Prostate Brachytherapy

prostate bracytherapy
article written by article by Dr Michael Rampaul

Historically, the most common form of treating prostate cancer, is surgery to remove the cancerous prostate (radical prostatectomy). The advantage of the surgery is that it is a one time procedure with relatively good success rates for cure. The drawback, however, is that the surgery has a relatively long recovery time and has a high risk for urinary and erectile problems following the procedure which can greatly impact the patient’s quality of life.

In the last twenty years, prostate brachytherapy, one of the most promising treatment methods has emerged as a viable and attractive option to radical surgery in treating prostate confined cancer. In follow-up studies since the emergence of the procedure, it has been found that brachytherapy has similar success rates to that of surgery while having much lower complication rates for severe urinary problems and sexual side effects. The procedure is also done in one day and the patient can usually return to his normal activity within days of the procedure.

Prostate brachytherapy is available in Trinidad and Tobago for the first time, in the English speaking Caribbean.

Prostate brachytherapy involves the implantation of tiny radioactive pellets (called seeds) into the prostate. These seeds are smaller than a grain of rice and emit very low energy radioactive rays which are absorbed almost entirely by the prostate. This radiation is emitted for about one year during which time the energy from the seeds slowly diminishes from month to month until it is no longer detectable. The radiation “cloud” over the prostate effectively kills the cancer cells without causing long-term harm to the normal tissues surrounding the prostate.

The actual procedure is done under general anaesthetic in an operating room. No cutting is done since the seeds are implanted via needles into the prostate, under ultrasound guidance. In a typical procedure, the patient arrives at the hospital in the morning and after recovery from anaesthetic, leaves the hospital in the afternoon.

The doctors involved in brachytherapy, continue to highlight one of the main challenges of prostate cancer treatment continues to be the need for more annual screening among men over the age of 40.

This is the key to a successful treatment for prostate cancer and men stand a better chance of recovery and maintaining their Quality of Life.

History

1903	Alexander Graham Bell first proposed the insertion of radioactive sources into the prostate as a treatment for prostate cancer.
1915	Barringer at New York’s Hospital (now Sloane-Kettering Cancer Centre) inserted radium needles into the prostate.
1922	Denning reported mixed results in a study of 100 prostate cancer patients treated with treanurethral insertion of radium into the prostate.
1950s–1960s	Flock’s University injected a solution of radioactive liquid gold directly into the prostate. While some patients were apparently cured using these procedures, others suffered complications related to radiation.
1960s-1970s	Elevated interest in prostate brachytherapy after Willet Whitmore and Peter Scardino pioneered the use of sealed, radioactive sources containing gold-198 and iodine-125 using open retropubic surgical technique.
1980s	The development of transrectal ultrasound stimulated more interest in radioactive seed implantation as a primary treatment for early stage disease.
1983	Hans Holm reported on the transrectal ultrasound guided approach to prostate sees implantation.
1984	John Blasko of Seattle performed the first ultrasound-guided prostate inplant in the United States.

Open Implant Technique

Nevertheless, real interest in prostate brachytherapy did not occur until the 1970s when Whitmore described his open implant technique using the radioisotope I-125.8 The isotope was contained in miniature, sealed titanium cylinders tailored to fit into and be administered by needles. The technique involved open surgery to achieve retropubic exposure of the prostate and to allow pelvic lymph node dissection. The prescribed dose of radiation was based on a nomogram derived from external beam and early brachytherapy planning concepts. The implant needles holding the I-125 seeds were inserted "free-hand" into the prostate without any imaging device for guidance while the index finger of one of the operator's hands was in the rectum to help verify the needle depth.

The open implant procedure had great appeal. Conceptually, a highly confined dose of radiation was delivered to the prostate gland, sparing the juxtaposed bladder and rectum from undue radiation damage. But, free-hand needle and seed placements all too often resulted in inconsistent dose distributions not recognized or appreciated until post-operative imaging was performed. Consequently, some areas of the gland received more radiation than planned ("too hot") while other areas received less radiation than intended ("too cold"). The "too hot" segments often led to serious complications, while the often sublethal radiation delivered to the "too cold" areas resulted in a high rate of local failure. Moreover, some investigators incorrectly advocated brachytherapy for patients with bulky, advanced lesions that were incurable with any therapy, which confounded already variable results.

