AUTHOR AND EDITOR INFORMATION

Section 1 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

INTRODUCTION

Section 2 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Currently, the potentially curative treatment modalities offered to patients with clinically organ-confined prostate cancer include radical prostatectomy, cryotherapy, external beam radiation therapy (EBRT; most recently termed intensity-modulated radiation therapy [IMRT]), and interstitial brachytherapy. By 1983, the advent of ultrasound- and template-guided placement of radioactive seeds into the prostate had led to a resurgence in the use of interstitial brachytherapy as a potentially curative treatment for localized prostate cancer. For appropriately selected patients, brachytherapy appears to offer comparable cancer control. However, although proponents of the technique claim better quality-of-life results, the evidence supporting this 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. Brachytherapy, arising from the Greek word brachys for brief or short, refers to electromagnetic radiation delivered via the insertion of radioactive materials a short distance from, or within, the tumor. The dose is the unit of absorbed energy per weight of tissue. For example, the basic unit of radiation is now the gray (Gy), which is 1 J/kg of tissue.

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.

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.¹

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.

Clinical

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

Section 3 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Primary treatment - Risk-dependent protocols

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.² 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.³ 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.⁴ Careful treatment planning should mitigate the adverse effects associated 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.⁵

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.
• 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.⁶ 

Temporary isotopes

In addition to permanent brachytherapy (discussed above), high dose rate brachytherapy has also been used. In this technique, the dose is delivered at a higher dose rate than is provided by a permanent implant. This delivers radiation to the prostate using temporary high dose rate radioactive implants. The most common isotope used for temporary brachytherapy is iridium (Ir)–192, which provides a higher dose of radiation than the I-125 or Pd-103 permanent implants. As such, the Ir-192 implants are not left in the prostate gland.

Using an imaging modality such as ultrasonography, MRI, or CT, temporary catheters that contain the implants are positioned in the prostate. Patients require hospitalization while the implants remain in place but may go home once the implants are removed. IMRT is usually used with this technique. The optimal patient population has not yet been determined. High dose rate brachytherapy is commonly delivered in 2 or more fractions of 810 Gy or more. Most series reported are from single centers.

Most brachytherapy for prostate cancer is performed using the permanent technique, which is the focus of the remainder of this article.

RELEVANT ANATOMY

Section 4 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. The blood supply to the base of the bladder and prostate is from the inferior vesicle, which is derived from the internal iliac. The capsular branches of the inferior vesicle artery help identify the pelvic plexus arising from the S2-4 and T10-12 nerve roots. The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function.

CONTRAINDICATIONS

Section 5 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Brachytherapy has several relative contraindications, as follows:

• Transurethral resection of the prostate: Initially, prior transurethral resection of the prostate was associated with increased symptoms and urinary incontinence rates as high as 50%, but more recent studies have reported incontinence rates of less than 10%.
• Pubic arch interference: Interference may occur because of a large prostate (a gland >40 g), and this interference may preclude adequate placement of seeds. Hormonal ablation, exaggerated lithotomy, horizontal probe position, and CT-guided placement are all potential solutions.
• Obstructive symptoms: Significant preoperative obstructive symptoms increase the likelihood of postoperative urinary retention. While glands larger than 40 g are more likely to have obstructive symptoms, symptoms can occur in anyone. Glands between 50 g and 60 g require downsizing. Hormone ablation has been reported to downsize the prostate gland by 25-40% and is used to facilitate brachytherapy in patients with large glands. One study randomized prostates of comparable size to brachytherapy alone or brachytherapy after hormone ablation.⁷ They found that the acute side effects of urinary retention and dysuria were actually greater in the hormone ablation group. Clinicians often compromise and use a 5-alpha reductase inhibitor rather than true androgen ablation for downsizing. Nonetheless, brachytherapy is not advisable in patients with glands larger than 60 g.
• Morbid obesity: Focusing on the target is feasible, but the equipment often cannot sustain the weight or is not long enough to reach the prostate.

