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.