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Prostate Cancer - Brachytherapy (Radioactive Seed Implantation Therapy)

Author: Dan Theodorescu, MD, PhD, Paul Mellon Professor of Urologic Oncology, Department of Urology, University of Virginia Health Sciences Center
Coauthor(s): Tracey L Krupski, MD, MPH, Assistant Professor, Department of Urology, University of Virginia

Updated: Apr 27, 2009

Introduction
Brachytherapy (the term derived from the Greek word brachys, which means brief or short) refers to cancer treatment with electromagnetic radiation delivered via radioactive material placed a short distance from, or within, the tumor. In prostate cancer, brachytherapy involves the ultrasound and template-guided insertion of radioactive seeds into the gland. Along with radical prostatectomy, cryotherapy, and external beam radiation therapy (EBRT; most recently termed intensity-modulated radiation therapy [IMRT]), interstitial brachytherapy is a potentially curative treatment for localized prostate cancer. For appropriately selected patients, brachytherapy appears to offer cancer control comparable to these other techniques. However, although proponents of brachytherapy claim better quality-of-life results, the evidence supportingthis claim is mixed. This article outlines both the technique and outcomes, with respect to cancer control and quality of life.

History of the Procedure
In the 1970s, several centers used brachytherapy to treat prostate cancer. Implants were placed into the prostate under direct vision following open pelvic lymphadenectomy. Unfortunately, long-term follow-up revealed less-than-satisfactory results in terms of cancer control. Currently, these less-than-optimal results are thought to have resulted from (1) a technical inability to accurately implant the sources and (2) the relative paucity of objective dosimetric criteria by which to analyze the radiation dose in that era. Interest in brachytherapy waned in the early 1980s because of these results, the advent of more advanced EBRT equipment, and the development of the nerve-sparing radical prostatectomy.

In the late 1980s and early 1990s, the emergence of transrectal ultrasonography (TRUS) and the development of template guidance led to the introduction of percutaneous brachytherapy for the treatment of localized prostate cancer. This technique was supported by improved dosimetry and offered the potential advantage of delivering a higher radiation dose to the prostate than would be possible with EBRT. This latter consideration was particularly important in view of the high rate of positive prostate biopsy findings following conventional EBRT.

Problem
Ionizing radiation delivered by either an external or interstitial source generates free radicals such as superoxide or hydrogen peroxide, which damage cellular DNA. The resultant cytotoxicity depends on cell division; therefore, the more rapid the cell turnover, the higher the cell death per unit of time. Thus, although lethally irradiated, in most cases, a tumor cell does not die until it attempts cell division.

Frequency
Prostate cancer is currently the most frequently diagnosed malignancy among men and the second leading cancer cause of death. With the advent of prostate-specific antigen (PSA) screening, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated in order to select the most appropriate treatment.

Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.

Approximately 1 in 6 men older than 50 years will be diagnosed with prostate cancer. Prostate cancer is rarely diagnosed in men younger than 40 years and is uncommon in men younger than 50 years. The prevalence of prostate cancer remains significantly higher in African American men than in white men.

Between 1989 and 1992, prostate cancer incidence rates increased dramatically. This rise was probably due to earlier diagnoses in asymptomatic men due to the increased use of serum PSA testing. In 1994, Catalona et al showed that the incidence of organ-confined disease at diagnosis was increased by evaluating PSA values in addition to performing the standard digital rectal examination (DRE). Prostate cancer incidence rates are continuing to decline; rates in white men peaked in 1992, and they peaked in African American men in 1993.

From 1992-1996, prostate cancer mortality rates declined significantly (by 2.5% per year). Although mortality rates are continuing to decline among white and African American men, mortality rates in African American men remain more than twice as high as rates in white men.

Prostate cancer is also found during autopsies performed following other causes of death. The rate of latent cancer or cancer found at autopsy is much greater than the rate of clinical cancer, possibly reaching as high as 80% by age 80 years.

The prevalence of clinical cancer varies by region. In northern Europe and North America, the rate is high. In southern Europe and Central and South America, the rate is intermediate. In Eastern Europe and Asia, the rate is low. These differences may be due to genetic, hormonal, and/or dietary factors. Interestingly, the prevalence of the latent or autopsy form of the disease is similar worldwide. This, together with migration studies, suggests that environmental factors such as diet may play a significant role in the development of clinical cancer from a latent precursor.