WORKUP

Section 6 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Lab Studies

• CBC count
• Prothrombin time
• Activated partial thromboplastin time
• CHEM-7
• Urine culture

Imaging Studies

• The amount of radiation to be delivered to the prostate and the configuration of the implants must be assessed prior to placement of the implants. As experience with the technique has broadened, the planning and dosimetry stage has evolved from preplanning days to weeks in advance to intraoperative planning. The ABS has defined the following terminology to clarify the differences in the techniques.
• • Preplanning is the creation of a plan days or weeks before the implant procedure.
  • Intraoperative planning is treatment planning in the operating room without moving the ultrasound probe.
  • Intraoperative preplanning is the creation of a plan in the operating room, with immediate execution of the plan.
  • Interactive planning is stepwise refinement of a plan using computerized dose calculations derived from images of needle placement.
• Intraoperative treatment planning does not eliminate the need for postimplant dosimetric analysis.
• Key issues related to planning and dosimetry are described as follows:
• • In order to perform accurate dosimetry and real-time visualization of percutaneous source placement, the prostate and margins of adjacent organs (eg, rectum, bladder) must be well visualized. TRUS and CT scanning are the two major modalities currently in use.
  • TRUS has the advantages of real-time imaging and sharp contour of the posterior prostate and rectal wall. Its disadvantage is that its accuracy depends on the operator's skill.
  • The accuracy of CT scanning, on the other hand, does not depend on the operator's skill, but prostate margins are less well defined with this imaging modality.
  • With either modality, initial 5-mm slices are obtained from the base of the bladder to the pelvic floor. A target, which includes the prostate contour, with a generous allotment to the apex and a tighter margin at the base, is developed from these images. The apex tends to allow for less seed migration because of the presence of the pelvic floor muscles here, as opposed to the looser periprostatic tissue at the base.
  • Traditionally, a portion of the seminal vesicles is included in the target of radiotherapy.
  • The information on the target volume and margins is then transmitted to a computer program, and the computer helps perform the dosimetry and helps to plan the number of seeds and to define their location on a 2-dimensional grid.
  • The strategy of seed placement is somewhat controversial, with some advocating uniform distribution of seeds and others emphasizing placement on the periphery of the prostate, where most cancers arise.

TREATMENT

Section 7 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Medical therapy

Forms of brachytherapy

IMRT and brachytherapy are treatment options for localized prostate cancer. They differ predominately in the areas of dose distribution, total dose, and dose rate.

In brachytherapy, the sharp radiation dose fall-off allows for a high degree of rectal sparing and for a higher total dose to be delivered to the prostate gland itself. Similar advantages can be obtained with conformal EBRT or IMRT. While brachytherapy has a much lower initial dose rate than EBRT, the aggregate radiation delivery is higher. The average doses are 10 Gy/wk for EBRT and 40 Gy/wk for Pd-103 and 13 Gy/wk for I-125 brachytherapy implants. In addition, high dose rate implants, such as Ir-192, can range from 2-36 Gy/min.

Early experience with the high-dose rate revealed excessive toxicity, and, subsequently, adjustments were made to fractionate the dose into 4-7 treatments. Advantages of the high-dose rate include a short duration of treatment (10-15 min), minimization of applicator movement, and optimization of dose distribution because sources are mobile. Disadvantages include increased adverse effects and the need for hospitalization.

Source options

Brachytherapy was first performed in 1914, shortly after Marie Curie discovered radium. Various sources have been used over the years, which vary in half-life and effective energy, as listed below.

• Radium (Ra)–226 - 1620 years, 1.2 J
• Cs-137 - 30 years, 0.66 J
• Gold (Au)–198 - 2.7 years, 0.41 J
• Ir-192 - 74 days, 0.34 J
• I-125 - 60 days, 0.027 J
• Pd-103 - 17 days, 0.39 J

Brachytherapy sources can be divided into permanent and temporary groups. Permanent sources tend to have lower energy and shorter half-lives and include I-125, Pd-103, and Au-198. The advantage of these lower energies is enhanced safety for medical personnel due to the rapid dose drop-off with distance. The disadvantage is that anatomical adjustments cannot be made once the sources are placed.

Currently, temporary implants consist primarily of Ir-192 and Cs-137. Ir-192 is the only one used for afterloading with interstitial placement, while Cs-137 is used for intracavitary placement. Commercial high-dose Ir-192 devices use computer technology to control both the position and time in that position to deliver a high dose to a very specific tissue volume.

