Implanted radioactive “ seeds” offer low-risk prostate cancer patients a minimally invasive treatment option that some investigators think could be as effective as surgical removal of the prostate if placed by experienced radiation oncologists, according to a series of recent studies.
Prostate cancer is the most frequently diagnosed cancer in men, and patients who receive the diagnosis often have several treatment options. The three most common treatments—radical prostatectomy, external-beam radiation, and implantation of radioactive isotope seeds—offer similar survival rates for low-risk patients (though they have not been compared directly in randomized trials). But until recently, few studies had been available to help patients and their doctors choose the best treatment for them. New reports suggest that minimally invasive options such as brachytherapy are associated with good long-term survival with minimal side effects.
“At this point, brachytherapy is becoming one of the most established treatments for prostate cancer,” said Jamie Cesaretti , M.D., assistant professor of radiation oncology at the Mount Sinai School of Medicine in New York. “Whereas it sat there throughout most of the 1990s being compared to the ‘gold standard’ of surgery, now it's becoming a gold standard treatment on its own.”
Low-dose brachytherapy for prostate cancer involves permanent placement of small radioactive isotopes, most often iodine-125 ( 125 I) or palladium-103 ( 103 Pd), encased in an inert titanium shell about the size of a grain of rice. The radiation oncologist uses a transrectal ultrasound device to map the prostate in two dimensions. This imaging forms the basis for placing a pattern of seeds inserted by a hollow needle directly into the prostate to create a continuous dose of radiation to the tumor and a small surrounding margin. The titanium shells remain in the body, but the radioactive material decays over several weeks.
Alexander Graham Bell first described the idea of inserting the radioactive element radium into the body to treat tumors in 1903. But early efforts at brachytherapy for cancer treatment yielded uneven results. The first isotopes used, including radium, have long half-lives and created toxic side effects. By the 1980s, radiation physicists had developed standards to ensure that patients received uniform radiation exposure and introduced new isotopes with lower energies and shorter half-lives that reduced side effects. Brachytherapy is now used to treat tumors of the head and neck, cervix, and breast, in addition to the prostate.
Beginning in 1990, physicians at Mount Sinai developed a technique, called the real-time imaging method, that uses multiple ultrasound images of the prostate during the implantation to guide placement of seeds next to the prostate tumor. These seeds deliver a maximum radiation dose while sparing normal issues, Cesaretti explained. Today, about 35%–40% of brachytherapy treatments use real-time imaging. The rest use what is called pretreatment planning, where ultrasound and sometimes computed tomography images are taken before surgery to determine where to place the seeds. Since the advent of image-guided placement, thousands of low- and intermediate-risk patients have chosen brachytherapy as their sole treatment for prostate cancer, and long-term outcome data are beginning to emerge.
A recent multi-institutional study evaluating the long-term results of brachytherapy in 2,693 men with early-stage prostate cancer demonstrated disease-free survival rates at 8 years of 93% for patients whose tumors received at least 90% of the maximum prescribed radiation dose. Patients whose tumors received less than 90% of the intended radiation dose had survival rates of 76%. The study, led by Michael Zelefsky, M.D., professor of radiation oncology and chief of the brachytherapy service at Memorial Sloan-Kettering Cancer Center in New York, is the first to look at such a large cohort of patients over a longer period. Zelefsky said that the study demonstrates the importance of proper seed placement to patient outcome.
Recently, more detailed information about the tradeoffs involved in the various treatment options indicated that the side effects of treatment may differ in clinically meaningful ways.
“Prostate cancer is a unique cancer in that it is very slow growing. Even in men who have aggressive cancers, after treatment they have a long life expectancy,” said John Gore, M.D., clinical instructor in the department of urology at the University of California, Los Angeles. “Therefore, prostate cancer is unique in that the quality of life that people incur after surgery is very important to consider, as their quantity of life is very long.”
Gore; senior investigator Mark Litwin, M.D.; and their colleagues recently tracked 580 men treated for prostate cancer at UCLA's Jonsson Comprehensive Cancer Center. The study results, published in June in the journal Cancer , show that the side effects vary with the treatment chosen.
“All of these treatments—surgery, radiation, brachytherapy—have pretty similar cancer control properties, so we are trying to see if they differentiate themselves in quality-of-life terms,” Gore said.