Etiology
Genetics
Alteration of genes on chromosome 1 and the X chromosome have been found in some patients with a family history of prostate cancer. In addition, genetic studies suggest that a strong familial predisposition may be responsible for as many as 10% of prostate cancer cases. Recently, several reports have suggested a shared familial risk (inherited or environmental) for prostate and breast cancer.

Race
Prostate cancer is more prevalent and aggressive in African Americans than in white men. The prevalence of prostate cancer is even lower in men of Asian origin. Studies have found that testosterone levels are 15% higher in young African American men than in young white men. Furthermore, evidence indicates that 5-alpha reductase may be more active in African Americans than in whites, implying that hormonal differences may play a role. Others argue that barriers to health care, not biological factors, lead to more advanced disease in African Americans.

Diet
A high-fat diet may lead to increased risk, while a diet rich in soy may be protective. These observations have been proposed as reasons for the low prevalence of prostate cancer in Asia. Cell culture work has shown that omega-6 fatty acids are positive stimulants of prostate-cancer cell growth, while omega-3 fatty acids are negative stimuli. These fats may exert their effects by altering sex hormones or growth factors or affecting 5-alpha reductase.

Soy seems to decrease the growth of prostate cancer cells in mouse models, but, apart from epidemiologic factors, no direct evidence has supported a beneficial effect in humans. The low-fat diet has some support based on the cell culture work mentioned above. Vitamin E may have some protective effects because it is an antioxidant. Decreased levels of vitamin A may be a risk factor because this can promote cell differentiation and stimulate the immune system. Vitamin D deficiency was suggested as a risk factor, and studies show an inverse relationship between ultraviolet exposure and mortality rates for prostate cancer. However, specific correlation between 1,25-dihydroxyvitamin D levels and palpable disease, well-differentiated tumors, or mortality is inconclusive.

Selenium may have a protective effect based on epidemiologic studies and is also believed to extend its effect via its antioxidant properties. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is an ongoing intergroup, phase 3, randomized, controlled trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer.

Hormones
Hormonal causes have also been postulated. Androgen ablation causes a regression of prostate cancer. In addition, as indirect evidence of hormonal causes, eunuchs do not develop adenocarcinoma of the prostate.

Hsing and Comstock performed a large study comparing patients with prostate cancer with controls and found no difference in levels of testosterone, dehydrotestosterone, prolactin, follicle-stimulating hormone, or estrone.

The effects of blocking the conversion of testosterone to dihydrotestosterone were examined in the Prostate Cancer Prevention Trial (PCPT). This trial studied the prevalence of prostate cancer between a control group and a cohort given a 5-alpha reductase inhibitor, finasteride. While the 5-alpha reductase inhibitor appeared to decrease the prevalence of tumors, those that did arise appeared histologically more aggressive. Whether these are biologically more aggressive remains as yet undetermined.

Pathophysiology
Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth.

Following the initial transformation event, further mutations of a multitude of genes, including TP53 and RB1, can lead to tumor progression and metastasis. Most prostate cancers (95%) are adenocarcinomas. Approximately 4% have transitional cell morphology and are thought to arise from the lining of the prostatic urethra. Few have neuroendocrine morphology. When present, they are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.

Seventy percent of prostate cancers arise in the peripheral zone, 25-30% in the transitional zone, and less than 5% in the central zone. These zones can often be identified using TRUS. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors. Multifocality may indicate a more aggressive tumor biology.

Presentation
Brachytherapy is an accepted treatment option for early-stage prostate cancer. The various institutions that offer brachytherapy have subtle differences in technique. Most of the techniques discussed in this article are generic in description, but some modifications are unique to the implant procedure performed at the University of Virginia.

Indications
Primary treatment - Risk-dependent protocols
Evidence-based protocols for brachytherapy have been developed, although data are limited. A 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) noted that no randomized controlled trials had compared brachytherapy alone with other major treatment options for clinically localized prostate cancer.3 The American Brachytherapy Society (ABS) formed a committee of experts in prostate brachytherapy to develop consensus guidelines through a critical analysis of published data supplemented by the experts' clinical experience.4 The recommendations of the panel were reviewed and approved by the board of directors of the ABS. They published a review of their recommendations concerning permanent (low-dose rate) implants in 2007.