Currently, the 2 most common permanent radioactive sources for brachytherapy seeds are I-125 and Pd-103. The lower the energy emitted by the photons, the higher the energy transfer. The higher the energy transfer, the higher the radiobiologic effect, which can lead to lower total doses. The energy of Pd-103 is 21 keV, compared with 30 keV for I-125. Because Pd-103 has the higher radiobiologic effect, the total dosing can be lower. Because some concern exists from in vitro data about the efficacy of I-125 in poorly differentiated and rapidly growing tumors, Pd-103 is used more commonly in higher-grade prostate cancers.

Ir-192 is used for high–dose rate treatment of prostate cancer. A preplan is devised using TRUS to deliver 15 Gy to the prostate and smaller doses to the urethra and rectum. During the implantation, hollow needles are inserted transperineally and checked via TRUS to ensure reproduction of the preplan template. The needles are then connected to an automated remote-controlled loading machine. This device successively moves Ir-192 to the dwell positions for various durations. The total irradiation time is usually only 5-10 minutes.

Androgen ablation in brachytherapy

The rationale for neoadjuvant or adjuvant hormone treatment is derived from extrapolations of existing EBRT data.

Neoadjuvant and adjuvant approaches

Outcomes of radiotherapy in patients with intermediate or high-risk prostate cancer have benefited from neoadjuvant hormonal ablation. In a randomized trial, Pilepich et al found that subjects randomized to receive luteinizing hormone–releasing hormone and flutamide in addition to EBRT showed improved local control and survival (in patients with higher-grade disease) compared with those treated with radiation alone.⁸

In the adjuvant setting, Laverdiere et al compared patients with localized prostate cancer treated with EBRT or EBRT with combined with androgen blockade in terms of both PSA failure and persistence of the cancer on prostate biopsy specimens. One hundred and twenty subjects with clinical stage B1-T2a, B2-T2b/T2c, or C-T3/T4 adenocarcinoma of the prostate were entered in this prospective randomized study. The subjects were randomly allocated to EBRT alone (group 1); 3 months of neoadjuvant combination therapy (luteinizing hormone–releasing hormone agonist plus flutamide) prior to EBRT (group 2); and combination therapy 3 months before, during, and 6 months after EBRT (group 3). The 3 groups had no significant differences in age, disease stage, tumor grade, and pretreatment PSA levels.

TRUS-guided needle biopsies were performed 12 and 24 months after the end of EBRT. Serum PSA levels were measured at scheduled visits. While 62% of control subjects in group 1 disclosed residual neoplasm upon biopsy at 12 months, only 30% and 4% showed residual disease in groups 2 and 3, respectively. When assessed at 24 months, 65%, 28%, and 5% showed residual cancer for groups 1, 2, and 3, respectively. The PSA measurements at 12 months also indicated differences between the 3 groups, except at 24 months, when the difference between group 2 and 3 was no longer significant.

Another randomized study (Bolla et al) further showed that androgen suppression prior to, during, and following radiation therapy increased disease-free survival (DFS) and overall survival in patients with locally advanced disease undergoing EBRT.⁹

A study by D'Amico et al compared patients treated with brachytherapy with those treated with brachytherapy and androgen ablation. They found no differences, except in patients with a Gleason score of 7. Whether this difference persisted over time is unclear. Several other reports analyzing subsets of intermediate- or high-risk patients have failed to confirm a benefit.

Salvage brachytherapy

In the past, additional EBRT was rarely an option because of the limits on cumulative doses. Hormonal therapy is not curative, and salvage prostatectomy has limited efficacy with significant adverse effects. Estimated 5-year survival rates for salvage prostatectomy range from 25-65%. Over the past few years, salvage brachytherapy and salvage cryotherapy have been increasingly advocated as therapeutic options in addition to salvage prostatectomy. A 2003 series by Koutrouvelis et al reported success with salvage brachytherapy after prior brachytherapy, but note that this success was reported in only one study with 31 patients¹⁰; therefore, such a treatment plan must be considered with caution. The tables presented below summarize some of the pertinent literature pertaining to these newer modalities.

Table 1. Salvage Cryotherapy

In December 2000, the Health Care Financing Administration (Coverage Analysis Group file no. 00064) revised the national noncoverage policy for cryosurgical salvage therapy to allow coverage only for patients with localized disease (1) in whom a trial of radiation therapy failed as their primary treatment and (2) who meet one of the following conditions: stage T2B or below, Gleason score less than 9, and PSA level less than 8 ng/mL. Cryosurgical ablation as salvage therapy remains uncovered for all other patients.

