Modern Brachytherapy for Localized Prostate Cancers: The Northwest Hospital (Seatle) Experience

Clinical Investigation

CLINICAL INVESTIGATION Modern Brachytherapy for Localized Prostate Cancers: The Northwest Hospital (Seattle) Experience Leroy J. Korb, MD, Michael K. Brawer, MD Northwest Prostate Institute, Seattle Modern ultrasound-guided prostate brachytherapy is rapidly changing the way localized prostate cancer is managed. With routine use of prostate-specific antigen screening, prostate cancer is being diagnosed in younger men, who are understandably concerned about the morbidity of radical treatments that may significantly decrease their quality of life. Numerous studies of prostate brachytherapy have shown the excellent disease control rates achieved while maintaining low levels of urinary and erectile difficulties. This report examines a modern implant method of brachytherapy; describes patient selection for brachytherapy, alone and in combination with external beam therapy; and presents results from a series of men followed for 12 years. [Rev Urol. 2001; 3(1):51-60] Key words: Brachytherapy • External beam radiation therapy • Prostate cancer • Prostatectomy, radical S ince its introduction in this country in 1985 at my institution, ultrasoundguided prostate brachytherapy, also known as prostate implants or prostate seeding, has become a major treatment option for patients with clinically localized prostate cancer (see “Historical Perspectives,” page 58). A Medicare utilization review done in 1999 demonstrated that prostate brachytherapy may be replacing radical prostatectomy as the treatment of choice for localized prostate cancer.1 This procedure, in which tiny radioactive sources are precisely implanted through the perineum into the prostate, has several advantages over conventional external beam therapy (EBT). The radiation sources, such as iodine 125 and palladium 103, are low-energy and exhibit rapid dose drop-off at the edge of the gland; hence, with accurate placement, the high dose of radiation is confined, essentially, to the prostate gland, dramatically limiting treatment-related complications by minimizing radiation to the bladder and rectum. Prostate motion, which significantly affects target volume and, therefore, the prescribed dose for conventional EBT, presents no problem for prostate implants because of real-time ultrasound guidance. During brachytherapy, radiation exposure to surgeons and to other operating room and floor personnel is negligible. Finally, the single-session outpatient implant procedure demands little of a patient’s time. Taken together, the advantages of brachytherapy over EBT are substantial. In addition, the precise conformal dose delivery with brachytherapy allows administration of a radiation dose roughly 50% to 60% higher than the dose that can WINTER 2001 REVIEWS IN UROLOGY 51 Brachytherapy continued Main Points • In a study of 229 patients with clinically localized prostate cancer, at 12 years’ follow-up, there was a 66% disease-free survival rate among patients receiving brachytherapy alone and a 79% disease-free survival rate among those receiving brachytherapy and external beam irradiation. • Patients at higher risk for extraprostatic extension of malignancy may receive additional external beam irradiation. • Transurethral ultrasonography helps determine prostate volume and guides placement of radioisotopes. • Precise placement of low-energy radioisotopes, aided by computer-generated “mapping,” confines radiation to the targeted prostate area. • Brachytherapy is a brief, convenient outpatient procedure; patients usually resume normal activities in 1 to 2 days. • Side effects of brachytherapy are considered significantly less than those of radical prostatectomy. be delivered safely by conventional EBT and still much more achievable than with 3-dimensional or intensitymodulated radiotherapy. This is important, because evidence is mounting that local disease control improves with increasing doses of radiation delivered.2 The comparison between brachytherapy and radical surgery also shows similar advantages for brachytherapy. Since spinal anesthesia is preferred for brachytherapy, patients with medical comorbidities that make general anesthesia unsuitable do well during the brachytherapy procedure. Brachytherapy is minimally invasive, involves no incisions or sutures, and produces essentially no blood loss. Recovery is rapid after brachytherapy, allowing patients to return to normal activities often within 1 to 2 days of the seeding. Importantly, the majority of men with good erectile function before the seeding will continue to have good function after the procedure. Modern-Day Prostate Brachytherapy Today, prostate brachytherapy is considered by many practitioners to be the most conformal form of radiotherapy. It is a minimally invasive, well- 52 REVIEWS IN UROLOGY WINTER 2001 tolerated