Brachytherapy (Radioactive Seed Implantation Therapy) in Prostate Cancer

In the 1970s, several centers used brachytherapy to treat prostate cancer. Implants were placed into the prostate under direct vision after 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 2 problems. The first was a technical inability to accurately implant the sources. The second was 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 external beam radiation therapy (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.

Along with radical prostatectomy, cryotherapy, and EBRT (also referred to as 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 that achieved with these other techniques. Although proponents of brachytherapy claim better quality-of-life results, the evidence supporting this claim is mixed.

The various institutions that offer brachytherapy have subtle differences in technique. Most of the techniques discussed in this article are generic, but some modifications are unique to the implant procedure performed at the University of Virginia.

Permanent versus temporary brachytherapy

In addition to permanent brachytherapy, temporary brachytherapy has also been used. In this technique, the implants deliver radiation to the prostate at a higher dose rate than is provided by a permanent implant. Currently, the isotope most commonly used for temporary brachytherapy is iridium (Ir)-192, which provides a higher dose of radiation than the iodine (I)-125 and palladium (Pd)-103 permanent implants.

For high-dose-rate brachytherapy (HDRB), a preplan is devised using TRUS to deliver 15 Gy/h 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 wires into the needles to the dwell positions for various durations. The total irradiation time is usually only 5-10 minutes.

HDRB is commonly delivered in 2 or more fractions of 810 Gy or more, with 6-24 hours between treatments. Patients require hospitalization while the implants remain in place but may go home once the implants are removed.

HDRB is usually used in combination with IMRT.[1] The optimal patient population has not yet been determined. Most series reported are from single centers.

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

The American Brachytherapy Society has published consensus guidelines for high-dose-rate prostate brachytherapy,[2] which note a growing experience with the use of this modality as monotherapy.

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

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 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. The Society published updated consensus guidelines for TRUS-guided permanent (low-dose-rate) prostate brachytherapy in 2012.[5]

Patients with a high probability of organ-confined disease are appropriately treated with brachytherapy alone. Most practitioners include patients with stage T1-T2a cancer (according to the American Joint Committee on Cancer/International Union Against Cancer 1997 staging), a prostate-specific antigen (PSA) level of 10 ng/mL or less, and a Gleason score of 6 or lower in this category. The recommended prescription doses for monotherapy are 145 Gy for I-125 and 120-125 Gy for 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:

• Gleason score ≥7

• PSA level >10 ng/mL

• 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.

Combination therapy was found to be beneficial in a study of high-risk patients (PSA >20 ng/mL, Gleason score 8-10, or clinical stage ≥T2c) with localized prostate cancer treated either with low-dose-rate brachytherapy alone or with brachytherapy supplemented by EBRT or androgen suppression therapy (AST) or both.[6]  Trimodality therapy that included EBRT and AST resulted in lower prostate cancer–specific mortality. This benefit is likely most important in men with multiple determinants of high risk.

The benefits of combination therapy was again demonstrated in a large scale study of 3424 patients with localized prostate cancer at 16 different Asian hospitals with a 10-year biochemical control of 81.4% and cancer-specific survival of 97.2%. HDR combined with external beam radiotherapy was an effective and safe treatment for localized prostate cancer. Pelvic irradiation was suggested to have an adverse effect on OS and combination of long-term ADT was suggested to be necessary and useful in suppressing late toxicities.[7]

Intermediate-risk patients have only 1 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.

The biochemical control rate and clinical outcomes with real-time inverse planning (inverse optimization prostate seed implant [IO-PSI]) for intermediate-risk (IR) prostate adenocarcinoma are also really promising and as high as 97% at 4 years. Reduced number of sources, needles, and total activity seem to be very acceptable in this "favorable risk" category of prostate cancer patients undergoing inverse optimization.[8]  

A patterns-of-care study conducted by Frank et al found that a subset of intermediate-risk patients are treated with brachytherapy monotherapy.[9]  Specifically, monotherapy is used to treat T1c disease characterized by absent perineural invasion, positive results in fewer 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 Radiation Therapy Oncology Group (RTOG) trial, RTOG 0232, assessed the role of IMRT plus brachytherapy boost versus brachytherapy alone in the treatment of intermediate-risk prostate cancer in a prospective randomized setting. The initial report suggests that the addition of external beam therapy to brachytherapy did not result in superior freedom from progression compared to brachytherapy alone at 5 years. Longer follow up is needed to confirm the durability of the findings.[10]

Salvage brachytherapy

Recurrent disease and residual disease after therapy are fairly common in patients with prostate cancer, with rates ranging from 25% to 85%, depending on initial therapy and disease type. The National Cancer Institute’s Physician Data Query (ie, PDQ - NCI’s Comprehensive Cancer Database, formerly known as CancerNet) reports that approximately 10% of patients initially treated with radiation experience relapse. Local recurrence presents a difficult challenge because the therapeutic options are limited.