Table 2. Salvage Brachytherapy

*American Society for Therapeutic Radiology and Oncology

Data on salvage brachytherapy are very immature but appear similar to those of cryotherapy. Larger studies and longer follow-up are needed before a definitive conclusion on the efficacy of this modality is established.

Overview of the permanent brachytherapy technique

A perineal template and TRUS guidance are used to guide placement of the needles into the prostate. Once the final needle position is established, the seeds are delivered. Postprocedure, a CT scan is repeated to confirm seed position and to generate imaging data for postimplant dosimetry.

Preoperative details

Preoperative workup includes (1) bowel preparation, both mechanical and antibiotic; (2) prophylactic intravenous antibiotics at the time of the procedure and an oral course for several days afterward; (3) subcutaneous heparin if the patient has a history of deep vein thrombosis; and (4) stoppage of all anticoagulants, including aspirin, nonsteroidal anti-inflammatory drugs, and warfarin.

Intraoperative details

TRUS-guided implantation technique

• Positioning: The lithotomy position is used. To differentiate the bladder from the prostate, use a urinary catheter to visualize the urethra or instill diatrizoate (Renografin) in the bladder. Secure the scrotum out of the perineal field with tape or towel clips.
• TRUS probe: A biplanar probe is best at 5, 6, or 7.5 MHz. Attach the probe to the stepping unit, which moves the probe in a cephalad or caudal direction at 0.5-cm intervals.
• Re-create planning images: Match the probe image to the planning image. Adjust the needle-guide template against the perineum, with 1-3 cm of space between the skin and the template. When intraoperative planning is being used, re-creation of the images is not necessary. The benefits of intraoperative planning are that optimal settings are determined in real time and variations are minimized (ie, no re-creation of prior plan). One drawback is that the operative time is longer, but the patient needs to come in only once.
• Needle insertion: The needle is inserted through holes in the template, then through skin. Watch for deflection, and reposition as needed. Avoid anterior pubic bones. Burnished-tip needles are easier to see when the sonogram becomes distorted by previously placed needles. Avoid piercing the urethra and ensure that no needle is closer than 0.5 cm to the rectal wall.
• Needle depth: Adjust the needle depth based on the preplan zero plane. Use a longitudinal ultrasonographic view. To mark the location of the bladder neck, perform fluoroscopy using a Foley balloon or instill diatrizoate.
• Source placement: Afterloading or Mick applicator techniques can be used. Remove the needle slowly to avoid source migration in the afterloading technique. Observe seed positioning under fluoroscopy.
• Postprocedure: Many brachytherapists perform cystoscopy to look for sources in the bladder or the urethra.

CT-guided implantation technique

• Planning: A planning CT scan is obtained several days before the procedure, with a urinary catheter in place. The catheter and diatrizoate serve to mark the bladder-prostate border. The prostate is scanned at 5-mm intervals with images that are 5 mm thick.
• Positioning: The patient is prone. A urethral catheter is placed that has wire through it and lead markers at 1-cm intervals. The template stand is mounted against the perineum. Most brachytherapists do not use a rectal marker.
• Needle placement: Initially, 2 needles are inserted simultaneously just posterior to the urethra on either side of the midline. Then, all anterior needles are inserted to limit prostate mobility. Anterior sources are placed first. Posterior needles are placed again, using 1-cm urethra markers for guidance.
• Source placement options: For the Mick applicator, pull the needle back from the zero plane at 5-mm intervals. Use preloaded needles. Rigid Absorbable Permanent Implant Device (RAPID; Amersham Health; Princeton, NJ) Strand seeds, ie, I-125 seeds adsorbed onto a silver rod are an option. Watch the placement of each source using repeat CT scanning. Perform a final CT scan of the prostate and postimplant dosimetry.

Postoperative details

Allow the patient to recover from anesthesia. A final CT scan of the prostate and postimplant dosimetry are performed (only in TRUS-guided cases) from 1-30 days following the procedure. If a "cold spot" is observed, reimplantation can be performed. A voiding trial is initiated. If the patient cannot void, a catheter is reinserted and another trial is performed in 5-7 days.

