancer invades the calcium matrix of the bone it stimulates the bone to accelerate its rate of calcium uptake.  Radium 223 has structural similarities to calcium so Xofigo is “mistakenly” taken up by the bone cells adjacent to the cancer in lieu of calcium. So after Xofigo is injected, it travels through the blood stream and concentrates in the irritated areas of the bone where the cancer is most active.

Xofigo would be effect against almost any type of cancer since most cancers that spread to the bone increase calcium turnover in the bone cells adjacent to the cancer. However, the manufacturers and distributors, Algeta and Bayer Pharmaceuticals, were wise to seek FDA approval for prostate cancer before pursuing development in other types of cancer. Prostate cancer has an extremely fastidious pattern of spread. Metastases occur almost exclusively in bone. The major organs like lung, liver, kidney or brain are almost always spared. Since prostate cancer spreads almost exclusively to bone, Xofigo targets most if not all of the disease.

Alpha Particles Only Travel a Few Millimeters
To most everyone, the thought of radiation easily conjures up horrible visions of toxicity. Also, the concept of radiation by injection is not new. Strontium and samarium are two radioactive elements that also concentrate in areas of increased bone activity. However, they emit a different type of radiation, gamma radiation, which acts over a much longer distance and induces collateral damage to the surrounding cells in the bone marrow, the cells of the all-important immune system. Fortunately, bone marrow toxicity appears to be rare in men treated with Xofigo because alpha particles characteristically dissipate over the distance of a couple of millimeters, restricting the radiation effect to the active area of the cancer where it is invading on the surface of the of the bone.

Potent, Highly-Targeted Therapy—Just What the Doctor Ordered
Advanced prostate cancer in the bones eventually becomes resistant to other treatments. Historically, external beam radiation therapy has been a potent method for killing cancer cells, particularly to control pain, when the effectiveness of other options seems to be failing. However, beam radiation must be used very judiciously because it also causes irreversible damage to the surrounding bone marrow. Xofigo is likely to rapidly gain widespread acceptance with both doctors and patients because it simultaneously targets multiple metastasis yet spares the closely adjacent bone marrow.

Value of a Single erection

BY RALPH BLUM

For many men who have trouble achieving potency— keeping an erection firm enough for sex—erection dysfunction (ED) medications--Viagra, Cialis, Levitra--work well and cause few side effects.

Sildenfil (Viagra), vardenfil (Levitra), and tadalafil (Cialis) are all medications that reverse ED by increasing nitric oxide, a chemical naturally produced by the body that opens and relaxes the blood vessels in the penis. While helping to get and keep an erection, these medications do not increase sex drive, and only cause erections if you are sexually stimulated.

In an article in My Generation magazine, Hal Ackerman wrote that after 12 months of hormone-deprivation therapy, his libido was totally gone, an empty balloon, with the result that women whose bodies in the past would have stimulated longing and desire, generated no more response than the sight of uncovered furniture. However Ackerman claims that “via the miracle of modern pharmacology” he was able to perform sex with his new girlfriend for her pleasure—though with little personal gratification.

Although they work in similar ways, each of the ED medications has a slightly different chemical make-up. These minor differences affect the way each medication works, such as how quickly it takes effect and wears off, as well as the potential side effects.

Viagra and Levitra can be taken without food, no more than once a day, about 30-50 minutes before sex, and are effective up to 5 hours. Cialis can be taken as a small daily dose, anytime, with or without food, and is effective anytime between doses. The 36 hour Cialis can be taken with or without food, no more than once a day, about 30 minutes before sex, and is effective for up to 36 hours.

Not all men can take these ED medications. They may not be safe if you have any kind of heart problems, high or low blood pressure that is not controlled, a history of stroke within the last six months, eye problems, severe liver disease, or kidney disease. Always check with your doctor, and be sure he knows any other drugs you are taking as ED medications can interact dangerously with a number of other drugs—including alpha blockers, antibiotics, anti-seizure drugs, blood thinners, and various heart medications. And a final caveat: as I wrote in a previous blog, if you have had a prostatectomy, ED medications only work if the nerves located close to the prostate have not been removed or damaged.

Most men who take Viagra, Levitra or Cialis are not bothered by side effects, but when they do occur they can include headache, flushing (Viagra and Levitra), indigestion, stuffy or runny nose, back pain and muscle aches (Cialis), temporary vision changes (Viagra and Levitra), and rarely, dizziness or fainting. Also rarely, priapism (an erection that doesn’t go away) can occur and requires medical treatment.

ED medications can be purchased over the Internet, but beware of scams. Check to see if an online pharmacy is legitimate—never order drugs if the pharmacy gives no phone number, if prices seem too good to be true, or if you are told no prescription is necessary. Make sure you get the exact dose and type prescribed by your doctor. And don’t be fooled into buying “herbal” or non-prescription equivalents. They are not as effective, and some can contain harmful substances. You may find yourself paying as much as $20 per dose. But then some of us would consider the restoration of potency a bargain at twice the price.

Potency

BY RALPH BLUM

One of the most worrying questions men diagnosed with prostate cancer face is: What are my chances of losing sexual function after treatment? The truth is all forms of prostate cancer treatment carry significant risk of impotence—defined as the inability to maintain an erection hard enough to penetrate. However, your chances vary greatly depending on a number of factors including your age, general health, potency prior to treatment, PSA levels, and last but not least, your treatment choice. Not surprisingly, regardless of which treatment they choose, older men whose sexual function is already low have the worst chance of good results.

While some men are willing to choose a therapy that offers a shorter life expectancy but better potency following treatment, for others the most important factor is curing the cancer. As one man said, “If you’re not alive, you don’t have to worry about sex.” Clearly it is a very individual choice as each man experiences sexual dysfunction in a profoundly personal way.

Since most men treated for early-stage prostate cancer typically live for decades, the choice of treatment is of paramount importance when it comes to quality of life issues. Surgery is still the preferred treatment for many men. But being operated on by less than the very finest surgeon dramatically increases the chances of impotence. The popularity of robotic surgery would lead one to believe that extensive studies have shown superior results compared to the traditional prostatectomy. However, according to Dr. Michael Barry of Massachusetts General Hospital in Boston and President of the Foundation for Informed Decision Making, it is not yet clear whether a robot-assisted laparoscopic prostatectomy is better or worse for maintaining sexual function than the older surgical techniques.

If retaining potency is your primary goal, IMRT or brachytherapy appear to give you the best results.  However, Dr. Durado Brooks, prostate cancer director for the American Cancer Society, cautions that sexual problems can show up later for men who also have either type of radiation therapy.

If you are like the gentleman in his early eighties who told me, “I’d rather be dead than unable to have another erection,” there are no easy answers. As far as I am concerned, the monastery beckons.

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 60’s, 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.