Prostate cancer: New studies of combination therapy

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Prostate cancer: New studies of combination therapy

Doctors have finally begun to understand prostate cancer. Geneticists have identified abnormal genes that increase a man’s vulnerability to the disease. Epidemiologists have discovered that a diet high in saturated fat is linked to an increased risk, while tomatoes, whole grains, fish, soy, and the mineral selenium appear to be protective. Urologists are learning how to use the PSA test to detect the disease. Radiologists are developing new ways to obtain images of the elusive gland, and oncologists have honed their understanding of what makes prostate cancers grow and what slows the multiplication of malignant cells.

It’s important progress that has resulted from teamwork. Every man stands to benefit from these new insights, but men with prostate cancer have an additional urgent need. Fortunately, there have been important gains here, too. In fact, each of the standard therapeutic options has registered major improvements:

• Surgical removal of the gland, the radicalprostatectomy, has become safer and requires a shorter hospital stay. In addition, the nerve-sparing operation can help preserve potency, and laparoscopic surgery can reduce postoperative pain, at least for some men.

• Radiation treatment has improved in two ways. Three-dimensionalconformaltherapy has made externalbeamradiation better than ever, allowing radiation oncologists to deliver more cancer-killing x-ray energy with fewer side effects. In addition, brachytherapy, a newer approach, allows doctors to place radioactive seeds directly into the gland, eliminating the need for daily trips to the hospital.

• Hormonal treatment has benefited from new drugs that can dramatically lower levels of testosterone, the male hormone that fuels the growth of prostate cells.

Watchful waiting — close observation without active therapy — has also been refined. Doctors have learned that this option is best suited to older men with less aggressive tumors, and they have improved their ability to follow the disease and initiate therapy if it becomes necessary.

Even as these standard options are improving, new approaches are being developed. Cryotherapy, for example, freezes the prostate to kill malignant cells. These developments are all for the good, but they have made it harder than ever for a man with prostate cancer to choose among the different therapies. And to make matters even more confusing — but even better — some studies suggest that combination treatments may outperform individual methods, at least for some men.

For treating prostate cancer, as for understanding the disease, teamwork is best.

The androgen cascade Blocking the androgen cascade Prostate cells depend on androgens for growth; they can be deprived of androgens in several ways: estrogens and LHRH agonists inhibit the release of LH (steps 1 and 2); Abarelix suppresses LH production; orchiectomy eliminates testicular testosterone (steps 2 and 4); finasteride blocks testosterone’s conversion to DHT (step 5); and antiandrogens block the binding of DHT to cellular receptors (step 6).

The hormone connection

Male hormones, androgens, are required for the growth of prostate cells, both benign and malignant. When prostate cells are deprived of these hormones, their growth is halted, at least for a time. Androgen-deprivation therapy has been used since the 1940s, but it has changed dramatically since.

Androgen production depends on a lengthy chain of events (see figure). It begins in the brain, where the hypothalamus produces the hormone that sets the wheels in motion. It’s a single protein, but it has two names: to urologists it’s luteinizinghormone-releasinghormone (LHRH), but to endocrinologists it’s gonadotropin-releasinghormone (GnRH). By either name, the hormone acts on a nearby part of the brain, the pituitary, which responds by producing two additional hormones.

One of these pituitary products, luteinizinghormone (LH), carries the chain further by traveling to the testicles, where it stimulates the Leydigcells to produce testosterone. About 95% of a man’s testosterone is made in his testicles, the rest in his adrenal glands. Whatever its source, testosterone undergoes a final transformation in the prostate itself, where the enzyme 5-alphareductase turns it into dihydrotestosterone (DHT).

Breaking the chain

The oldest method of androgen deprivation is also the fastest; testosterone levels plummet within hours after an orchiectomy, the surgical removal of the testicles, and they stay low. Permanence may be an advantage to men with advanced prostate cancer, but it makes orchiectomy useless for combination therapy, which relies on temporary androgen deprivation to enhance the effect of other treatments. Although estrogens could be used to temporarily lower testosterone levels, they have not been studied in combination treatment. And while the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart) can help some men with benignprostatichyperplasia, they do not have a role in prostate cancer. But two other hormonal approaches have been useful in combination therapy.

LHRH agonists are synthetic drugs that resemble LHRH. Unlike the real thing, however, they block the release of LH by the pituitary, thus reducing testosterone production by the testicles. After a brief surge, testosterone levels decline dramatically, and they stay low as long as the drug is injected every one to four months, depending on the preparation. The major LHRH agonists are goserelin (Zoladex), leuprolide (Lupron, Eligard, Viadur), and triptorelin (Trelstar). They are equally effective and equally likely to produce side effects such as fatigue, breast pain and enlargement, hot flashes, loss of bone calcium, anemia, and sexual dysfunction. They are also equally expensive.

The GnRH antagonist is a newer medication for advanced prostate cancer. Abarelix (Plenaxis) suppresses the production of LH and follicle-stimulating hormone (FSH), thus reducing testosterone levels. Unlike the LHRH agonists, it does not cause an early surge in testosterone, but it can produce allergic reactions that may be serious. As of 2005 Abarelix is approved only for certain men with advanced prostate cancer.