outpatient procedure that has high patient acceptance. The reasons for acceptance are obvious: with similar probabilities of cure, spending 3 hours in an outpatient surgical center for seed implantation and returning to one’s usual daily activities in 1 to 2 days are much easier than spending several days in the hospital following radical surgery and spending 4 to 8 weeks in convalescence. Similarly, brachytherapy compares favorably with the rigors of traveling to receive EBT daily for 7 to 8 weeks. Most implants today are “permanent”; the seeds containing the isotopes (iodine 125 or palladium 103) remain in the body once implanted. Relatively few centers in the country practice “temporary” brachytherapy implants, typically using the isotope iridium 192. In temporary treatments, the patient is connected to a robotic device via catheters implanted in the prostate, each of which serves as access for the radiation source into the prostate via connecting tubes. Because the radiation source leaves the patient at the end of each treatment session, it is termed “temporary” brachytherapy. Since it is not possible to deliver enough radiation with this technique in a single setting, several applications are required. It is often necessary to combine high-dose–rate (HDR) brachytherapy with additional EBT.3 Problems inherent with the HDR technique include difficulty in verifying tumor volume for each treatment and in stabilizing the catheters within the patient during treatment, plus increased patient discomfort and inconvenience. Because of these and other concerns, including a lack of longterm data regarding HDR brachytherapy in prostate cancer, we—at the Northwest Prostate Institute in Seattle—have elected not to use temporary implants. The physical characteristics of the common prostate brachytherapy isotopes used in both temporary and permanent prostate brachytherapy are shown in Table 1; however, the remainder of this article will focus on permanent implants. Table 1 Physical Characteristics of Common Prostate Brachytherapy Isotopes Size (mm) Half-life (d) Energy (KeV) Half-value layer (cm) I-125 0.8  4.5 60 28 2, tissue Pd-103 0.8  4.5 17 21 1.6, tissue Ir-192 N/A 74 380 2.5, lead KeV, kiloelectron volt; I-125, iodine 125; Pd-103, palladium 103; Ir-192, iridium 192; N/A, not available. Brachytherapy The Permanent Implant Process In its most basic form, brachytherapy involves a 4-step process: pretreatment patient evaluation; prostate volume determination with ultrasound, followed by implantation planning; seed insertion; and postprocedural evaluation of implant quality. The preliminary workup and planning for prostate brachytherapy is done in a physician’s office. Only the actual implant requires a limited ambulatorysurgical facility. Patient Evaluation. In patients with a diagnosis of clinically localized prostate cancer, by definition all cancer is restricted to the prostate and, hence, is treatable by local means (either surgery or irradiation). Consequently, as for radical surgery patients, the patients selected for seedimplant monotherapy must have strong clinical, radiographic, and laboratory evidence of organ-contained disease as well as a correspondingly low risk of microscopic extracapsular metastases. In the era before prostate-specific antigen (PSA) and transrectal ultrasonography (TRUS), pretreatment prognostic assessments of patients were unreliable, consisting of digital rectal examinations, bone scans, and serum acid phosphatase level determinations. Today, predictive pretreatment nomograms, using reliable measurements of PSA, Gleason sum, and clinical stage as prognostic variables, have provided a better method for quantifying risks for extraprostatic extension of the malignancy. Recent advances in staging both local and metastatic disease include MRI with an endorectal coil and Prostascint scans, which use isotope-tagged monoclonal antibodies to prostate cells. For patients who are determined to be at risk for pelvic micrometastases, combination therapy (EBT and seed implantation) has been shown to improve long-term biochemical diseasefree survival.4,5 At the Northwest Prostate Institute at Northwest Hospital, the policy is to recommend seeds alone as monotherapy for patients with a biopsy Gleason sum of less than 7, a pretreatment PSA level of less than 10 ng/mL, and a clinical stage of less than T2b. Combination therapy is recommended to patients with a Gleason sum of 7 or higher, a pretreatment PSA level of 10 ng/mL or higher, a clinical stage of T2b or greater, or a combination of factors that would increase the risk for extracapsular disease. Other factors, such as patient age, the number of positive biopsy cores, the amount of tumor in each core, and the presence or absence of perineural invasion, play a smaller role in treatment recommendations. For patients with several high-risk factors, neoadjuvant/adjuvant androgen