Over the past few years, salvage brachytherapy has been increasingly advocated as a therapeutic option in addition to salvage prostatectomy. A 2003 series by Koutrouvelis et al reported success with salvage brachytherapy after previous brachytherapy, but it should be kept in mind that this success was reported in a single study with 31 patients[11] ; therefore, such a treatment plan must be considered with caution. Some of the pertinent literature pertaining to these newer modalities is summarized in Table the below.

Table. Results of Salvage Brachytherapy Studies (Open Table in a new window)

At present, the data on salvage brachytherapy are sparse. Larger studies and longer follow-up are needed before a definitive conclusion on the efficacy of this modality is established.

 

Relative contraindications to brachytherapy include the following:

• Previous transurethral resection of the prostate (TURP)

• Pubic arch interference

• Obstructive symptoms

• Morbid obesity

Initially, previous TURP was associated with increased symptoms and urinary incontinence rates as high as 50%. Subsequent studies reported incontinence rates lower than 10%.

Pubic arch interference may occur because of a large (>40 g) prostate, and this interference may preclude adequate placement of seeds. Hormone ablation, exaggerated lithotomy positioning, horizontal probe positioning, and computed tomography (CT)-guided placement are all potential solutions.

Significant preoperative obstructive symptoms increase the likelihood of postoperative urinary retention. Although patients with glands larger than 40 g are more likely to have obstructive symptoms than patients with smaller glands, symptoms can occur in anyone.

Glands between 50 and 60 g should be downsized. Hormone ablation has been reported to downsize the prostate gland by 25-40% and is used to facilitate brachytherapy in patients with large glands. However, in a randomized study of patients with prostates of comparable size who underwent brachytherapy alone or brachytherapy after hormone ablation, acute urinary retention and dysuria were actually greater in the hormone ablation group.[14]

Clinicians often compromise and use a 5-alpha reductase inhibitor for downsizing instead of true androgen ablation. Nonetheless, brachytherapy is not advisable in patients with glands larger than 60 g.

In morbidly obese patients, the equipment often cannot sustain the patient’s weight or is not long enough to reach the prostate.

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 that brachytherapy is equal to surgery in terms of biochemical recurrence.

A 12-year study by Ragde et al, which reported on patients treated with I-125 seeds with or without additional EBRT, found that 66% of patients who underwent brachytherapy alone and 79% of those who underwent external radiation plus brachytherapy were free of biochemical or clinical recurrence.[15]

Similarly, Kuban et al found no evidence of disease in only 64% of patients treated with I-125 at 10-year follow-up but reported negative findings in all of these patients after posttreatment prostate biopsy.[16]  In patients with positive findings after prostate biopsies, only 19% remained actuarially disease-free at 10 years.

According to a trial presented at the European Society for Radiotherapy and Oncology (ESTRO), men with intermediate- or high-risk prostate cancer who are treated with brachytherapy in addition to EBRT are twice as likely to have progression-free survival at 9 years.[17]

Polascik et al compared brachytherapy with radical prostatectomy and demonstrated that at 7 years, the progression-free survival rate was 87% for surgery and 79% for brachytherapy in comparable patients.[18]  High-risk patients have been reported to have progression-free survival rates of 65-80%. In the evaluation of these control rates, careful attention must be given to variables such as the addition of EBRT or androgen ablation and length of follow-up.

To date, however, no prospectively performed randomized studies have compared the efficacy of surgery with that of either brachytherapy or high-dose EBRT 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 between clinical and pathologic staging.

A comprehensive literature review with statistical analysis from the Prostate Cancer Results Study Group[19]  suggested the following:

• For low-risk disease, brachytherapy provides superior outcome in terms of biochemical-free progression

• For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone

• For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone, or EBRT

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

Salvage brachytherapy

Salvage high-dose brachytherapy has been successfully used in patients with local macroscopic relapse in tumor bed after radical prostatectomy. This was achieved in conjunction with multiparametric MRI and TRUS fusion guided salvage.[20]

A retrospective analysis of clinical outcomes in patients treated with salvage low-dose rate brachytherapy for locally recurrent prostate cancer after radiotherapy found that overall survival at 5 years was 87%.[21] Reduced-dose brachytherapy was also used in treating recurrence after EBRT to the prostate, combined with androgen deprivation therapy. This approach was associated with favorable relapse-free survival as high as 79% in some series.[22]  These strategies will require larger cohorts and longer follow-up in order to draw strong conclusions.

