Promising technologies for the treatment of prostate cancer

Thanks to widespread prostate-specific antigen (PSA) testing, most men diagnosed with prostate cancer today have small, low-grade tumors confined to the prostate gland. In fact, these tumors are so tiny that they don’t cause symptoms and can’t be felt during a digital rectal examination. Since many of them grow so slowly that they never cause a problem, men diagnosed with localized prostate cancer face questions for which there are no easy answers: Should the cancer be treated? If so, when and how should it be treated?

Although surgery and radiation have both proven effective in controlling cancer, most patients subsequently experience sexual difficulties, urologic side effects, or both, and their quality of life suffers. For elderly patients or those who cannot undergo surgery or radiation, physicians may prescribe hormone therapy to treat the cancer. But like surgery or radiation, it can cause serious side effects, including erectile dysfunction, loss of libido, a drop in bone mineral density and muscle mass, and an increased risk of cardiovascular trouble.

The lack of urinary, sexual, and other side effects can make active surveillance appealing, at least at first, for appropriately selected patients. But patients who hold off on treatment to see how the cancer progresses often report tremendous anxiety. They start to wonder if delaying treatment might reduce the chances of a cure in the future and may opt for a potentially unnecessary treatment out of fear. Lacking a way to accurately characterize tumors and determine who can safely pursue active surveillance, physicians typically recommend, and patients agree to, some form of treatment. Between 1989 and 2000, only 7% of 5,365 men with localized prostate cancer in the CaPSURE national registry elected active surveillance (sometimes called watchful waiting) for initial disease management.

Over time, active surveillance has gained greater acceptance. A National Cancer Institute database of 96,769 men diagnosed with prostate cancer between 1995 and 1999 showed that 32% took a “wait-and-see” approach. In my own practice, a sizable number of patients pursue active surveillance with the intent to treat their cancer more definitively in the future.

Even so, I hear patients bemoan the fact that there isn’t a better option. They press me and my colleagues to come up with a safe and effective treatment that won’t leave them impotent and incontinent. (I certainly wish we could!) A few emerging treatments do show some promise:

  • Cryotherapy (also called cryosurgery and cryoablation) kills cancer cells by freezing them.
  • High-intensity focused ultrasound (HIFU) ablates tumors with ultrasound energy.
  • Focal therapies target individual spots of cancer — using cryotherapy, HIFU, radiation, or photodynamic therapy — rather than the entire prostate gland.

Despite the fact that these treatments have been effective at controlling cancer in clinical trials, the data are limited. They’ve been tested in relatively few patients (who, by the way, still experience complications) and lack a long track record of success. They have not been compared with surgery or radiation therapy in randomized controlled trials, so we don’t know whether they are as good or better at controlling cancer than these traditional treatments. And only one, cryotherapy, has received the FDA’s stamp of approval.

But because interest in these therapies is on the rise, and because an increasing number of men travel to Mexico, Canada, and Europe for treatments not offered in the United States, I wanted to share what researchers have learned thus far about cryotherapy, HIFU, and focal therapies. Depending on where you live and the nature of your cancer, you may be able to enroll in a clinical trial or pursue treatment with one of these therapies now or in the future.*

*Note: To find clinical trials under way in your area, log on to www.clinicaltrials.gov.

Cryotherapy

Since the 1960s, physicians have used cryotherapy to destroy skin tumors and precancerous moles. But it wasn’t until the 1990s, after significant improvements were made in imaging technology and the devices that control extreme temperatures, that researchers started testing cryotherapy on tumors inside the body. Before that, doctors had had no way to monitor the treatment internally or see how much tissue had been frozen.

With the patient under anesthesia, a physician guides several small needles into the patient’s prostate gland through the perineum, the area between the rectum and scrotum (see Figure 1 below). To accurately position the needles and tailor the treatment to the tumor’s shape and location, the physician relies on real-time images of the prostate generated by an ultrasound probe inserted in the rectum. To help protect the urethra from freezing, the physician inserts a warming catheter. This also helps keep dead tissue from blocking urine flow later on. Similarly, the physician inserts warming needles into the tissue between the prostate and the rectal wall to prevent damage to the rectum.

Figure 1: An inside look at cryotherapy

An inside look at cryotherapy

During modern cryotherapy, a physician inserts several thin needles into the prostate. The needle tips are rapidly cooled to −40° F with argon gas, which freezes prostate tissue and destroys cancer cells. A rectal ultrasound probe generates real-time images that allow the physician to monitor cycles of freezing and thawing. Warming needles (not shown) inserted between the prostate and rectal wall prevent damage to the rectum.