ablation therapy may be added, and the pelvic radiation field may be increased in size to include additional lymph node areas. At our facility, before seed implantation, we also employ an Advanced Intelligent Predictive System (AIPS) or a neural network computer program (developed in collaboration with Xaim Corporation) to determine the likelihood of success or failure of brachytherapy and whether the addition of adjuvant EBT would af- fect disease-free survival. The input variables employed by the AIPS are clinical TNM (tumor, node, metastasis) stage, age, serum PSA level, and Gleason sum. Prostates above a certain volume (typically, about 60 cc), particularly in patients whose pubic arch may overlay the gland, may need to be reduced before seed implantation. A 3-month course of androgen deprivation therapy usually effects this. Another reason for reduction is the increased risk of temporary urinary retention following implantation of larger glands. Even though we have successfully implanted glands as large as 100 cc without problems, many men with large glands will have high American Urological Association (AUA) symptom scores, indicating a higher likelihood of postoperative urinary retention. General guidelines for selecting combination or monotherapy are described in Table 2. Isotope Selection. Permanent brachytherapy implants, either as monotherapy or in combination with EBT, employ the low-energy sources iodine 125 and palladium 103, which are left in the prostate to decay to an inert state over time. The main difference between the 2 isotopes is the initial rate of radiation delivery required at Table 2 Primary Selection Criteria for Seeds Alone Versus Seeds Plus External Beam Therapy Monotherapy Nodule Gleason sum PSA Biopsy Other criteria that may affect decision Combination therapy None or small 2-6 < 10 ng/mL Unilateral disease Large or multiple 7 - 10 ≥ 10 ng/mL Bilateral or locally extensive disease Perineural invasion, age of patient, comorbidities, number or percent of positive biopsy results, likelihood of understaging or undergrading PSA, prostate-specific antigen. WINTER 2001 REVIEWS IN UROLOGY 53 Brachytherapy continued the time of implantation. Iodine, with a half-life of 60 days, emits radiation at 8 to 10 centigrays (cGy) per hour; palladium, with a half-life of 17 days, produces 20 to 24 cGy per hour. Although there is no clinical evidence from human trials to document tumoricidal differences between the isotopes based on histology, some investigators prefer palladium 103 for patients with higher Gleason sum tumors.6 Table 3 shows the current doses of irradiation used for the different treatment groups. These doses change from time to time because of various external factors, and the reader is cautioned to verify the latest dose information. Ultrasound Volume Determination and Dosimetry. The computer-generated dose calculations are preceded by a volume study using TRUS, generating cross-sectional images of the prostate at 5-mm intervals. Each image is further inscribed with a 5-mm peripheral margin of nonprostate tissue. The aggregate area represents the target volume, the perimeter of which will receive the prescribed minimum peripheral dose. Each of the crosssectional images is then entered into a treatment-planning computer pro- Table 3 Brachytherapy Doses Used for I-125 and PD-103 With and Without External Beam Therapy Protocol I-125 monotherapy Seed dose (Gy) 144 I-125 + 45 Gy external beam radiation 108 Pd-103 monotherapy 125 Pd-103 + 45 Gy external beam radiation 100 I-125, iodine 125; PD-103, palladium 103; Gy, grays. 54 REVIEWS IN UROLOGY WINTER 2001 Figure 1. Transverse ultrasonographic image of the prostate acquired by the treatment planning system. Seed placement and resultant isodose curves are shown. Figure 2. Three-dimensional reconstruction of the prostate along with seed placement and resultant radiation dose cloud around the gland. Apex of the gland is to the lower left. gram, which creates a 3-dimensional model of the gland. The software allows interactive virtual placement of seeds within the prostate, instantly superimposing the resultant planar isodose curves over the images of the prostate’s cross sections (Figure 1). Seeds are placed according to our institutional protocols, ensuring adequate coverage of the target volume while limiting the radiaion dose to critical structures, such as bladder, rectum, and intraprostatic urethra. To supply additional information, 3-dimensional views of radiation doses around the prostate (Figure 2) as well as dose-volume histograms are generated. The Implant Procedure. At our center, prostate brachytherapy is performed as an outpatient procedure, taking about 45 minutes to complete. The patient usually receives spinal anesthesia and is placed in the dorsal lithotomy position. The perineum is prepped in a sterile fashion, and an adhesive drape is used to hold the