Follow-up

Patients are discharged home the same day. Hematuria is expected for the first 1-2 weeks, and all patients experience dysuria. Most studies report urinary retention rates of less than 10%. However, if acute retention develops, a Foley catheter is inserted and alpha-blockers initiated. In most cases, perioperative edema resolves within the first 48 hours or certainly within the first week. A small subset of patients continue to have difficulty voiding beyond that period. These patients are taught the technique of clean intermittent catheterization. If voiding does not return within 3 months, urodynamics testing may be considered to ensure that this is truly obstruction rather than bladder dysfunction. In patients with true obstruction, transurethral resection of the prostate may be performed.  

If obstructive symptoms are present, patients are started on alpha-blockers and maintained on this therapy for 9 months. Infection, perineal pain, and rectal bleeding are less common; nonsteroidal anti-inflammatory drugs and mesalamine (Rowasa) suppositories may help.

For excellent patient education resources, visit eMedicine's Prostate Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education article Prostate Cancer.

Tumor follow-up

PSA should be measured and a DRE should be performed every 3-6 months for 5 years and then yearly. If the PSA or DRE findings are abnormal at follow-up, appropriate increased follow-up frequency (PSA abnormality only) or biopsy (DRE abnormality) should be considered.

Definitions of biochemical failure

The PSA definition of disease freedom after radiotherapy for prostate cancer is still disputed. Historically, several different approaches have been used to define biochemical failure.

The first approach is to use absolute values to define failure, similar to the use of PSA levels following prostatectomy. Various cutoffs have been used, ranging from 4-0.2 ng/mL. The alternative approach is to use increasing values of PSA over time as a definition of failure. The ASTRO has proposed that 3 consecutive elevations should define failure if each elevation satisfies certain requirements. A principal rationale behind the ASTRO definition is the well-documented occurrence of benign spikes in PSA levels that can occur following brachytherapy; allowing for these spikes prevents an incorrect diagnosis of a recurrence.

Recent studies have shown that the ASTRO Consensus Panel definition of biochemical failure following radiation therapy correlates well with clinical distant metastases–free survival, DFS, and cause-specific survival. These findings suggest that this definition may be a surrogate for clinical progression and survival. However, determining the date of recurrence has been controversial. In the ASTRO definition, the date of failure is the point halfway between the nadir and first rise in PSA level. This ambiguity and the fact that the definition performed poorly in patients treated with hormone ablation has led to the development of a new definition. The Phoenix definition is characterized by a rise in PSA level of 2 ng/mL above the nadir. This is used to define biochemical failure after EBRT, with or without hormone ablation.

Both definitions are currently used in brachytherapy research protocols. Regardless of the definition used, the reported date of biochemical control should be cited as 2 years short of the median follow-up. In other words, prolonged follow-up is necessary in good studies.

The faster the PSA level nadir is reached, the better the outcomes. 

The following are the PSA level nadir levels with the corresponding 5-year DFS rates:

• PSA level less than 0.5 ng/mL - 79%
• PSA level 0.5-0.99 ng/mL - 66%
• PSA level 1-1.99 ng/mL - 49%
• PSA level greater than 2 ng/mL- 25%

COMPLICATIONS

Section 8 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Needle puncture sites

The perineum is tender and bruised and may have slight bleeding from needle holes. Treatment is predominately ice and mild analgesics.

Urinary symptoms

Hematuria may be observed in the first 24 hours. Irritative symptoms such as dysuria, frequency, and urgency last from days to months. Studies have shown that 34-45% of patients have symptoms that persist for up to 1 year. The incidence rate of incontinence is 10-35% in the first few months, with few patients having any leakage at 1 year. As mentioned above, a small subset of patients may have persistant urinary retention, which is managed initially with a Foley catheter, then clean intermittent catheterization, and possibly transurethral resection of the prostate.

Reported rectal symptoms

As many as a third of patients report urge, diarrhea, and painful bowel movements. These symptoms improve over the first year. At 1 year, only 2% have persistent symptoms. Some studies report as many as 20% of patients have bright red blood per rectum. Symptoms have been reported to persist as long as 49 months after the procedure. Prostatorectal fistulas occur in 1-7% of all patients in published series. Recent data from the primary authors' institution suggest that, after brachytherapy, these fistulas result from biopsy of the anterior rectal wall by gastroenterologists. The wall likely appears irritated and ulcerated following brachytherapy, thus prompting the biopsy. Patients should be counseled to undergo colonoscopy prior to or one year after brachytherapy. 