During the procedure, the cryotherapy unit super-cools the needle tips in the prostate with argon gas. Early cryotherapy technology used liquid nitrogen for freezing, which necessitated the use of thicker probes. Today’s thinner needles and the use of a gas instead of a liquid allow for greater treatment precision.

For cryotherapy to be as effective as possible, tissue must be rapidly frozen — temperatures plunge to about −40° F — and then slowly thawed at least twice. As sharp, jagged ice crystals form inside the cells, they tear the cells apart. Cells may also burst when they swell and shrink during the repeated cycles of freezing and thawing. Ice forms inside the small vessels feeding the tumor, too, choking off its blood supply. To determine when tissue has been sufficiently frozen, the physician checks ultrasound images of the prostate and monitors the temperature in and around the gland.

Afterward, immune system cells swoop in to clean up the dead tissue. Interestingly, some evidence indicates that the procedure “tells” the immune system to be on high alert for any remaining cancer cells and to attack them.

Results have varied depending on the type of equipment used and the definition of biochemical progression, making it difficult to draw direct comparisons between groups of patients (see “A selection of articles on cryotherapy,” below). In one trial of 590 patients, the seven-year biochemical recurrence–free survival rates were 61% for low-risk patients, 68% for medium-risk patients, and 61% for high-risk patients. Researchers defined biochemical recurrence as a PSA of 0.5 ng/ml or higher. If the threshold for biochemical recurrence had been set at 1.0 ng/ml, those percentages would have jumped to 87%, 79%, and 71%, respectively. Also, 90% of patients were on hormone therapy prior to treatment, making it hard to know how effective the procedure is on its own.

In a multicenter trial of cryotherapy in 175 patients, 78% of those who were considered to be at low risk for disease progression had a PSA of less than 0.4 ng/ml after one year. Each of the institutions participating in this trial used third-generation ultra-thin cryoneedles. Yet another trial, which included 76 patients, reported that after five years, the PSA was less than 0.3 ng/ml in 60% of the low-risk, 77% of the moderate-risk, and 48% of the high-risk patients. But not every patient in this study, which employed second-generation equipment and thicker cryoprobes to freeze tissue, had two freeze-thaw treatment cycles. And some underwent two or three separate cryotherapy procedures. As you can see, study conditions and definitions make it difficult to compare “apples to apples,” but over all, cryotherapy appears to be an effective treatment for prostate cancer.

Most complications from cryotherapy, such as incontinence, urinary obstruction, and the development of a fistula (a hole in the rectum), have decreased dramatically thanks to modern technology and the evolution of techniques to keep the urethra and rectum warm. (A rectal fistula is now quite rare.) But nearly all patients who are potent before treatment are impotent afterward because there’s no way to avoid freezing some nerves. In the studies I just described, 80% to 95% of the patients were unable to have an erection by the time their particular study ended.

Recent research, however, indicates that penile rehabilitation can help restore potency after cryotherapy. Before treatment, 39.1% of 325 patients enrolled in a Texas study were potent; all were impotent afterward. In the months that followed, they were encouraged to use a penile vacuum pump without a constriction ring to increase the flow of oxygen to the penis and prevent atrophy. After one year, the probability that a previously potent patient would regain the ability to have an erection, either with or without oral medication, was 29.1%. After two years, the probability increased to 48.5%, and after four years, to 51.3%. Compared to years ago, I’d say those are pretty good odds.

So who’s a good candidate for cryotherapy? Older patients and those with multiple medical conditions that might be aggravated by surgery or radiation find cryotherapy an attractive option. Others who might want to consider cryotherapy include patients who

  • have cancer that may have spread locally, increasing the likelihood of positive margins with a radical prostatectomy (cryotherapy can freeze cancers that have escaped from the prostate)
  • have a moderate to high risk of recurrence even after radical prostatectomy or radiation therapy (unlike other procedures, cryotherapy can be repeated)
  • opt for hormone therapy and later find out that their PSA is rising again
  • do not want radical surgery or other procedures.

Although approved by the FDA and covered by Medicare, cryotherapy for localized prostate cancer isn’t offered at many hospitals. Finding experienced physicians to perform the procedure in your area may be challenging. Be sure to have them describe their technique, and find out how many procedures they’ve done.