penis and scrotum anteriorly out of the perineal field. The ultrasound probe, with its attached needle-guide template, is inserted into the rectum and adjusted so that the cross-sectional images correlate with the preplan volume-study images. In many men, the prostate is a very mobile and malleable organ, and realtime monitoring of the needle and seed insertion process is of utmost importance. Our primary imaging device is the biplane ultrasound, and we switch often between transverse and sagittal views for confirmation of needle position. Fluoroscopy is used to a lesser extent. Any deviation and internal distortion of the gland should be recognized and adjusted accordingly. By following the seed and needle “map” generated by the treatmentplanning computer program, we insert the needles 1 tier at a time, beginning with the most posterior row. These posterior-row needles are left in place until all of the other seeds have been deposited; with this technique, the needles maintain their critical place in the prostate and also stabilize the gland during the procedure (Figures 3 and 4). Patients are generally discharged from the outpatient treatment facility about 2 hours after completion of the procedure, and most return to their customary daily activities in 1 to 2 days. Postoperative medications include antibiotics, anti-inflammatory agents, analgesics, and an -blocker. Evaluation of Implant Quality. Following the procedure, a dosimetric evaluation of the implant is performed on every patient, using 3-dimensional Brachytherapy Figure 3. The posterior row of needles is placed first and remains in position, immobilizing the gland, until all other needles have been placed and their seeds deposited. Figure 4. The 2 posterior rows of needles are inserted beyond the gland to allow treatment of the seminal vesicles. Figure 5. Postoperative CT of a large prostate (about 90 cc) following seeding. Note the planned lack of seeds near both the rectum and the urethra. CT-based analysis. The evaluation consists of dose computation and analysis for the target structure and surrounding organs. Five-millimeter– thick slices are acquired and printed with both soft tissue and bone windows, allowing for prostate and seed delineation (Figure 5). The interactive, 3-dimensional display of the prostate and seeds is then computer-analyzed and presented with radiation isodose overlays on the CT-defined structures. This slice-by-slice, 3-dimensional analysis permits detailed and accurate evaluation of the implant quality. We strive to ensure that 99% of the gland receives at least 90% of the prescription dose (Figure 6). particular treatment. A post-treatment rising PSA level may precede clinical failure with a lead time of years. A successful outcome today requires that the patient has no PSA-based evidence of relapse with long-term follow-up. Any PSA elevation after radical prostatectomy is a reliable indication of treatment failure. The interpretation of postradiation PSA values, however, other than a rising profile, is complicated by the continued presence of radiation-damaged benign prostatic epithelium, which continues to secrete PSA, albeit in small quantities. Nevertheless, increasing serum PSA levels following irradiation, regardless of absolute value, strongly suggest treatment failure. The critical PSA end points of the past often differed, making it difficult to compare outcomes between radiation studies. To allow for more objective comparisons, investigators today are likely to use the PSA end point recommended by the American Society for Therapeutic Radiology and Oncology (ASTRO): biochemical failure is defined as 3 consecutive rises in serum PSA level (and measured at Outcome Evaluation It is now generally accepted that posttreatment PSA levels are the most sensitive means to assess disease status and determine the efficacy of a Figure 6. Three-dimensional isodose color wash showing doses of radiation projected onto the surface of the gland. Bar at left shows corresponding dose for representative colors. WINTER 2001 REVIEWS IN UROLOGY 55 Brachytherapy continued least 6 months apart, as is part of our requirement). Morbidity. Our clinical experience with more than 4000 treated patients shows that most implant patients experience some degree of irritative and/or obstructive urinary tract symptoms that last for a few weeks to months. The symptoms are generally mild and of short duration but may be a bother to patients who expect rapid recovery and return to preimplant health. Urinary retention requiring intermittent or long-term catheterization is uncommon, occurring in fewer than 5% of all brachytherapy patients. It has been noted that a subset of patients presenting with enlarged glands and preexisting urinary obstructive symptoms is particularly prone to development of acute retention.7,8 It is our belief that urinary obstructive symptoms that develop