In the late 1960s, Bagshaw and others began publishing results of treatment of prostate cancer with newly emerging, megavoltage external beam radiation technology. Their data demonstrated that external radiation therapy could cure prostate cancer by the delivery of high doses of radiation to the prostate gland. This form of radiation and Young's newly developed technique of removing the prostate surgically soon became the preferred treatments for prostate cancer; interest in prostate brachytherapy gradually declined.

This was where things stood until 1983, when Holm, a urologist from Copenhagen, Denmark, published his technique of implanting the prostate gland with radioactive seeds transperineally. The seed-bearing needles were guided into precise positions in the prostate gland by transrectal ultrasonography. His novel and elegant technique has been shown to be generally reproducible and yielded clinically meaningful results. Holm went on to train Ragde (senior author of this article) in prostate brachytherapy.

In 1985, Radge performed the first prostate seed implantation in the US at Northwest Hospital in Seattle. Two years later, he performed the first Pd-103 implantation for prostate cancer and established a national brachytherapy implant course. His unswerving commitment to development of this modality, namely radioactive seed implantation for treatment of prostate cancer, as well as dedication to the training of other physicians in the technique, soon led to a resurgence of interest in prostate brachytherapy.

Prostate Brachytherapy Process

The first step of prostate brachytherapy is a transrectal ultrasound prostate volume study, which takes 15-30 minutes and determines the prostate's total volume, contour, and length. The evaluation can be done as a hospital outpatient procedure. The transrectal ultrasound verifies that the prostate volume is appropriate, and that the prostate "map" the procedure produces is used to determine the number, activity, and precise coordinates of each seed's placement in three dimensions.

The medical physicist uses the volume study images to specify a "target volume," the area to be covered by radiation from implanted seeds. To protect against the possibility of cancer cells outside the prostate, the target volume is greater than the actual prostate volume, especially at the base and apex (Figure 4). Next, the seeds are ordered from the seed distributor, arriving in time for the carded implant.

Figure 4. A Transrectal Ultrasound Prostate Volume Study. The prostate "map" is used to determine the number, activity, and precise coordinates of each seed's placement.

The procedure is performed with a urologist, medical physicist and ultrasonographer, working together as a team. General anesthesia is used for most procedures, but occasionally a patient needs a spinal anesthetic. With the patient in an extended lithotomy position, the stabilization apparatus, stepper, template grid, and ultrasound probe are arranged in the same position they were in at the time of the ultrasound volume study.

Once the patient and all the implant apparatus are positioned, the needles containing the radioactive seeds are inserted through the template grid and perineal skin into the prostate and visualized on the ultrasound monitor (Figure 5). Once the needles are in the proper position, each needle is slowly withdrawn over its stationary "stylet", so that a row of radioactive seeds and absorbable vycryl spacers are left behind in a relatively straight line as per the pretreatment dosimetric plan.

This process continues, needle after needle, until all the seeds are placed. Fluoroscopy is then used to evaluate the quality of the implant (Figure 7). If any gaps in the seed distribution ("cold spots") are identified, extra seeds can be implanted to fill the gap. The seeds remain in the prostate permanently, but slowly lose their radioactivity over the next few months until they become inert (the half-lives of I-125 and Pd-103 are 60 days and 17 days, respectively.

Figure 5. Seed Insertion. Needles containing the radioactive seeds are inserted through the template grid and perineal skin into the prostate and visualized on the ultrasound monitor. Figure 7. Fluoroscopy to Evaluate Implant Quality

The procedure takes approximately 90 minutes to perform and the patient is discharged to home in a few hours. He is able to perform most normal activities almost immediately and usually returns to work a few days later.

Side Effects

Mild prostate edema develops after the implant procedure is performed. This edema, combined with irritation of the urethra, bladder neck, and prostate by the slow release of radioactivity, results in temporary lower urinary tract symptoms. Virtually all patients experience some degree of urinary frequency and urgency for two to six months following an implant. Most patients respond well to alpha-blocker medications, such as Flomax® and nonsteriodal anti-inflammatories (NSAIDS). Rectal side effects are uncommon. If they occur at all, they tend to be transient and mild.

