“Brachy”(therapy), meaning “short” in Greek, describes treatment with radioactive sources or materials placed into, or at a short distance from, the tissue to be radiated. Brachytherapy stands in contrast to “tele”(therapy), Greek for “long,” which refers to external radiation delivered at a distance from the patient and the tumor. Although early attempts at delivering this form of spatially controlled radiation to the prostate date back to the early part of the century, significant clinical investigation of this treatment method did not get under way until the 1960s. At that time, Carlton and co-workers began using radioactive gold combined with external beam irradiation, and Whitmore and associates implanted radioactive iodine. Both procedures consisted of retropubic exposure, bilateral pelvic lymph node dissection, and free-hand insertion of the implant needles for placement of the seeds.
Initially, this innovative treatment for prostate cancer excited interest. A highly confined radiation dose was delivered to the prostate, sparing adjacent, uninvolved tissue. The complication rates, notably incontinence and impotence, were lower than those reported after surgery and external beam therapy of the time period. The free-hand placement technique, however, all too often resulted in poor radiation dose distributions and unsatisfactory local control rates6,7. Additionally, in an era of digital tumor detection, the local failure rates were further escalated by implanting bulky prostates at advanced stages of disease. The unfavorable local control rate, coupled with ongoing improvements in competing treatment modalities, soon led to dwindling interest in prostate brachytherapy.
Significant new developments occurred in the 1980s that served to remedy the shortcomings of the open implant method and rekindle interest in the procedure. These improvements included high-tech imaging and computer software that permitted precise measurement of prostate volume and shape and optimal dose determination. Further, transperineal insertion of the implant needles under real-time transrectal ultrasound monitoring allowed for accurate and reproducible seed placement and more uniform source distribution1. Using low-energy, short-range radioisotopes that favored protection of the adjacent uninvolved tissue permitted delivery of higher radiation doses than could safely be administered by external beam techniques and had the potential for improving local control.
Today, modern prostate brachytherapy can be performed on a cost-effective outpatient basis. It does not require a surgical incision, early results are encouraging, morbidity is minimal, and the patient can usually resume his normal activities in a day or two after treatment.
Dictated by isotope selection, transperineal prostate seed implantation can be divided into temporary and permanent implants. Temporary implants, always combined with external beam irradiation, utilize high-energy sources, such as iridium-192, that are left in the patient for a specific time period and removed. Permanent implants, on the other hand, are left in the patient to decay to an inert state over a specific time period. Although a few centers continue to use gold-198 for implantation, the majority of present-day permanent implants use iodine-125 and palladium-103, both low-energy, short-range sources. This chapter is limited to permanent implantation with these two radionuclides.
Information available to patients to help evaluate and select a treatment program for prostate cancer has significantly increased over the last several years. Prostate brachytherapy, therefore, incorporating up-to-date dosimetry and seed placement technology, should provide the urologist with a timely and practical treatment alternative for patients who either are medically unfit for surgery or do not wish to have it.
Essential to successful application of brachytherapy techniques are proper planning, technical expertise, and meticulous execution. As practiced today, it is a team effort requiring urologic surgical skills, radiotherapeutic planning expertise, and medical physics. The combined efforts and continuous participation of these specialties are important for the success of the procedure. The technique is a three-step process: preimplant planning, operative implant, and postimplant quality evaluation.
INDICATIONS FOR SURGERY
Indications for brachytherapy are any patient with localized adenocarcinoma of the prostate who otherwise has a life expectancy greater than 5 years.
ALTERNATIVE THERAPY
Alternatives to brachytherapy include observation, hormonal deprivation, external beam radiation (teletherapy), and radical prostatectomy.
SURGICAL TECHNIQUE
Preimplant Planning
The main purpose of implant planning is to assure a systematic approach to the individual patient. The custom-tailored plan permits delivery of a high dose of radiation to the prostate with maximal sparing of juxtaposed healthy tissue. The “preplan” has several components.
Patient Selection
With the effective radiation encompassing only a 5-mm margin beyond the prostate, patients selected for interstitial radiation with iodine-125 and palladium-103 as monotherapy should have a high probability of organ-confined disease. No generally accepted and applied criteria for the selection of organ-confined lesions exist. However, increasing data indicate that the combination of clinical stage, number and locations of positive biopsies, presenting PSA level, and biopsy Gleason pattern scores are helpful in singling out patients with the highest probability of having lesions confined to the prostate, i.e., having all the prostate cancer included in the effective radiation field. For patients suspected of having periprostatic extension of the disease, an implant alone is not adequate therapy. The addition of external beam irradiation to a dose of 45 Gy may be indicated in order to sterilize periprostatic tumor extension.