  • Patients with a high probability of organ-confined disease are appropriately treated with brachytherapy alone. Most practitioners include patients with stage T1-T2a (according to the American Joint Committee on Cancer/International Union Against Cancer 1997 staging), PSA level of 10 ng/mL or less, and Gleason score of 6 or lower in this category. The recommended prescription doses for monotherapy are 145 Gy for iodine (I)–125 and 120-125 Gy for palladium (Pd)–103.
  • Brachytherapy candidates with a significant risk of extraprostatic extension should be treated with supplemental IMRT. A high risk of extraprostatic extension is defined as the presence of 2 or more of the following risk factors: a Gleason score greater than or equal to 7, a PSA level greater than 10 ng/mL, and a stage higher than T2b. The IMRT dose is 40-50 Gy with a boost of 110 Gy or 100 Gy, depending on which IMRT dose was administered.
  • Intermediate-risk patients have only one of the aforementioned risk factors. Brachytherapy monotherapy appears to demonstrate good results in several studies. The combination of IMRT and brachytherapy has not uniformly produced better cancer-control results. Length of follow-up time is critical for discerning treatment differences.
A patterns-of-care study conducted by Frank et al found that a subset of intermediate-risk patients are treated with brachytherapy monotherapy.5 Specifically, monotherapy is used to treat T1c disease characterized by absent perineural invasion, positive results in less than 30% of core samples, and a Gleason score of 7 or a PSA level of 10-20 ng/mL. Even select T2a and T2b cases were treated with monotherapy.

A current Radiation Therapy Oncology Group (RTOG) trial, RTOG 0232, is assessing the role of IMRT plus brachytherapy boost versus brachytherapy alone in the treatment of intermediate-risk prostate cancer in a prospective randomized setting. Until results of this study are available, individual radiation oncologists typically assess risk across the wide range included within the intermediate-risk category to base treatment recommendations.

While clinical evidence to guide selection of the radionuclide (Pd-103 or I-125) is lacking, many practitioners use Pd-103 (in combination with IMRT) as the isotope of choice in the treatment of locally advanced disease because of its higher dose rate.

A prospective randomized multicenter trial examined long-term morbidity associated with I-125 compared with that of Pd-103 in the treatment of low-risk prostate cancer. The study found that patients who received I-125 were more likely to develop proctitis, while patients who received Pd-103 were more likely to develop prostatitis.6 Careful treatment planning should mitigate the adverse effects associated with I-125. A study by Niehaus et al evaluated International Prostate Symptom Scores (IPSSs) in 976 patients treated with brachytherapy and demonstrated that neither isotope was favorable in terms of IPSS resolution, catheter dependence, or need for postbrachytherapy surgical intervention.

Studies of cesium (Cs)–131 in permanent prostate brachytherapy have been increasing. Cs-131 is an attractive alternative, as its average energy is similar to that of I-125 and it has a half-life of only 9.7 days.

The modern technique of prostate brachytherapy requires 3 components: (1) dosimetric planning, (2) placement of sources, and (3) evaluation of implant quality.
  • Dosimetric planning of the implant should be performed in all patients before or during seed insertion. Debate persists as to whether intraoperative planning or preplanning is preferred. A modified peripheral loading plan is preferred when the sources are placed. The ABS also recommends that, for optimal patient care, postimplant dosimetry should be performed in all patients undergoing permanent prostate brachytherapy. At present, CT-based dosimetry is recommended, based on availability, cost, and the ability to image the prostate and the seeds. Additional plain radiographs should be obtained to verify the seed count.
  • Brachytherapy for prostate cancer. Abdominal radi...
    Brachytherapy for prostate cancer. Abdominal radiograph following the procedure.

  • Until the ideal postoperative interval for CT scanning has been determined, each center should perform dosimetric evaluation of prostate implants at a consistent postoperative interval. This interval should be reported. Isodose displays should be obtained at 50%, 80%, 90%, 100%, 150%, and 200% of the prescription dose and displayed on multiple cross-sectional images of the prostate. Dose-volume histography of the prostate should be performed, and all centers should report the D90 (dose to 90% of the prostate gland). Additionally, the D80; D100; the fractional V80, V90, V100, V150, and V200 (ie, the percentage of prostate volume receiving 80%, 90%, 100%, 150%, and 200% of the prescribed dose, respectively); and the rectal and urethral doses should be reported and ultimately correlated with clinical outcome in the research environment. Urbanic et al recently reported that a review of 4 series confirms that freedom from recurrence depends on adequate dosimetry.

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