Sexual dysfunction

Generally, 33% of patients have a decrease in sexual function and activity. Decreased semen volume is observed. Results from studies on impotence vary, with rates as widely disparate as 2.5-25%. In some studies, 40% of the patients experienced some degree of erectile dysfunction following radiation therapy.

Quality of life

The ABS recommends using validated, patient-administered health-related quality-of-life methods to evaluate baseline and follow-up bowel, urinary, and sexual dysfunction. Recent studies have shown that, over time, quality of life among patients who have undergone radical prostatectomy is comparable with that of patients who have undergone brachytherapy alone. Initial differences in the adverse effect profile dissipate over time (2-4 y). However, the quality of life in patients treated with brachytherapy and EBRT was significantly worse at all time points compared with that in patients treated with radical prostatectomy and brachytherapy alone. The effect of androgen ablation on health-related quality of life is mixed, with some studies suggesting a worsening of health-related quality of life and others finding no discernible change.

OUTCOME AND PROGNOSIS

Section 9 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

When compared with historical series using classic EBRT to treat prostate cancer, brachytherapy series appear to offer equivalent or better disease-specific survival as measured by biochemical failure rates. Patients must be appropriately selected and treated at an accredited institution. Although brachytherapy is still in its infancy, 5-, 7-, and 12-year follow-up studies suggest brachytherapy is equal to surgery in terms of biochemical recurrence.

A 12-year study by Ragde et al (2000) reported on patients treated with I-125 seeds, with or without additional EBRT.¹⁸ Of these patients, 66% and 79% of the brachytherapy alone and external radiation plus brachytherapy groups, respectively, were free of biochemical or clinical recurrence. Similarly, Kuban et al found no evidence of disease in only 64% of patients treated with I-125 at 10-year follow-up, but negative findings were found in all of these patients after posttreatment prostate biopsy.¹⁹ In patients with positive findings after prostate biopsies, only 19% remained actuarially disease-free at 10 years.

Polascik et al compared brachytherapy with radical prostatectomy and demonstrated that, at 7 years, surgery had an 87% progression-free survival rate versus 79% for brachytherapy in comparable patients.²⁰ High-risk patients have been reported to have progression-free survival rates of 65-80%. When evaluating these control rates, careful attention must be given to variables such as the addition of EBRT or androgen ablation and length of follow-up.

However, no prospectively performed randomized studies have compared the efficacy of surgery with that of and either brachytherapy or high dose external beam radiotherapy as delivered with modern treatment techniques. Because of a known migration in stage and histology between biopsy and prostatectomy specimens, any retrospective advantage must be interpreted with caution owing to differences in clinical versus pathologic staging. 

The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis.

FUTURE AND CONTROVERSIES

Section 10 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Imaging

MRI may become the standard imaging modality in the future instead of CT scanning or TRUS, in view of its superb imaging of the pelvic anatomy and the possibility of performing interventional studies in open MRI systems.

Cancer control

Early PSA recurrence and biopsy data support brachytherapy as a viable option for localized prostate cancer. Longer studies evaluating survival and disease-free recurrence will help clarify the role for brachytherapy in prostate cancer treatment. In addition, the hormonal ablation achieved with EBRT has yet to be demonstrated in the context of brachytherapy.

Adverse effects and quality of life

While initially thought to leave patients essentially free of symptoms and adverse effects, brachytherapy is now associated with significant early and late adverse effects. In addition, combining brachytherapy and EBRT may result in a higher rate of complications than brachytherapy alone. Finally, the effect of brachytherapy on quality of life and sexual function is only beginning to be studied.

FURTHER READING

Section 11 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

For more information, visit Medscape’s Prostate Cancer Resource Center.

MULTIMEDIA

Section 12 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

Media file 1:  Brachytherapy for prostate cancer. Lithotomy positioning and graphic representation of how brachytherapy is performed.
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Media file 2:  Brachytherapy for prostate cancer. Dosimetry plan.
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Media file 3:  Brachytherapy for prostate cancer. Needle insertion of radioactive implants.
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Media type:  Photo

Media file 4:  Brachytherapy for prostate cancer. Abdominal radiograph following the procedure.
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Media type:  X-RAY

REFERENCES

Section 13 of 13

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Further Reading
• Multimedia
• References

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