immediately after seed implantation are caused primarily by the mechanical trauma of the implantation rather than from the radiation. The radiation-induced symptoms may seem similar, but they generally appear several days after the implant. Symptoms generally peak about 7 to 10 days after palladium 103 implants and 14 to 21 days after iodine 125 implants. Large glands, which require a greater number of seeds, may be subjected to more trauma from needle punctures than are smaller glands, with subsequent development of symptoms. Most patients have returned to baseline urologic function within 12 months of the implant. Previous studies of postimplant morbidity established that the risk of impotence increased with age and averaged 30% for all ages.7,9,10 It has been our experience that postimplant erectile dysfunction may be largely related to age and degree of pretreatment erectile competence (H. Ragde, MD and L.J.K., unpublished data, Recent Brachytherapy Results 100 90 80 Percent survival 70 60 50 40 30 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 (215) (213) (176) (169) (155) (147) (138) (130) (127) (122) (111) (109) (109) Months to fail (patients at risk) Figure 7. Disease-free survival (DFS) versus years from implant for the entire cohort, using the American Society for Therapeutic Radiation and Oncology failure criteria (observed DFS through year 10, projected to year 12). The numbers of patients who were available for evaluation (ie, at risk) are shown in parentheses (12-year DFS rate, 70%). 56 REVIEWS IN UROLOGY 2000). Patients younger than 60 who claimed sexual fitness before the implant generally maintained their sexual competence postoperatively; about 20% of patients between ages 60 and 70 who claimed to be sexually active before the implant suffered erectile dysfunction after the procedure. The sexual dysfunction rate appeared similar for patients treated with seeds alone and with combination therapy. Likewise, we discovered early on that patients without a previous transurethral resection of the prostate (TURP) had little or no risk of becoming incontinent of urine. With a TURP history, however, we found the incontinence rate at our institution to be 24%.11 This led us to modify our implant technique by shifting some of the central seeds away from the urethra in TURP patients, which appears to have largely eliminated this side effect (H. Ragde, MD and L.J.K., unpublished data, 2000). WINTER 2001 Physicians who use brachytherapy are starting to publish significant longterm data. Recently, we—at the Northwest Hospital—published 12-year results of patients treated with prostate brachytherapy with radioiodine.4 Between January 1, 1987, and September 1, 1989, 229 patients with prostate cancer (stages T1 to T3, NO - Nx, MO, low to high Gleason grades) underwent prostate implants with iodine 125. Median age was 70 years (range, 53 to 92 years). The patients were divided into 2 groups based exclusively on clinical stage and Gleason grade. A pretreatment PSA level was obtained in all patients, but the result did not impact the treatment group assignment. Group 1 consisted of 147 lower-stage/lower-grade patients treated with an implant alone (monotherapy); group 2 comprised 82 patients deemed to be at higher risk for extraprostatic extension of the malignancy. Group 2 patients, in ad- Brachytherapy 100 90 80 70 Percent survival dition to receiving seed implants, were also treated with 45 Gy EBT to the pelvis (combination therapy). None of the patients underwent operative staging, and none received concurrent androgen manipulation. Fourteen patients were excluded from follow-up—7 by death from noncancerous causes within 18 months postimplant, and 7 patients who had incomplete PSA-level follow-up—leaving 215 patients for complete evaluation. The median post-treatment follow-up was 110 months. The observed disease-free survivals at 12 years of the 2 groups combined was 70% (66% in the monotherapy group and 79% in the combination therapy group). Figures 7, 8, and 9 show the disease-free survival results. 60 50 40 30 20 10 0 0 12 24 36 48 (140) (138) (112) (107) (95) 72 (85) 84 (80) 96 (79) 108 (76) 120 (67) 132 (66) 144 (66) Months to fail (patients at risk) Discussion Figure 8. Disease-free survival (DFS) versus years from implant for the group receiving monotherapy, using the American Society for Therapeutic Radiation and Oncology failure criteria (observed DFS through year 10, projected to year 12). The numbers of patients who were available for evaluation (ie, at risk) are shown in parentheses (12-year DFS rate, 66%). 