Antiandrogens don’t reduce the body’s production of hormones, but they block the hormone’s ability to stimulate cells. Antiandrogens act against both testosterone and DHT, and they also block the effects of the weaker androgens produced by the adrenal glands. The major preparations include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron). All are taken orally, and all are expensive. Antiandrogens can cause breast enlargement, but they don’t usually provoke hot flashes, and they are less likely to cause sexual dysfunction than LHRH agonists.

Teaming up

A similar tactic to combination therapy for prostate cancer has proven its worth in another hormonally responsive malignancy, breast cancer. Doctors have learned that the antiestrogen drug tamoxifen can improve the results of surgery or radiation in women with estrogen-responsive breast cancer.

Some studies of prostate cancer revealed that a combination of androgen-deprivation therapy and external beam radiation could help men with locally advanced cancer by reducing its progression more effectively than radiation alone. In contrast, men treated surgically did not appear to benefit from antiandrogen therapy. But three newer studies extend the reach of combination therapy. Two found that it can prolong survival in men receiving radiation, and the third reported that it could reduce the progression of disease in men treated with radiation, surgery, or watchful waiting.

The EORTC trial

The European Organization for Research and Treatment of Cancer (EORTC) conducted the first study. Between 1987 and 1995, 415 men volunteered to be randomly assigned to receive either external beam radiation alone or similar radiation combined with androgen deprivation (an LHRH agonist for three years with an antiandrogen for the first month). All of the men had locally advanced prostate cancer, but none had been previously treated. Scientists tracked the men for an average of 66 months, evaluating three factors: freedom from prostate cancer, survival from prostate cancer, and overall survival. At the end of five years, combination therapy was better than radiation alone in all three respects; it improved overall survival (79% vs. 62%), survival from cancer (98% vs. 88%), and survival without any evidence of cancer (67% vs. 30%). The study did not describe the side effects of either treatment, but it did note that 6% of the men in the combination group did not complete the full three years of LHRH treatment because of adverse symptoms.

A Harvard study

The EORTC trial demonstrated that three years of androgen-deprivation therapy can improve the results of radiation treatment. But long-term hormonal treatment is expensive, and it often produces unpleasant side effects. To find out if short-term androgen treatment is beneficial, Harvard researchers studied 206 volunteers with clinically localized but high-grade prostate cancer. Half the men received standard external beam radiotherapy; the others received the same doses of radiation plus six months of androgen deprivation with an LHRH agonist and an antiandrogen. After an average follow-up of more than four and a half years, the men who received combination therapy enjoyed a higher overall survival rate (88% vs. 78%), a lower risk of dying from prostate cancer, and a lower risk of requiring additional cancer treatment. However, combination therapy produced more breast enlargement and impotence.

The Casodex trial

The Casodex Early Prostate Cancer Trialist Group, a consortium of scientists in Europe and the United States, conducted a much larger trial. A total of 8,113 men volunteered to be randomly assigned to receive either standard treatment plus a placebo or standard treatment plus 150 mg a day of the antiandrogen bicalutamide. The patients had localized or locally advanced prostate cancers. The patients and their doctors selected the standard treatments, which included surgery, radiotherapy, and watchful waiting. The scientists tracked patients for an average of three years. They were unable to detect any differences in survival between the two groups, at least in part because there were so few deaths from prostate cancer (less than 2%). But combination therapy did reduce the risk of local recurrence from 14% to 9%. However, it did produce more side effects, including breast enlargement in 73% and breast pain in 66% of the men. In all, 26% of the men in the bicalutamide group withdrew from the trial because of adverse symptoms, while only 8% of the placebo group dropped out.

The Casodex trial – still in progress in 2005 – will hopefully determine if this form of combination therapy prolongs survival in addition to reducing the risk of recurrences. It is also important to evaluate the quality of life in both groups. The FDA has approved bicalutamide only for the treatment of advanced prostate cancer in combination with an LHRH agonist.

What’s best?

The EORTC trials showed that long-term combination treatment can offer real advantages to men with locally advanced prostate cancer, and the Harvard study found similar benefits from short-term androgen deprivation in men with clinically localized but high-grade disease. The Casodex trial is less convincing, demonstrating a reduced risk of recurrence but no effect on survival.

Despite these encouraging results, the new trials leave some questions unanswered. Doctors don’t know if combination therapy will help men with low-risk disease, and they don’t know the best time to start androgen deprivation or how long to continue it. Finally, the research on combination therapy does not address the $64,000 question: Which primary treatment (surgery, external radiation, brachytherapy, watchful waiting) is best? That crucial answer depends on still other randomized clinical trials.

When it comes to prostate cancer, every new answer seems to trigger still more questions. But those queries, too, will be resolved — and in the meantime, the cycle of questions and answers has already improved the outlook of prostate cancer patients.

Last updated:	August 21, 2006