Brachytherapy patients, who represented slightly less than 20% of the total, experienced more obstructive and irritating urinary symptoms than did surgery patients. The reason for this, Gore said, is that the prostate surrounds part of the urethra, the tube that carries urine from the bladder to the outside of the body. When the urethra is exposed to radiation, it can be constricted, causing difficulty starting or stopping urine flow.
“Despite the success of brachytherapy controlling the disease, in the hands of a good practitioner, it is not totally benign,” said Jeffrey Williamson, Ph.D., a research physicist and professor of radiation oncology at Virginia Commonwealth University. “It has a different profile of complications [from that of surgery or external-beam radiation]. It has much more urethral strictures.”
Brachytherapy patients also reported more bowel dysfunction, such as frequency and urgency of bowel movements, diarrhea, and pain with stools. External-beam radiation patients suffered from urinary irritation and bowel dysfunction similar to that in brachytherapy patients. And surgery patients more often reported incontinence symptoms such as urine leakage and erectile dysfunction. Essentially, Gore said, all treatments have side effects, and physicians should share that information so that patients can make an informed decision.
Looking to the Future
Knowing that the major complication associated with brachytherapy is irradiation of the urethra and bowel, physicians are beginning to incorporate imaging technologies to minimize incidental exposure. One of the problems with image-guided therapy is that ultrasounds don't show the edges of the tumor, Williamson said. The challenge is to overlay the ultrasound image with more detailed imaging techniques such as computed tomography or magnetic resonance imaging that show biological activity. Doing so would allow the surgical team to more carefully focus the radiation, give a lower dosage to the whole prostate, and thereby end up with fewer complications, such as damage to the urethra.
“A really active area of research in my field is a more quantitative use of image-guided brachytherapy to try to control the positioning of the seeds so you can more accurately place them,” Williamson said. “For example, magnetic resonance spectroscopy shows a lot of promise in being able to highlight the exact location inside the prostate where gross disease is located.”
The trouble with magnetic resonance spectroscopy is that it takes 45 minutes to get an image, making it impractical to use in a surgical suite.
“It's necessary to somehow register the really difficult-to-acquire biological images to the constantly-being-updated real-time images that you have in the surgery suite,” Williamson said. Solving that problem is “one of the hottest topics in engineering and physics research in radiation oncology.”
But even without magnetic resonance imaging, Cesaretti has shown that younger men, those aged 50–59 years, who go into brachytherapy treatment with good sexual function and urinary function are likely to retain these functions over the long term. Drawing on long-term follow-up data from 3,000 prostate cancer patients treated at Mount Sinai beginning in 1990, Cesaretti analyzed the outcome of brachytherapy patients in a report published in August in the journal BJU International .
The research team evaluated the effect of low–dose rate prostate brachytherapy on the sexual health of men with at least 7 years of follow-up after treatment ranging from prostate tumors limited to the primary site to intermediate tumors that had spread outside the initial area. All the subjects had optimal erectile function or urinary function before treatment.
While 32% of patients developed erectile dysfunction, younger patients reported fewer problems, and those problems resolved over time for most patients.
Cesaretti said that he published the reports to show that the rate of erectile dysfunction reported among brachytherapy patients could be misleading, because brachytherapy patients have tended to be older and sicker to start. These results, he said, show that among younger patients with fewer comorbid symptoms, brachytherapy can provide good results with few side effects.
For patients whose disease is confined to the prostate, Cesaretti said that any of the three dominant forms of treatment works well, and the type of treatment men receive depends largely on whether patients see a urologist or radiation oncologist. A study presented by Justin Bekelman, M.D., a radiation oncologist at Memorial Sloan-Kettering, at the 2007 American Society of Clinical Oncology meeting, showed that when men aged 65–69 years saw only a urologist, 70% had a radical prostatectomy, but when they also saw a radiation oncologist, only 15% had a radical prostatectomy.
“There's a major bias built into the system [depending on who diagnosed the patient],” Cesaretti said. “I think what's going to happen, and the way this is being handled at big cancer centers, is that newly diagnosed patients are basically having to see a radiation oncologist to make sure that they get all their options.”