Comorbidity status as it relates to anesthetic risks must be evaluated, though restrictions for a 45-minute bloodless seed implantation need not be as stringent as for surgery.
Additionally, it is important to identify risk factors that may give rise to urinary and rectal complications after implantation. Significant urinary obstructive symptoms, for example, may lead to urinary retention because of swelling from the radiation. If the lateral lobes are the cause of obstruction, a 3-month course of total androgen ablation before implantation will usually rectify the condition. Median bar obstruction, in our experience, responds poorly to hormonal manipulation and is best corrected before the implant with a transurethral incision of the prostate (TUIP). A previous transurethral prostate resection (TURP), performed even years before, carries increased risk for stress incontinence. In such patients, differential loading of the sources away from the prostatic urethra may help prevent this complication.
Selecting large glands for implantation carries two types of risks. First, the bony pubic arch may overlay the anterolateral part of the prostate and prevent transperineal needle insertion. Second, large glands require more seeds. Consequently, there is an increase in total dose, which may adversely affect adjacent tissue, such as the rectum and bladder. For these reasons, current knowledge dictates caution in implanting glands over 50 cc. The majority of large glands may be reduced to acceptable volumes by total androgen ablation for 3 months before brachytherapy.
Prostate Volume Specification
An accurate prostate volume description with delineation of adjacent rectum, urethra, and bladder is fundamental to precise source positioning and conformal dosimetry. Although volume determination and treatment planning can be performed using computed tomography, most centers prefer to use transrectal ultrasound step-sectional planimetry. Advantages include its low cost, excellent cross-sectional anatomy, and high correlation with real-time monitoring during the actual implant. The circumference of 5-mm spaced transverse prostate images from apex to base of the gland, overlaid with a template configuration corresponding to the template needle puncture channels, are demarcated with a lightpen. Computer software calculates the volume.
Prostate–Pubic Arch Relationship
Pubic arch interference, where the pubic rami may prevent the transperineal insertion of implant needles, most commonly occurs in glands over 50 cc but may also be encountered with smaller glands. It is important to recognize this condition in the planning stage rather than in the operating room. A simple method of detecting pubic arch obstruction entails the superimposition of the ultrasound image of the pubic arch over the widest transverse image of the prostate. In the face of pubic arch obstruction, shrinkage of the gland through total androgen blockade for 2 to 3 months may be necessary to make an implant possible.
Seed-Loading Method Selection
Once the prostate volume and its spatial geometry have been determined, the seed-loading pattern is selected. The Quimby pattern is characterized by a uniform source distribution across the target volume. The Patterson–Parker motif uses a peripherally weighted source allocation, implanting 60% to 70% of the total activity into the periphery of the gland. The Quimby method results in a radiation distribution that is characterized by a high central dose at the midpoint of the prostate and by a larger number of lower-strength seeds. Implants by this method are technically easier because small seed movements are less apt to result in underdosage or overdosage.
The high central dose may have the further advantage of greater tumor destruction but must be applied with caution in patients who have had a prior transurethral resection and consequent damage to the urethral blood supply. In these patients, the peripherally weighted Patterson–Parker method, with its lower central dose and lower likelihood of urethral damage, may be preferable. However, peripheral loading represents a more difficult implant and demands greater precision in source placement for a homogeneous dose distribution. It has the further disadvantage of delivering lower central doses to the tumor and involves a higher risk of rectal injury because high-activity seeds are placed close to the rectum.
Target Volume Specification
The target volume differs from the prostate volume in that it encompasses a 2- to 5-mm margin beyond the prostate periphery on the 5-mm-spaced transverse images, with slightly more generous margins at the apex, base, and biopsy-positive tumor sites.
Isotope Selection (Iodine-125/Palladium-103)
The two sources are both low-energy emitters. Both are physically similar, enclosed in miniaturized biocompatible titanium cylinders. With their low tissue penetration ability, they pose little or no hazard to medical personnel. The isotopes differ primarily in their half-lives and, therefore, in the rate at which they deliver radiation. Iodine-125, with a half-life of 60 days, emits energy at 8 to 10 cGy per hour, whereas palladium-103, with a half-life of 17 days, delivers at a rate of 20 to 24 cGy per hour. With lower dose rates, recovery of sublethally damaged cells may, at least conceptually, lessen the ultimate tumoricidal effect of the radiation. Some investigators therefore prefer to use the higher-dose-rate palladium-103 when treating poorly differentiated tumors. Because of the increased biological effect of the higher dose rate of palladium-103, some reduction in the total target dose is necessary.