The amount of radiation to be delivered to the prostate and the configuration of the implants must be determined before the implants are placed. 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 American Brachytherapy Society (ABS) has devised the following terminology to clarify the differences in brachytherapy planning techniques:

Preplanning – Creation of a plan days or weeks before the implant procedure

• Intraoperative planning – Treatment planning in the operating room (OR), without moving the patient or the ultrasound probe

• Intraoperative preplanning – Creation of a plan in the OR just before the procedure, with immediate execution of the plan

• Interactive planning – Stepwise refinement of a plan using computerized dose calculations derived from images of needle placement

• Dynamic dose calculation – Constant updating of dose distribution calculations using continuous deposited seed position feedback

Intraoperative treatment planning does not eliminate the need for postimplant dosimetric analysis.

Laboratory studies

Laboratory studies that should be ordered before brachytherapy include the following:

• Complete blood count

• Prothrombin time

• Activated partial thromboplastin time

• Metabolic panel

• Urine culture

Imaging studies

In order to perform accurate dosimetry and real-time visualization of percutaneous source placement, the prostate and the margins of adjacent organs (eg, the rectum and bladder) must be well visualized. Transrectal ultrasonography (TRUS) and computed tomography (CT) are the 2 major modalities currently in use.

TRUS has the advantages of providing real-time imaging and sharply delineating the contours 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 TRUS or CT, 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 less seed migration because of the presence of the pelvic floor muscles at this site, as opposed to the looser periprostatic tissue at the base. Traditionally, a portion of the seminal vesicles is included in the target.

Information on the target volume and margins is then transmitted to a computer program, and the computer helps perform the dosimetry, plan the number of seeds, and define the location of the seeds on a 2-dimensional grid (see the image below).

The optimal strategy for seed placement is somewhat controversial. Some experts advocate uniform distribution of seeds, whereas others emphasizing placement on the periphery of the prostate, where most cancers arise.

Endorectal coil MRI is helpful in assessing the severity of prostate cancer. By placing a coil in the rectum to obtain high-quality images of the prostate, an accurate assessment can be made of seminal vesicle and capsular invasion. The Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center recently published a study that used endorectal coil MRI to assess recurrence of prostate cancer after treatment with combination brachytherapy and external-beam radiotherapy. The study concluded that extracapsular extension, tumor size, and T stage were all associated with biochemical relapse; however, extracapsular extension was the only imaging finding that was an independent predictor of recurrence.[23]

Equipment

Currently, the 2 most common permanent radioactive sources for brachytherapy seeds are I-125 and Pd-103. Of the 2, Pd-103 has a higher radiobiologic effect, and thus, its total dosing can be lower. Clinical evidence to guide selection of the radionuclide is lacking. However, because in vitro data have raised some concerns about the efficacy of I-125 in poorly differentiated and rapidly growing tumors, Pd-103 is used more commonly in higher-grade prostate cancers.

A prospective randomized multicenter trial examining the long-term morbidity associated with the use of I-125 or Pd-103 in the treatment of low-risk prostate cancer found that patients who received I-125 were more likely to develop proctitis, whereas those who received Pd-103 were more likely to develop prostatitis.[24]

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 superior to the other in terms of IPSS resolution, catheter dependence, or need for postbrachytherapy surgical intervention.[25]

There is growing interest in the use of cesium (Cs)-131 for permanent prostate brachytherapy. Cs-131 is an attractive alternative to I-125 and Pd-103, in that its average energy is similar to that of I-125 and it has a half-life of only 9.7 days.

Epidural, spinal, or general anesthesia may be used for placement of implants. The patient is placed in a lithotomy position for brachytherapy (see the image below).

In addition, the following measures are taken preoperatively:

• Bowel preparation, both mechanical and antibiotic

• Prophylactic intravenous antibiotics at the time of the procedure

• Subcutaneous heparin if the patient has a history of deep venous thrombosis

• Stoppage of all anticoagulants, including aspirin, nonsteroidal anti-inflammatory drugs, and warfarin

After brachytherapy, prostate-specific antigen (PSA) levels should be measured and a digital rectal examination (DRE) should be performed every 3-6 months for 5 years and yearly thereafter. If the PSA or DRE findings are abnormal at follow-up, an appropriately increased follow-up frequency (for PSA abnormalities only) or biopsy (for DRE abnormalities) should be considered.