The risk of long-term complications, such as urinary incontinence and impotence, is low after prostate bachytherapy. If the patient has not previously undergone a TURP, most series report a less than 1 percent incidence of incontinence, including stress incontinence. The incidence of impotence is age related. The Seattle data, based on a self-administered patient questionnaire, reveal a 10 percent risk of impotence in men in their 50s, a 15 percent risk for men in their 60s, and a 25 percent risk for men up to 70 years old.

Davis and colleagues compared the late toxicity of radical prostatectomy, prostate brachytherapy, and 3-D conformal radiation. Using five different patient-reported, self-administrated, validated quality-of-life questionnaires, they noted that patients treated with prostate brachytherapy suffered significantly less urinary and sexual dysfunction and less sexual bother than surgical patients. ( Sexual bother is a measurement of how much a man's sexual impairment "bothers" him, as opposed to sexual function, which measures how well he can physically function sexually.) The prostate brachtherapy patients also suffered less rectal dysfunction and bother and had a lower fear of cancer recurrence than the EBRT patients.

Quantative Implant Analysis

Postoperative CT scan-based dosimetry is performed on day 0 or day 30. To compensate for postoperative edema and its gradual resolution, each center should perform the dosimetry on a consistent postoperative day of its choice. Dose volume histogram (DVH) analysis determines how much of the prostate volume has received 100, 150, and 200 percent of the prescription dose (V100, V150, and V200, respectively). It also measures the dose delivered to 90 percent of the prostate (D90) and produces isodose curves for more detailed anatomical dose-distribution analysis.

Postoperative DVH analyses correlate well with biochemical relapse-free survival rates and the rates of rectal and urinary toxicities and erectile dysfunction] This ability to quantitatively evaluate the quality of the treatment is a unique feature of brachytherapy. If an underdosed region is found in a clinically significant area of the prostate, additional seeds can be placed or the patient can be treated with supplemental EBRT or high-dose brachytherapy before biochemical or clinical failure takes place.

Quantitative DVH analysis also allows physicians to compare the quality of their treatment with that of other physicians in an unbiased manner.

High Does Rate Brachytherapy

Another form of brachytherapy that has been used to treat prostate cancer is high-dose rate (HDR) brachytherapy. A limited number of centers in the US use this technique, which employs high activity Iridium-192, usually in combination with a course of external beam radiation. A robot assists in moving the radioactive sources through plastic catheters inserted in the prostate. As the radioactive source is removed from the patient at the end of each HDR treatment, the procedure is termed temporary brachytherapy. It is not possible to deliver an adequate radiation dose in a single session, and several administrations are required.

The technique is associated with several problems, such as difficulty achieving optimal catheter stabilization and faultless movement of the sources through the prostate. Because of these concerns, combined with the lack of long-term outcome results with HDR brachytherapy treatment in prostate cancer, do not to employ temporary implants at this time.

High Does Rate Brachytherapy

Our patients are generally evaluated every three months for the first year, and annually thereafter. The follow-up includes clinical evaluation and serum PSA measurement. The necessity for additional studies is dictated by patients' symptoms and signs.

Many patients experience a ‘bounce’ in PSA after prostate brachytherapy which may cause concern to them. However, The Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA, conducted a multivariate analysis of factors thought to predict for PSA bounce. They performed 295 consecutive patients with T1-T2 prostate cancer treated by prostate brachytherapy as the sole radiotherapeutic modality and a minimum follow-up of 2 years. The variables examined included age, initial PSA level, biopsy Gleason score, use of androgen deprivation, occurrence of PSA bounce, dose received by 90% of the prostate gland, and volume of gland receiving 100% of the prescribed dose. A PSA bounce was defined as a rise of at least 0.2 ng/mL greater than a previous PSA level with a subsequent decline equal to, or less than, the initial nadir. A second analysis investigating the same factors and adding PSA bounce as a predictor of biochemical relapse-free survival (bRFS) was also performed. RESULTS: The median follow-up was 38 months. A PSA bounce was noted in 82 (28%) of 295 patients. On multivariate analysis, only younger age (younger than 65 years) significantly predicted for a PSA bounce. Patients who experienced a PSA bounce were less likely to have biochemical failure (P = 0.037). Overall, the bRFS rate at 5 years in those experiencing a PSA bounce was 100% versus 92% in those with no bounce.