Conformal, Computer-Based Dosimetry
Most institutions performing brachytherapy use the matched peripheral dose (MPD) convention developed at the Memorial Sloan-Kettering Cancer Center to describe the dose of radiation delivered to the tumor over the entire period of decay for the radioisotope used. The aim here is to deliver a dose to the prostate margins approximating that achieved with external beam therapy, which has been determined to be 160 Gy for iodine and 115 Gy for palladium. When brachytherapy is combined with a preliminary course of 45 Gy of external beam supplement, the iodine dose is lowered to 120 Gy, and palladium to 90 Gy. The spatial seed configuration is determined by entering each of the serial target volume images into a dosimetry computer to determine source spacing and strength for optimum dose homogeneity and distribution that will deliver the prescribed MPD to the periphery of the prostate while limiting radiation to adjacent structures. Isodose curves are then calculated for each transverse ultrasound image to determine if the proposed dose adequately covers the entire gland. If not, the seed location, number of seeds, or seed strength is adjusted to assure optimal coverage.
The Implant Worksheet
The computer-derived isodose plan with digitized target volume contours and resultant seed configuration is tabulated onto a worksheet. This reference facilitates needle loading and guides the urologist and radiation oncologist during the operative implant.
Operative Implant
The implant, as described by Holm and associates in 1983, consists of implanting 18-gauge needles preloaded with seeds and spacers. The treatment plan designates specific template coordinates and prostate location. In order to ensure accurate placement of the needles within the prostate, needles are guided to their specific designations in the prostate by transrectal ultrasound.
The procedure is done under spinal anesthesia with the patient in the dorsal lithotomy position and the urethra injected with an ultrasound enhancement agent (emulsion of air and K-Y jelly) for visualization. The scrotum is displaced toward the abdominal wall with a plastic/adhesive drape, and the perineum is prepped. Brackets fastened to the operating table support a stepping unit to hold a biplanar, multifrequency endorectal transducer (Bruel & Kjaer model 8551, Marlborough, MA) that is attached to an ultrasound system (Bruel & Kjaer model 3535). A multichannel needle-steering device, which corresponds to the electronic grid matrix superimposed on the transverse ultrasound prostate images of the volume specification, is attached to the rectal probe.
The probe with the transducer is inserted into the rectum. While scanning through the gland with the template coordinate grid activated, the probe is adjusted until the sequential images on the TV monitor correlate with the planning scan images. At that time the support brackets are locked in position. The prostate is very mobile and may need to be stabilized before needle insertion. The implantation begins anteriorly and proceeds posteriorly to prevent target shadowing of seeds already placed. Each needle is guided to its preplanned position in the gland under direct transverse and/or sagittal ultrasound observation.
Real-time monitoring of the needle insertion process is of critical importance. Even though the prostate has been stabilized, needle insertion may distort and move the gland. Any deviation and internal distortion should be recognized and adjusted for. When a needle is correctly positioned, the obturator is held stationary by an assistant, and the needle is withdrawn. In this way, rows of alternating seeds and spacers are deposited into the preplanned positions in the gland.
The position of the base and prostatorectal interface are monitored throughout the procedure. The operator must regularly observe the transverse and sagittal images. The ultrasound transducer is adjusted in 5-mm increments in the caudal direction for those template coordinates that do not call for seeds at the most cephalad portion (base) of the gland. At the completion of the needle insertion, an AP fluoroscopy is performed to assess the uniformity of seed distribution. Extra seeds may be implanted wherever there appears to be a spatial deficiency. Also, fluoroscopy will portray stray seeds in the bladder, which may be removed cystoscopically and reinserted.
Postimplant Evaluation and Management
Evaluation of implant quality is performed on every patient using three-dimensional CT-based calculations. The evaluation consists of dose computation and dose analysis for target and surrounding structures based on the actual implant. Five-millimeter slice thicknesses are scanned using soft-tissue-density images for prostate volume and bone density windows for seed delineation. Isodose curves are generated for each CT image, yielding a detailed analysis of radiation distribution relative to the CT-determined target volume.
Patients are routinely examined at 3-month intervals for the first 2 years, every 6 months for the next 3 years, and yearly thereafter. All follow-up visits consist of clinical evaluation and serum PSA measurement. Four-quadrant TRUS-guided postimplant needle biopsies are recommended for all patients. Treatment results are determined based on clinical freedom from disease, freedom from biochemical (PSA) failure, and repeat biopsy results. There is now increasing evidence that, of these, the PSA assay is the most sensitive index of tumor biological activity. Unlike surgery, where the presence of PSA activity after removal of the prostate is a reliable indicator of treatment failure, irradiated prostate epithelial cells continue to secrete measurable amounts of the antigen, albeit in small quantities. What the exact level should be is as yet uncertain, but several investigators believe the posttreatment level should decrease and remain at 1.0 ng/ml or less to validate biological cure.