A selection of articles on cryotherapy

Bahn DK, Lee F, Badalament R, et al. Targeted Cryoablation of the Prostate: 7-Year Outcomes in the Primary Treatment of Prostate Cancer. Urology 2002;60(Suppl 2A):3–11. PMID: 12206842.

Donnelly B, Saliken J, Ernst D, et al. Prospective Trial of Cryosurgical Ablation of the Prostate: Five-Year Results. Urology 2002;60:645–49. PMID: 12385926.

Ellis DS, Manny TB Jr., Rewcastle JC. Cryoablation as Primary Treatment for Localized Prostate Cancer Followed by Penile Rehabilitation. Urology 2007;69:306–10. PMID: 17320669.

Han KR, Cohen JK, Miller RJ, et al. Treatment of Organ-Confined Prostate Cancer with Third Generation Cryosurgery: Preliminary Multicenter Experience. The Journal of Urology 2003;170:1126–130. PMID: 14501706.

Ismail M, Ahmed S, Kastner C, Davies J. Salvage Cryotherapy for Recurrent Prostate Cancer After Radiation Failure: A Prospective Case Series of the First 100 Patients. BJU International 2007;100:760–64. PMID: 17662081.

Mouraviev V, Polascik TJ. Update on Cryotherapy for Prostate Cancer in 2006. Current Opinion Urology 2006;16:152–56. PMID: 16679851.

Salvage cryotherapy

Cryotherapy actually got its start as a “salvage” treatment. An admittedly unfortunate term, salvage therapies for prostate cancer are used when a primary treatment, such as radiation therapy, fails and cancer returns. The risk of recurrence after initial radiation therapy depends on a number of factors: PSA level before treatment, Gleason score, and tumor stage. One study found that 47% of patients with early-stage tumors who were treated with external beam radiation between 1986 and 1995 experienced biochemical recurrence within eight years of treatment. Patients with advanced tumors and a Gleason score of 8 or greater are even more likely to experience a recurrence.

If you’ve already had radiation therapy for prostate cancer, physicians won’t subsequently perform surgery to remove the prostate in most cases because of the technical challenges associated with cutting through scar tissue and the increased risk of complications. Hormone therapy and active surveillance (watchful waiting) are options, but neither one is considered curative.

However, according to a handful of short-term studies, cryotherapy can effectively ablate previously irradiated prostate tissue. Two years after salvage cryotherapy, the biochemical progression–free survival rate has been reported as high as 55% to 74%. That’s why the American Urological Association and Medicare have approved the use of salvage cryotherapy if radiation therapy fails.

One warning: The complications associated with salvage cryotherapy are the same as with primary cryotherapy — urinary incontinence, urinary obstruction, rectal injury, and impotence. The complication rate, however, tends to be higher. So if you are considering salvage cryotherapy, expect lasting erectile dysfunction.

High-intensity focused ultrasound (HIFU)

Perhaps the easiest way to understand HIFU is to think about a science experiment you might have done as a child. If you hold a magnifying glass at just the right angle over a leaf, the sun’s rays will converge below the lens, burning the leaf at the point where they intersect. Move the leaf away from the intersection of the sun’s rays or shift the magnifying glass, and the leaf doesn’t burn.

Instead of sunlight, HIFU relies on sound waves generated by a transducer. When physicians use ultrasound as a diagnostic tool, the low-intensity sound waves deposit small amounts of energy as they travel through tissues. According to how much energy the tissues absorb (and how much they reflect), they look white, black, or gray in the resulting pictures. By increasing the intensity of the sound waves and focusing them on a single point, HIFU sends a large amount of energy into the tissue, in this case, the prostate (see Figure 2 below). The energy creates heat — temperatures can rise to 140° F in just a few seconds — that irreversibly damages cells. The sound waves also create vibration in the tissue, which further disperses the energy and enhances tissue ablation.

Figure 2: An inside look at HIFU

An inside look at HIFU

High-intensity focused ultrasound (HIFU) uses sound waves produced by a rectal probe to ablate cancer. Pulses of energy destroy tissue at the point where all of the sound waves converge. Because the urethra runs through the treatment area, urinary infections, bladder obstruction, and incontinence are relatively common side effects.

HIFU destroys only a small volume of tissue with each pulse of energy. After treating one spot, the physician focuses the sound waves on the next point, making sure that the new treatment area overlaps a bit with the previous one. This process continues until the entire prostate has been ablated. Because tissue destruction occurs only at the point where the sound waves intersect, skin and other tissues are unharmed. Even so, HIFU devices monitor the temperature of the rectal wall, which is sensitive to temperature changes, and keep it cool during treatment.