100 90 80 70 Percent survival With increasing life expectancy and widespread use of PSA as a screening test, cancer of the prostate has become one of the most commonly observed malignancies in American men. Although prostate cancer is still one of the most frequent causes of death from cancer, increased PSA testing has resulted in a downward shift in the stage and grade at presentation. In the pre-PSA era, the majority of prostate tumors were clinically and pathologically advanced, whereas tumors recognized today, after modest PSA elevations, are likely to be of a lower grade and confined to the prostate, leading to potentially high cure rates effected by locally directed treatment. These potentially successful interventions for localized prostate cancer include prostate brachytherapy, radical prostatectomy, external beam irradiation, and cryotherapy. Over the years, each has been anointed and embraced with varying degrees of enthusiasm. Before the advent of the PSA test and in the absence of outcomes data from randomized clinical trials, it was difficult to determine which would be the most effective and better-tolerat- 60 (92) 60 50 40 30 20 10 0 0 (75) 12 (75) 24 (64) 36 (62) 48 (60) 60 (55) 72 (53) 84 (50) 96 (48) 108 (46) 120 (44) 132 (43) 144 (43) Months to fail (patients at risk) Figure 9. Disease-free survival (DFS) versus years from implant for the group receiving combination therapy, using the American Society for Therapeutic Radiation and Oncology failure criteria (observed DFS through year 10, projected to year 12). The numbers of patients who were available for evaluation (ie, at risk) are shown in parentheses (12-year DFS rate, 79%). WINTER 2001 REVIEWS IN UROLOGY 57 Brachytherapy continued Historical Perspectives Reports documenting efforts to eradicate prostate cancer by local application of radioactive isotopes go back to the start of the 20th century, when Pasteau and Degrais first described their insertion of capsules containing the isotope radium 226 into the prostate through the urethra using digital rectal guidance.20 This early technique of brachytherapy is the oldest process to deliver radiation to the prostate gland, preceding external beam therapy (EBT) by several decades and antedating modern prostate cancer surgery. In 1917, Barringer,21 at New York’s Memorial Hospital (now Memorial Sloan-Kettering Cancer Center), inserted needles containing radium 226 into the prostate. In the 1950s and 1960s, Flocks,22 from the University of Iowa, injected a solution of colloidal radioactive gold 198 into the prostates of patients with inoperable prostate cancer. Real interest in prostate brachytherapy, however, did not occur until the 1970s, following commercial availability of the first iodine 125 seed developed by Donald Lawrence, PhD, in 1967. Shortly after, Whitmore and associates23 described an “open” implant technique using iodine seeds. Whitmore’s technique involved retropubic exposure of the prostate and a pelvic lymph node dissection. The number and activity of the iodine seeds were calculated from a nomogram, and the dose was extrapolated from EBT concepts. The implant needles were inserted freehand, with a surgeon’s finger in the rectum providing depth guidance but without any imaging devices for intraoperative seed or needle spacing. Conceptually, the open implant procedure had great appeal. A highly confined dose of irradiation was delivered to the prostate, sparing the juxtaposed bladder and rectum from undue damage. All too often, however, the freehand needle and seed placements, aided solely by visual and tactile cognition, resulted in erratic dose distributions, in all but the most experienced hands. Some areas of the gland were “too hot” and likely to cause complications; others were “too cold,” delivering sublethal radiation to the cancers, resulting in an unacceptable rate of local failure. Compounding the problem, some practitioners also advocated brachytherapy for patients with bulky, incurable lesions.24 As other promising treatments gained momentum, interest in prostate brachytherapy gradually declined. In the late 1960s, Bagshaw et al25 and others26-28 began publishing the results of management of prostate cancer with the newly emerging, megavoltage EBT. Their research demonstrated that EBT could be curative by uniform delivery of high but tolerable doses of irradiation throughout the prostate gland. This form of radiation as well as the technique of surgical removal of the prostate, originally developed by Young29 and later popularized by Jewett,30 rapidly became the preferred treatments. Interest in prostate brachytherapy continued to decline. The situation remained that way until the early 1980s, when Holm and coworkers31 of Denmark published their technique of implanting the prostate transperineally, guiding seed-bearing needles into precise positions of the gland by the (then) recently introduced transrectal ultrasonography. His novel and elegant technique, shown to be reproducible and to provide good disease control, was almost lost when Dr Holm stopped performing it because of problems inherent in combining it with EBT. Before Dr Holm stopped using his technique, he taught it to Haakon Ragde, MD, who then brought it to the United States in 1985. This, along with the introduction (in 1987, also by Ragde) of the newly developed isotope palladium 103, gave rise to a resurgence of interest in prostate seed implantation. 