Immediate salvage therapy in patients with a rising PSA level should not be initiated provided the PSA increase does not exceed the pretreatment PSA value. A PSA bounce may be associated with improved biochemical relapse-free survival but not associated with any of the pretreatment clinical and dosimetric factors examined.

Results

Due to the long natural history of prostate cancer and the delay between diagnosis, the appearance of bony metastasis, and death, the effectiveness of prostate cancer therapy is usually measured by biochemical relapse-free survival. The pretreatment PSA level, the Gleason score of the biopsy sample, and the initial clinical stage by digital rectal exam (DRE) are all independent prognostic factors. In the PSA era, the vast majority of patients are diagnosed with stage II disease, so centers have recently been subdividing these patients into low, intermediate, and high-risk groups based on these prognostic factors.

The Memorial Sloan-Kettering Cancer Center and the Seattle Prostate Institute (SPI) define low-risk patients as those presenting with PSA values less than or equal to 10 ng/ml, Gleason scores between 2 and 6 and T1-T2b disease. These are good prognostic factors. Intermediate-risk patients have at least one poor prognostic factor (a PSA greater than 10 ng/ml, Gleason scores of 7 to 10, and/or a minimum of T2c disease), and high-risk patients have two or three of these poor factors. Several centers have achieved excellent five-year biochemical relapse-free survival results with implant monotherapy (seeds alone) in low-risk patients (Table 1), and some have also reported that intermediate-risk patients had excellent five-year biochemical relapse-free survival results after the same treatment or a combination of TIPPB and EBRT.

Surgical results based on risk-group analysis have been reported from the Hospital of the University of Pennsylvania (HUP), Brigham and Women's Hospital (B&W), and the Cleveland Clinic (CC) by D'Amico and Kupelian. Five-year biochemical relapse-free survival with 3-D conformal EBRT using doses greater than or equal to 75 Gy have recently been reported by Zelefsky. The five-year biochemical relapse-free survival of TIPPB appears to compare favorably with radical prostatectomy and 3-D conformal EBRT reports.

The Seattle Prostate Institute has published nine- and 10-year results with 103-Pd and 125-I prostate brachytherapy as monotherapy, respectively. The long-term biochemical relapse-free survival results from Seattle (with and without EBRT) were recently reported at the 2001 Annual Dutch Urological Association conference and the 2001 American Society for Therapeutic Radiology and Oncology conference. These 10-year results compare favorably to the five-year results from the surgical studies.

It should be noted that EBRT, surgery, and prostate brachytherapy are all local therapies aimed at controlling local disease. The high doses of radiation delivered by prostate brachytherapy result in extremely high local control rates. In Grimm's 10-year 125-I study, a 97 percent local control rate (as determined by DRE and post-implant biopsies) was achieved. These patients were all treated between 1988 and 1990, when the quality of those implants was not as high as the quality that can be realized with current prostate brachytherapy techniques. In the last five years, less than 1 percent of patients treated by the Seattle Prostate Institute's physicians have suffered local failure. Clearly prostate brachytherapy, when performed properly, results in extremely high control of local disease.