Monitoring temperature in precise spots in the prostate with ultrasound is not yet possible, so physicians turn to magnetic resonance imaging (MRI) for this task. They also use MRI to monitor treatment, ensure tissue destruction in the targeted areas, and avoid overheating surrounding structures. Areas that have been treated don’t always look accurately defined on ultrasound images, so MRI has become the gold standard for evaluating the success of the procedure.

Proponents of HIFU tout the fact that it is even less invasive than cryotherapy. Physicians still use the rectal ultrasound probe, but they don’t insert needles through the perineum and into the prostate. HIFU can also be repeated if necessary.

Several recent scientific papers have concluded that HIFU appears effective for the treatment of prostate cancer (see “A selection of articles on HIFU, below”). For example, Japanese researchers reported in 2006 that 87% of 63 HIFU patients enrolled in a clinical trial had negative biopsies six months after the procedure. After three years, 75% were biochemically disease-free.

A French study of 227 patients noted that 86% of them had negative prostate biopsy specimens three months after HIFU. Although patients were followed for an average of 27 months, researchers projected that 66% of them would be free of biochemical or pathologic recurrence after five years.

And last fall, a team of German researchers reported long-term results of HIFU treatment for localized prostate cancer in 140 patients who were followed, on average, for nearly six-and-a-half years. The results echoed those reported in the French study: about 86% of participants had a negative biopsy following HIFU, and the projected disease-free survival rate after five years was 66%. The projected rate after seven years dropped to 59%.

Three to four months after HIFU treatment, the PSA reaches its low point, or nadir. Several studies have demonstrated that the PSA nadir was a significant predictor of treatment failure. Patients with a PSA nadir greater than 0.2 ng/ml after HIFU are four times more likely to have cancer detected in a biopsy sample than patients with a PSA nadir of 0.2 ng/ml or less. The Japanese researchers came to a similar conclusion: in their study, all 20 patients with a PSA nadir of 0.2 ng/ml or less were biochemically disease-free after three years. As with other types of prostate cancer treatment, patients who had relatively low PSA levels, Gleason scores of 7 or less, and early-stage disease seemed to fare the best.

Many of the patients participating in these studies reported urinary problems in the first few months after HIFU treatment. Some had difficulty urinating that was caused by swelling or by bits of tissue obstructing the flow. Others suffered incontinence, developed infections, or experienced changes in urinary frequency or urgency. In most cases, these side effects were only temporary. Reported impotence rates ranged from 20% to nearly 50%, though these numbers should be taken with a grain of salt because validated questionnaires of erectile dysfunction were not used consistently.

As with cryotherapy, physicians have used HIFU to treat patients who’ve “failed” other therapies. Few studies of the treatment, however, have been published. One trial involved 118 patients with a biopsy-proven local recurrence and no evidence of metastases after radiation therapy. The five-year actuarial progression-free survival rate was 78%, 49.5%, and 14% for low-, intermediate-, and high-risk patients, respectively. Only one study, which included just four patients, has demonstrated the feasibility of treating recurrent prostate cancer following a radical prostatectomy with HIFU, depending on where the cancer recurs.

These seemingly positive results and reportedly low rates of impotence have lured a growing number of American men across the border to undergo HIFU treatment in Mexico or Canada, outside the regulatory authority of the FDA. Some have reported that they are doing well, but others have said that their cancer was never eradicated and that they have had serious complications, such as incontinence. But there’s a reason that HIFU has not been approved for clinical use in the United States: we don’t know whether the preliminary findings will stand the test of time. Simply put, more patients need to be studied over longer periods before we can justify using HIFU instead of other methods. Until then, men should consider HIFU only as part of a clinical trial and only if they are older and have a limited life expectancy or they cannot tolerate surgery or radiation therapy.

A selection of articles on HIFU

Blana A, Murat FJ, Walter B, et al. First Analysis of the Long-Term Results with Transrectal HIFU in Patients with Localized Prostate Cancer. European Urology 2007; E-publication. PMID: 17997026.

Dubinsky TJ, Cuevas C, Dighe MK, et al. High-Intensity Focused Ultrasound: Current Potential and Oncologic Applications. AJR 2008;190:191–199. PMID: 18094311.