Evaluation of disease-free survival

The proper use of the PSA level to define disease freedom after radiotherapy for prostate cancer is still disputed. Historically, 2 main approaches have been used to define biochemical failure. The first approach is to use absolute values to define failure, much as PSA levels are currently employed after prostatectomy. Various cutoff points have been used, ranging from 4 to 0.2 ng/mL. The second approach is to use increasing values of PSA over time as a definition of failure.

The American Society for Therapeutic Radiology and Oncology (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 after brachytherapy; allowing for these spikes prevents an incorrect diagnosis of a recurrence.

Studies have shown that the ASTRO Consensus Panel definition of biochemical failure after radiation therapy correlates well with clinical distant metastases–free survival, disease-free survival, 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 the first rise in the PSA level. This ambiguity, coupled with the poor performance of this definition in patients treated with hormone ablation, has led to the development of a new definition. This new definition, the Phoenix definition, is characterized by a rise in the PSA level of 2 ng/mL above the nadir. It is used to define biochemical failure after EBRT, with or without hormone ablation.

Both the ASTRO definition and the Phoenix definition 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 and their corresponding 5-year disease-free survival rates:

• PSA level < 0.5 ng/mL - 79%

• PSA level 0.5-0.99 ng/mL - 66%

• PSA level 1-1.99 ng/mL - 49%

• PSA level >2 ng/mL- 25%

Assessment of 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. Studies have shown that over time, quality of life among patients who have undergone radical prostatectomy is comparable to that among patients who have undergone brachytherapy alone. Initial differences in the adverse-effect profile dissipate over time (2-4 y).

However, quality of life is significantly worse at all time points in patients treated with brachytherapy and intensity-modulated radiation therapy (IMRT) than in in those 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.

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 (see Periprocedural Care). A modified peripheral loading plan is preferred when the sources are placed.

The dose is quantified in terms of the unit of absorbed energy per weight of tissue. For example, the basic unit of radiation, the gray (Gy), is 1 J/kg of tissue.

In brachytherapy, the sharp radiation dose falloff allows a high degree of rectal sparing and permits delivery of a higher total dose to the prostate gland itself. Similar advantages can be obtained with conformal intensity-modulated radiation therapy (IMRT), but whereas brachytherapy has a much lower initial dose rate than IMRT, its aggregate radiation delivery is higher. The average dose rates are 10 Gy/wk for IMRT, 40 Gy/wk for Pd-103 brachytherapy implants, and 13 Gy/wk for I-125 brachytherapy.

A perineal template and either transrectal ultrasonography (TRUS) or computed tomography (CT) are used to guide placement of the needles into the prostate. Once the final needle position is established, the seeds are delivered.

The emergence and widespread use of multi-parametric MRI provides unparalleled assessment of the prostate and periprostatic anatomy, making it a very beneficial imaging modality to facilitate prostate BT treatment planning, imaging and implantation, and follow-up.[26]

Benefits of a new brachytherapy technique: 4D brachytherapy

Although the theory and principles of brachytherapy have been around for decades, there are still ways to improve efficiency and precision while decreasing the number of complications. In February 2012, an article was published on 4D brachytherapy, a novel real-time prostate brachytherapy technique using stranded and loose seeds, that explains an innovative approach to the brachytherapy technique.

4D brachytherapy is a one-stage prostate brachytherapy technique that uses stranded and loose seeds. The advantage of placing loose seeds in the center of the prostate gland and stranded seeds in the periphery of the prostate gland is decreased migration of seeds to other organs. This can potentially decrease bladder and rectal complications. In addition, the loose seeds placed centrally can increase the dosage of radiation to the prostate apex and thus improve its dosimetry (median D90 143 and 153Gy [P< .005] and median V100 88% and 93% [P< .005] for the Seattle technique and 4D brachytherapy implant technique, respectively).[27]