Tx	Series (Yr)	N	PSA Failure Definition	FU	bNED*
Seeds	Blasko[34]	276	> 1.0 absolute	5 yr	88%
	Stock[35]	34	> 1.0 & 2 rises	5 yr	89%
	Beyer[36]	320	> 1.0 absolute	5 yr	79%
	Wallner[37]	50	> 1.0 & rising	5 yr	83%
Seeds + EBRT	Blasko[34]	73	> 1.0 absolute	5 yr	84%
	Dattoli[38]	41	> 1.0 & rising	5 yr	85%
	Critz[32]	210	2-3 rises > nadir	5 yr	82%

*No evidence of disease (through biochemical tests)

Table 2. 5-Year Biochemical PSA NED* by Risk Group

Risk Group	RP D'Amico[5] (HUP) (B&W)		RP Kupelian[6] (Cleveland)	3D-CRT Zelefsky[33] (5-Yr FU)	Seeds Blasko[13] (Seattle)	Seeds ± EBRT Sylvester[39] (10 Yr)
Low	85%	83%	81%	90%	94%	87%
Intermediate	65%	50%	40%	70%	82%	79%
High	32%	28%	-	47%	65%	51%

Studies at the Northwest Hospita: 229 patients with stage T1/T3, low-to-high Gleason grade prostate cancer underwent prostate implants with I-125 or Pd-103 between January 1, 1987 and September 1, 1989. Patients, whose median age was 70 years (range, 53 to 92 years), were divided into two groups based exclusively on clinical stage and Gleason grade. Pretreatment PSA measurement was obtained in all patients but did not impact upon the treatment group assignment. 7 lower stage/grade patients treated with an implant alone (monotherapy); and Group 2 comprised 82 patients deemed to have higher risk of extra-prostatic extension of the malignancy. Group 2 patients, in addition to receiving a seed implant, were also treated with 45 Gy external beam radiation to the pelvis (combination therapy). None of the patients underwent operative staging, and none received concurrent androgen manipulation. Fourteen patients were lost to follow-up: Seven by death from non-cancer causes within 18 months post-implant, and seven because of incomplete PSA follow-up, leaving 215 patients for complete evaluation. The median duration of post-treatment follow-up was 110 months. The observed disease-free survivals of the two groups combined at 12 years was 70%; 66% in the monotherapy group and 79% in the combination therapy group. Trinidad and Tobago Prostate Brachytherapy

Conclusion

Brachytherapy is considered to have several advantages over radical prostate surgery. These include: It is a simple, cost-effective outpatient procedure that can typically be performed in less than two hours.
It is a minimally invasive procedure requiring no incisions or sutures.
Prostate brachytherapyis safer for men who may be considered at increased risk for general anesthesia.
Bleeding is generally unworthy of notice.
Recovery is rapid, allowing most men to return to work or resume usual activities within a day or two. In contrast, men who undergo radical prostatectomy require weeks of recovery.
Lifestyle changes, frequently required after a radical prostatectomy, are uncommon after a seed implant.
When compared with external beam radiation therapy, the spatially controlled radiation deposited by modern brachytherapy is considered to have the following advantages: Using real-time ultrasound imaging, radiation sources can be placed safely and accurately, ensuring that the therapeutic dose delivery is confined to the prostate gland.
The low-energy radioactive sources, such as Iodine-125 (I-125), have limited tissue penetration. This allows for a sharp drop-off of the radiation dose at the edge of the gland, limiting radiation delivery to normal tissues and minimizing potential treatment-related complications.
Prostate gland movement that can significantly affect the accuracy of external beam therapy and compromise both prostate and normal-tissue doses is generally not a factor during implantation with real-time ultrasound imaging.
Radiation exposure to physicians, nursing personnel, and family members is negligible.
A single outpatient treatment for placement of an implant as monotherapy is convenient, taking little of the patient's time compared with a protracted seven-week course of external beam radiation.
The precision and conformation of the brachytherapy dose to the gland allows for administration of a radiation dose roughly 50% to 100% greater than that which can be safely delivered by conventional or conformal external beam therapy. This is especially important, as increasing evidence shows that local tumor control improves with the amount of radiation delivered.

Taken together, the advantages of brachytherapy compared with other treatments for prostate cancer are substantial.
Prostate Brachytherapy (radioactive seed implantation) continues to grow rapidly as a treatment approach for patients diagnosed with prostate cancer in the modern PSA era. Five-year data from multiple centers and long-term data (10-plus years) from the Seattle Prostate Institute show that prostate brachytherapy can achieve local control and biochemical relapse-free survival results that are at least equal to the best that surgery and EBRT can offer, with less risk of long-term urinary incontinence, rectal toxicity, and impotence.