Murat FJ, Poissonnier L, Pasticier G, Gelet A. High-Intensity Focused Ultrasound (HIFU) for Prostate Cancer. Cancer Control 2007;14:244–49. PMID: 17615530.

Poissonnier L, Chapelon JY, Rouviere O, et al. Control of Prostate Cancer by Transrectal HIFU in 227 Patients. European Urology 2007;51:381–87. PMID: 16857310.

Uchida T, Ohkusa H, Nagata Y, et al. Treatment of Localized Prostate Cancer Using High-Intensity Focused Ultrasound. BJU International 2006;97:56–61. PMID: 16336329.

Focal therapies

In 2007, two teams of researchers, one in England and the other in the United States, published papers arguing in favor of testing focal therapy, in which only the tumor and a small margin of normal tissue around it are treated instead of the entire prostate gland. This approach, they say, would minimize damage to “structures essential for sexual, urinary, and bowel function” and allow for re-treatment later on if necessary.

To support their thinking, the U.S. team pointed to a recent study showing that 38% of prostate tissue samples analyzed after radical surgery had a single cancerous lesion. In patients with multiple disease sites, or foci, 80% of the total tumor volume could be attributed to the largest cancerous spot, according to another study. Because the secondary tumors rarely have higher Gleason scores than the main tumor, the thinking goes that they are unlikely to affect overall disease progression. As a result, the researchers suggest targeting just the primary tumor, or in doctor-speak, the index tumor.

Because they can reliably target a specific point, cryotherapy, HIFU, and radiation therapy can be used as focal therapies to attack a single cancerous lesion. Photodynamic therapy (PDT), which has been used to treat skin cancer, shows potential as a focal therapy for the treatment of prostate cancer, too. During PDT, patients are given a photosensitizer, a light-sensitive chemical that accumulates in the target tissue. When it’s exposed to light, the photosensitizer releases toxic substances that destroy tumor cells. (Optical fibers inserted into the prostate through catheters deliver the light.) Newer, experimental photosensitizers seem to destroy tumors primarily by attacking the blood vessels that feed them.

Since the entire prostate is not treated with focal therapy, consistently finding and hitting the target area is essential. Thanks to dramatic improvements in imaging technologies, such as MRI, physicians can better determine whether cancer has spread to the seminal vesicles and can map a tumor’s location more precisely than ever before.

Even so, few studies of focal therapy have been completed, and those studies included only a few dozen patients, used varying techniques, and lacked solid data on adverse effects (see “A selection of articles on focal therapies, below”). Proponents of focal therapies also assume that tiny secondary tumors won’t become a problem later on, but we can’t bank on it; in some cases, they have metastasized. Then there’s the fact that cells from the primary tumor may have already spread; these micrometastases can escape detection with current technology. (Estimated accuracy rates for MRI in focal therapy range from 40% to 90%.) Incomplete treatment or a missed spot of cancer could have profound consequences. And although one would think that the extent and number of complications would be less with focal therapies than with whole-gland treatment, we don’t yet know that for certain.

Cryotherapy, HIFU, and focal therapies hold tremendous promise for treating prostate cancer and preserving quality of life, and researchers should continue to test them individually and in comparison to standard therapies. The lack of solid evidence of their lasting success in treating prostate cancer does not mean that you shouldn’t avail yourself of these treatments if they are appropriate in your situation. But because we can’t say whether the “latest” therapy is also the “greatest” without more data, proceed with caution: get all of the information you need to make an informed decision. Most importantly, find experienced physicians who are willing to share their results, including complication rates, and explain how they developed their expertise with a particular therapy.

A selection of articles on focal therapies

Ahmed HU, Pendse D, Illing R, et al. Will Focal Therapy Become a Standard of Care for Men with Localized Prostate Cancer? Nature Clinical Practice Urology 2007;4:632–42. PMID:17965641.

Eggener SE, Scardino PT, Carroll PR, et al. Focal Therapy for Localized Prostate Cancer: A Critical Appraisal of Rationale and Modalities. The Journal of Urology 2007;178:2260–67. PMID: 17936815.

Ellis DS, Manny TB Jr., Rewcastle JC. Focal Cryosurgery Followed by Penile Rehabilitation as Primary Treatment for Localized Prostate Cancer: Initial Results. Urology 2007;70(Suppl 6):9–15. PMID: 18194712.

Originally published April 1, 2008; last reviewed April 7, 2011.

Comments
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Thomas Moore

Any updated information available on HIFU for BPH? Still not approved by FDA? Options outside the US? Downsides?

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