Efficiency in the operating room is another area of brachytherapy that needs improvement. 4D brachytherapy is a one-stage technique that can be performed in less than 45 minutes, compared with other one-stage techniques, which can take 2-3 hours. In previous one-stage techniques, the radiation oncologist and the dosimetry technician performed the TRUS and seed mapping while the patient is under anesthesia the same day of seed placement in the operating room. The 4D brachytherapy technique uses an initial outpatient TRUS to measure the height, width, length, and 2 parasagittal lengths of the prostate. These measurements are factored into a nomogram created from more than 1000 brachytherapy procedures in order to map out the seed implants beforehand. The stranded and loose seeds are then preloaded prior to the procedure, ultimately reducing operative and anesthesia time, in addition to less time for patients being in the dorsal lithotomy position.[27]

Prospectively collected data show significantly improved dosimetry compared with other brachytherapy techniques. The improved dosimetry reduces short-term urinary morbidity, which was assessed using the international prostate symptom score.[27] Improved urinary morbidity can be attributed to the placement of loose seeds in the apex of the prostate, allowing for more control of radiation delivery to the region. This minimizes the dose to surrounding structures at risk for unnecessary radiation, such as the membranous urethra and penile bulb. Decreased urethral stricture and erectile dysfunction have been seen with improved dosimetry.[28, 29]

Stepwise approach to 4D brachytherapy is as follows:

1. Outpatient TRUS: Height, width, length, and 2 parasagittal lengths of prostate measured

2. Seed order: Measurements of height, width, length, 2 parasagittal lengths plugged into Web-based nomogram, which can calculate proper seed order

3. Seed placement: Implant preloaded stranded seeds peripherally, followed by implanting loose seeds centrally

4. Dosimetric assessment: Each seed order comes with an extra 15 loose seeds in case of under-dosed region of prostate

Postimplant CT scanning is recommended within 24 hours of the procedure.

While the basic approach for brachytherapy has not really changed, multiple innovations, like the multi-source rotating shield brachytherapy that performs precise simultaneous angular and linear measurements and positioning, have been suggested for delivering less radiation to adjacent healthy tissues like the rectum or urethra. Other centers have tested using endorectal probe sensors for better imaging of seed implants.[30]      

TRUS guidance

A biplanar TRUS probe with a frequency of 5, 6, or 7.5 MHz is preferable. Attach the probe to the stepping unit, which moves the probe in a cephalad or caudal direction at 0.5-cm intervals. To differentiate the bladder from the prostate, use a urinary catheter to visualize the urethra, or instill diatrizoate into the bladder. Secure the scrotum out of the perineal field with tape or towel clips.

Match the probe image to the planning image. Adjust the needle-guide template against the perineum, leaving 1-3 cm of space between the skin and the template. When intraoperative planning is being used, recreation of the images is not necessary. The benefits of intraoperative planning are that optimal settings are determined in real time and that variations are minimized (which means that there is no need to reproduce an earlier plan). A drawback is that the operating time is longer; however, the patient needs to come in only once.

Insert the needles through holes in the template, and then through skin (see the image below). Watch for deflection, and reposition needles as necessary. 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.

Adjust the needle depth on the basis of the preplan zero plane. Use a longitudinal ultrasonographic view. To mark the location of the bladder neck, perform fluoroscopy using a Foley balloon catheter, or instill diatrizoate.

For source placement, afterloading or Mick applicator (Mick Radio-Nuclear Instruments, Mount Vernon, NY) techniques can be used. Remove the needle slowly to avoid source migration in the afterloading technique. Observe seed positioning under fluoroscopy.

CT guidance

Obtain a planning CT scan several days before the procedure, with a urinary catheter in place. The catheter and the diatrizoate serve to mark the bladder-prostate border. The prostate is scanned at 5-mm intervals with images that are 5 mm thick.

At the start of the procedure, place a urethral catheter that has wire through it and lead markers at 1-cm intervals. Mount the template stand against the perineum. Most brachytherapists do not use a rectal marker.

Initially, insert 2 needles simultaneously just posterior to the urethra on either side of the midline. Next, insert all anterior needles to limit prostate mobility. Anterior sources are placed first. Then, place posterior needles again, using the 1-cm markers on the urethral catheter for guidance.

For source placement with the Mick applicator, pull the needle back from the zero plane in 5-mm steps. 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. Obtain a final CT scan of the prostate, and perform postimplant dosimetry.