58 REVIEWS IN UROLOGY WINTER 2001 ed treatment. Since these necessary randomized trials are unlikely to be instituted or concluded in the near term, treatment decisions will continue to be made on the basis of probabilities, in conjunction with patient and physician preferences. Indeed, even if the proof of the superiority of 1 method over another is rigorously documented, there would still remain several viable treatment options in use, because no single treatment is optimal for all patients. It is now generally accepted that post-treatment PSA values are the most sensitive means to assess disease status and predicate efficacy of a treatment. A successful outcome today from any curative therapy requires that the patient have no PSA-based evidence of relapse with long-term follow-up.12-14 In our review of our 12-year results, we examined the concordance between our old definition of PSA failure (PSA level greater than 0.5 ng/mL) and the new ASTRO definition. We found no significant difference between the methods in observed disease-free survival.4 The durability of brachytherapy to control prostate cancer is also confirmed by this same study. With an average PSA level of only 0.16 ng/mL in the disease-controlled group at both 10 and 12 years, we can demonstrate that prostate cancer managed in vivo can indeed be cured with brachytherapy. Of the patients who were classified as “failed” in the 12year study, failure occurred in the majority (75%) within the first 5 years. Indeed, the endurance of brachytherapy is further demonstrated by the fact that no patients failed past 115 months. Even patients with stable relatively high postseeding PSA levels (such as 0.8 ng/mL) have shown no evidence of progression when followed for up to 12 years. Thus, it is possible for an intact gland to continue to produce small amounts of PSA through “normal” mechanisms and yet be clear of all malignant cells. Brachytherapy This phenomenon is demonstrated in many other human adenocarcinomas, such as salivary gland cancers, in which cured patients retain salivary function, albeit at reduced levels. It has been claimed that brachytherapy does not have enough long-term follow-up by which to evaluate treatment efficacy. This claim is insupportable, because modern prostate cancer treatment results rest largely on PSA follow-up. Most published treatment studies, including those of radical prostatectomy and EBT, have only small numbers of patients who have PSA follow-up for more than 5 years. Therefore, no treatment modality can lay claim to a “longer” follow-up. Excellent brachytherapy results are reported by many different centers, sometimes using varying techniques for the actual seed implantation and locations.15-17 Brachytherapy is also being used as salvage treatment for patients in whom previous radiother- apy, either EBT or brachytherapy, has failed. Our group has used salvage brachytherapy to treat many patients and has achieved results upward of 34% actuarial control at 5 years, with less morbidity than shown with other salvage therapies.18 In an age in which market forces are driving health care organizations to “prove” quality while diminishing cost, such factors must also be taken into account when different treatments are considered. Some physicians argue that younger patients should be treated with radical prostatectomy—implying, perhaps, that younger patients will somehow lose forever the chance of a cure if they select a treatment other than radical prostatectomy. We have been unable to find any published evidence to validate this claim. Indeed, a significant portion of our practice is now composed of younger men wishing to avoid the morbidities associated with radical prostatectomy. We compared our recently published brachytherapy results with the often-referenced Swedish study by Johansson and colleagues,19 which purports to show high 10-year survival in a group of 223 men with early-stage, untreated prostate cancer. Both our studies and the Swedish study had similar populations and follow-up. Nineteen (8.5%) of the men who went untreated in Sweden died of prostate cancer, whereas only 4 (2%) of our patients did. Only 86 of our patients died of any cause versus the 124 reported by Johansson. Even comparing the Swedish study’s “progression-free” survival rate (53%) with our diseasefree survival rate (70%) shows the potential survival benefit of treating patients with early-stage prostate cancer via brachytherapy. To fully sanction a new therapy requires proof that the success and risks of the new procedure are at least comparable to the treatments already in Figure 10. Fluoroscopic image of seed positions following implant. Note the even