OUTCOMES
Complications
Early Complications
Adverse effects up to 12 months after the implant include obstructive and irritative symptoms. They occur to some extent in most patients, with the severity of symptoms often related to the degree to which such symptoms were experienced before treatment. The symptoms subside over a few weeks to a few months. Should obstructive symptoms persist, it is best to manage the patient by intermittent catheterization for at least three half-lives of the isotope—6 months for iodine and 2 months for palladium—before intervening surgically. A prostate incision at the 6-o’clock position (TUIP) is often all that is required. Transurethral resection is associated with an increased risk of incontinence in patients who received a uniform-distribution (Quimby) implant and is best avoided. Peripherally weighted (Patterson–Parker) implants minimize the urethral dose and do not appear, at least in a short-term follow-up study, to be associated with any increase in complications in patients with transurethral resections.
Late Complications
In one series, 320 patients were implanted by the uniform source distribution method (Quimby) and followed for 7 years. Two of the 320 (0.6%) required urinary diversion for severe urethral stricture and incontinence, and another 25 (8%) required minor office procedures such as cystoscopy, urethral dilation, and sigmoidoscopy. Erectile dysfunction did not present itself in patients below 60 years of age but occurred in 20% of patients between the ages of 60 and 70 years. Another series reported on 71 patients implanted with the peripherally weighted (Patterson–Parker) implant technique and followed for a mean of only 2 years. Investigators noted only mild radiation proctitis in 4.2% and urinary retention in 5.6%. During this time period, only 6% of the patients experienced erectile difficulties.
Results
Three hundred twenty T1/T2 patients were treated with iodine-125 or palladium-103 as monotherapy at Northwest Hospital between January 1987 and June 1993. Median presenting PSA was 6.7 ng/ml (range 0.2 to 74.6), and the Gleason pattern scores at diagnosis, available in 313 patients, were: 2 to 4 (130), 5 and 6 (161), and 7 to 10 (22). Median follow-up was 50 months (range 24 to 97 months). No patients were pathologically staged, and none was treated with hormones.
The 7-year actuarial local control rate was 97%, the distal disease-free control rate 95%, and the PSA progression-free status 83%. In patients with no clinical/pathologic evidence of prostate cancer, PSA progression is defined as two consecutive increases in serum PSA from a minimum inflection (nadir) regardless of absolute PSA levels. In this series of patients, PSA progression—however minimal—preceded all local and distal clinical failures.
Posttreatment biopsy was obtained in 192 of 320 (60%). Biopsy results and corresponding PSA levels are: negative, 83% (median PSA 0.3); indeterminate, 13% (median PSA 0.6); positive, 4% (median PSA 3.0). Biopsy specimens were interpreted as indeterminate based on the presence of residual neoplastic cells exhibiting severe radiation effect. The viability of such cells is uncertain; however, experience with this pathologic category suggests that the majority of these biopsies convert to negative with time.
A subset of 112 patients in this cohort has been followed for a minimum of 5 years. The PSA progression-free rate (non-Kaplan–Meier) is 105 of 112 (94%); the PSA £ 1.0 ng/ml rate is 101 of 112 (90%); and the PSA £ 0.5 ng/ml rate is 95 of 112 (85%). Eighteen patients agreed to repeat needle biopsy 5 years or more beyond treatment, three of whom were biopsied because of PSA progression. Negative biopsy was found in 16 of 18 (89%), one patient (5.5%) was graded indeterminate, and one patient (5.5%) failed locally with a positive biopsy.
These results are encouraging, but randomized trials to support the therapeutic advantages of prostate brachytherapy are lacking. Thus, the definitive curative potential of brachytherapy must await longer-term follow-up. Brachytherapy does, however, offer some distinct advantages over the common treatment modalities. It is a one-time, low-morbidity, and cost-effective outpatient procedure that is less socially disruptive than either surgery or external beam treatment.
The utilization of transrectal ultrasound and template guidance systems has greatly improved radioisotope implantation of the prostate. These improvements allow for high radiation doses to be safely delivered to the target tissue in an accurate and reproducible manner. The curative results with brachytherapy, at least at intermediate durations of follow-up, are comparable to those achieved with radical surgery and external beam irradiation. Current success and the prospects for further improvement argue that, at least for the immediate future, incorporating brachytherapy in the treatment armamentarium will allow the urologist to play a wider role in providing care for patients with localized prostate cancer.
Urology Surgery 