Suboptimal Implantation:

Suboptimal permanent seed brachytherapy implantation and a D90 of < 130 Gy can be predictive factors for biochemical failure. In these cases, other factors are taken into consideration before recommending further treatments. One study with a follow-up time of 8 years of suboptimal implanted seeds reported that patients with a PSA-D < 0.15 would be less likely to have biochemical failure. These results will have to be ultimately verified in large cohorts.[31]

 

Allow the patient to recover from anesthesia. Patients are discharged home the same day. Continue antibiotic prophylaxis, using oral antibiotics, for several days postoperatively. Initiate a voiding trial. If the patient cannot void, a catheter is reinserted, and another trial is performed in 5-7 days.

A final CT scan of the prostate and postimplant dosimetry are performed (only in TRUS-guided cases) 1-30 days after the procedure. If a “cold spot” is observed, reimplantation can be performed.

Many brachytherapists perform cystoscopy to look for sources in the bladder or the urethra. Additional plain radiographs should be obtained to verify the seed count (see the image below).

Until the ideal postoperative interval for CT scanning has been determined, each institution 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 (ie, the dose to 90% of the prostate gland). Additionally, the following should be reported and ultimately correlated with clinical outcome in the research environment:

• D80 (the dose to 80% of the prostate gland)

• D100 (the dose to 100% of the prostate gland)

• 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)

• Rectal and urethral doses

Urbanic et al reported that a review of 4 series confirms that freedom from recurrence depends on adequate dosimetry.[32]

Perineal, urinary, and rectal symptoms may complicate brachytherapy, as may sexual dysfunction.

Perineal symptoms

The perineum is tender and bruised and may have slight bleeding at needle puncture sites. Treatment predominantly consists of application of ice and administration of mild analgesics.

Urinary symptoms

Hematuria is expected for the first 1-2 weeks, and all patients experience dysuria. Irritative symptoms (eg, 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 of incontinence is 10-35% in the first few months. Few patients have any leakage at 1 year. 

Interesting data suggest that the incidence of lower urinary tract symptoms decline with increasing institutional experience with brachytherapy. In this study, more than 75% of the patients reported complete resolution of urinary symptoms by 24 months after brachytherapry.[33]

In most cases, perioperative edema resolves within the first 48 hours; virtually all resolve within the first week. A small subset of patients continues 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 confirm that the cause is truly obstruction rather than bladder dysfunction. If obstructive symptoms are present, patients are started on alpha-blockers and maintained on this therapy for 9 months. In patients with true obstruction, transurethral resection of the prostate (TURP) may be performed.

Rectal symptoms

As many as one third of patients who have undergone brachytherapy report urge, diarrhea, and painful bowel movements. These symptoms improve over the first year. Nonsteroidal anti-inflammatory drugs and mesalamine suppositories may help.

At 1 year, only 2% have persistent symptoms. Some studies report that 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. Data from the primary authors’ institution suggest that after brachytherapy, these fistulas result from biopsy of the anterior rectal wall by gastroenterologists. The wall probably appears irritated and ulcerated after brachytherapy, thus prompting the biopsy. Patients should be counseled to undergo colonoscopy before or 1 year after brachytherapy.

Sexual dysfunction

Generally, 33% of patients experience a decrease in sexual function and activity. Decreased seminal volume is observed. Studies report widely varying impotence rates, ranging from 2.5% to 25%. In some studies, 40% of the patients experienced some degree of erectile dysfunction after radiation therapy. Many studies comparing brachytherapy to EBRT or radical prostatectomy suggest better erectile functional outcomes with brachytherapy when taking into consideration the impact of age.[34]

The goals of pharmacotherapy are to prevent complications and reduce morbidity.

Class Summary

Prophylactic intravenous antibiotics may be given at the time of the procedure. Prophylactic therapy should cover all likely pathogens in the context of this clinical setting.

Ciprofloxacin (Cipro)

Ciprofloxacin is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Ciprofloxacin has no activity against anaerobes.

Cefazolin

Cefazolin is a first-generation semisynthetic cephalosporin, which, by binding to 1 or more penicillin-binding proteins, arrests bacterial cell wall synthesis and inhibits bacterial replication. It has a poor capacity to cross the blood-brain barrier. Cefazolin is primarily active against skin flora, including Staphylococcus aureus. Regimens for intravenous and intramuscular dosing are similar.

Class Summary

Administer subcutaneous heparin if the patient has a history of deep venous thrombosis. Anticoagulants prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation. In patients with heparin-induced thrombocytopenia, left ventricular assist device (LVAD) implantation has been performed successfully, albeit with additional risk, by using alternative anticoagulants.

Heparin

Heparin may be used if thrombocytopenia is not present. Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents recurrence of a clot after spontaneous fibrinolysis.