spacing, symmetry, and conformation to the gland shape. WINTER 2001 REVIEWS IN UROLOGY 59 Brachytherapy continued use. With the data presented here and others previously published, we conclude that the efficacy of prostate brachytherapy compares favorably with results reported from modern surgical and EBT studies. Brachytherapy also demonstrates fewer side effects and complications. A recent forecast by the AUA, based on Medicare data, suggests that prostate brachytherapy may replace radical surgery as the treatment of choice for patients with organ-confined prostate cancer. This conclusion is reasonable. Numerous precedents exist in medicine and clinical results that when a treatment becomes less invasive, less deforming, and less expensive (in terms of both dollars and lifestyle impact) and yet accomplishes the same goals as more radical interventions, that treatment will be favored by society. As an example, one can consider the results of another glandular, hormonally responsive tumor: breast cancer. In the late 1970s, women elected to forgo the extensive radical mastectomy in favor of breast conservation therapy. Similar to the treatment protocol for prostate cancer, conservative breast cancer treatment consists of EBT directed to the entire breast (because of the size and position of the breast cancer to the chest wall), followed by a brachytherapy boost at the site of the tumor that has been removed. Now, breast conservation therapy is considered the gold standard for women with localized breast cancer, obviating the need for the more extensive surgery that resulted in the removal of the entire breast. Conclusions Modern prostate brachytherapy with permanent implants is a minimally invasive procedure that offers a viable alternative to surgery and conventional EBT, with excellent reported results for the treatment of patients with clinically localized prostate cancer. Our review and analysis should 60 REVIEWS IN UROLOGY WINTER 2001 give clinicians current, evidencebased information. The use of low-energy, implanted radioactive sources, placed into the prostate under direct ultrasound visualization with preplanned dosimetry calculated according to prostate volume, results in a curative radiation dose limited essentially to the prostate (Figure 10). This radiation dose has been shown to be excellent for long-term control of prostate cancer while resulting in little, if any, clinically significant toxicity or side effects in most patients. Augmenting the tumor control and low side-effect profile are the convenience of a simple outpatient procedure and rapid resumption of a patient’s daily activities. As the population continues to age, we predict continued growth of brachytherapy as a curative treatment of choice for patients with localized prostate cancer. ■ References 1. Hudson R. Brachytherapy treatments increasing among Medicare Population. 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Prestidge BR, Prete JJ, Buchholz TA, et al. A survey of current clinical practice of permanent prostate brachytherapy in the United States. Int J Radiat Oncol Biol Phys. 1998;40:461-465. 7. Stock RG, Stone NN, Iannuzzi C. Sexual potency following interactive ultrasound-guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 1996;35:267-272. 8. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol. 1998;160:1379-1382. 9. Robinson JW, Dufour MS, Fung TS. Erectile functioning of men treated for prostate carcinoma. Cancer. 1997;79:538-544. 10. Peneau M. Interstitial radiotherapy and prostate cancer: analysis of the literature. Subcommittee of Prostate Cancer of C.C.A.F.U. Prog Urol. 1999;9:440-451. 11. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasound-guided implantation of the prostate: morbidity and complications. 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French, MD Chief Resident Department of Urology Dalhousie University Halifax, Nova Scotia Steven R. Potter, MD Chief Resident The Brady Urological Institute The Johns Hopkins Hospital Baltimore Debby Chao, BS Medical Student University of California, Los Angeles, School of Medicine Liam Hickey Medical Student Dalhousie University Halifax, Nova Scotia Christopher P. Smith, MD Physician Scientist Fellow in Neurourology and Female Urology University of Pittsburgh School of Medicine Michael Conlin, MD Assistant Professor of Urology Oregon Health Sciences University Portland Karyn S. Eilber, MD Resident in Urology University of California, Los Angeles, School of Medicine 62 REVIEWS IN UROLOGY WINTER 2001 Leroy J. Korb, MD Northwest Prostate Institute Seattle Ganesh S. Palapattu, MD Resident in Urology University of California, Los Angeles, School of Medicine Allan J. Pantuck, MD Fellow, Urologic Oncology University of California, Los Angeles, School of Medicine Amnon Zisman, MD Stephen and Mary Meadow Fellow in Urologic Oncology University of California, Los Angeles, School of Medicine