Steven Sutlief

125I versus 103Pd for low-risk prostate cancer: preliminary PSA outcomes from a prospective randomized multicenter trial ☆

PURPOSE To compare prostate cancer control rates in patients who received (125)I vs. (103)Pd. MATERIALS AND METHODS Of a planned total of 600 patients with 1997 American Joint Committee on Cancer clinical Stage T1c-T2a prostate carcinoma (Gleason score 5-6, prostate-specific antigen [PSA] 4-10 ng/mL), 126 were randomized to implantation with (125)I (144 Gy) vs. (103)Pd (125 Gy). The prostate biopsies were reviewed for Gleason score by one of us (L.T.). A single manufacturer of (125)I sources (Model 6711, Amersham, Chicago, IL) and (103)Pd sources (Theraseed, Theragenics, Buford, Georgia) was used. Isotope implantation was performed with standard techniques, using a modified peripheral loading pattern. Of a total of 126 patients randomized, 11 were excluded, leaving 115 randomized patients for this analysis. Twenty patients received a short course of preimplant hormonal therapy, none of whom continued hormonal therapy after their implant procedure. Postimplant CT was obtained 2-4 hours after implantation. The dosimetric parameters analyzed included the percentage of the postimplant prostate or rectal volume covered by the prescription dose (V(100)) and the dose that covered 90% of the postimplant prostate volume (D(90)). Freedom from biochemical failure was defined as a serum PSA level < or =0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA level was still decreasing. Patients whose serum PSA had reached a nadir at a value >0.5 ng/mL were scored as having failure at the time at which their PSA had reached a nadir. The follow-up period for patients without failure ranged from 2.0 to 4.9 years (median 2.9). Freedom-from-failure curves were calculated by the Kaplan-Meier method. Differences between groups were determined by the log-rank method. RESULTS The actuarial biochemical freedom-from-failure rate at 3 years was 89% for (125)I patients vs. 91% for (103)Pd patients (p = 0.76). The 3-year biochemical freedom-from-failure rate for patients with a D(90) <100% of the prescription dose was 82% vs. 97% for patients with a D(90) > or =100% of the prescription dose (p = 0.01). Similarly, the 3-year biochemical freedom-from-failure rate for patients with a V(100) <90% of the prescription dose was 87% vs. 97% for patients with a V(100) > or =90% of the prescription dose (p = 0.01). The effect of the dosimetric parameters on biochemical control was most pronounced for (125)I, but also apparent for (103)Pd. CONCLUSIONS The 3-year actuarial biochemical control rates for low early-stage prostate cancer are similar after (125)I and (103)Pd.

Prostate brachytherapy seed identification on post-implant TRUS images.

TRUS is a conceptually appealing alternative to CT-based dosimetry, offering the substantial practical advantage of being readily available intraoperatively. To test the feasibility and reliability of seed identification on post-implant TRUS using standard two-dimensional images, ten patients treated with I-125 or Pd-103 brachytherapy were studied. A set of transverse images (6 MHz) were taken immediately following completion of the implant procedure. Original thermal images were sent to four physicians and the sources were identified independently by placing marks on a cellophane overlay, with grids to match the axial TRUS images. The number and type of seed implanted were not revealed to the investigators. Instead, they were instructed to mark the positions of what they would consider, with reasonable certainty, to be seeds. The overlays were then manually compared for source identification and agreement between observers regarding each alleged source. The actual number of implanted seeds ranged from 44 to 108 (median: 60). In contrast, the mean number of seeds allegedly identified per patients ranged from 26 to 82 (median: 43). The average percent of the seeds allegedly identified per patient ranged from 51% to 83% (mean: 74%). The four physician investigators--KW, JS, BH, and GM--identified an alleged median of 90%, 44%, 63%, and 91% of the total seeds, respectively. There were five instances in which investigators alleged more seeds than were actually implanted. The consistency of seed identification among the investigators was evaluated by noting how many investigators identified each bright spot on the images. The percent of bright spots identified by all four investigators ranged from 8% to 33% (median: 20%). Despite considerable interest among some of our clinical and commercial colleagues in developing TRUS-based intraoperative post-implant dosimetry, the use of TRUS-based seed identification for post-implant dosimetry should be viewed with skepticism.

Short‐term sexual function after prostate brachytherapy

Sexual function was evaluated in 34 patients with low‐risk prostate cancer (PSA ≤ 10, Gleason score ≤ 6, clinical stage T1/T2) undergoing brachytherapy in a phase III prospective randomized trial comparing iodine‐125 (125I) to palladium‐103 (103Pd). The mean and median International Index of Erectile Function (IIEF) scores for the entire group were 14.2 and 16.5, respectively, and there was no difference between these scores when stratified by isotope. IIEF scores < 6, 6 to 11, and ≥ 12 were recorded in 35% (12/34), 6% (2/34), and 59% (20/34) of patients, respectively. Hematospermia, orgasmalgia (pain at the time of orgasm), and alteration in intensity of orgasm were documented in 26% (9/34), 15% (5/34), and 38% (13/34) of patients, respectively, but these side effects were of limited duration for most patients. There was no relationship between radiation dose to the neurovascular bundles (NVB), which averaged 209% of the prescribed prostate dose, and the development of postbrachytherapy impotence. All four impotent patients who used sildenafil responded favorably. With a median follow‐up of 13 months, 65% of patients undergoing prostate brachytherapy maintained sexual function without pharmacologic support. Including sildenafil responses, 76.5% of patients sustained erections sufficient for sexual intercourse. 2001 Wiley‐Liss, Inc.

Brachytherapy radiation doses to the neurovascular bundles

PURPOSE To investigate the role of radiation dose to the neurovascular bundles (NVB) in brachytherapy-related impotence. METHODS AND MATERIALS Fourteen Pd-103 or I-125 implant patients were studied. For patients treated with implant alone, the prostate and margin (clinical target volume [CTV]) received a prescription dose of 144 Gy for I-125 or 115 Gy for Pd-103. Two patients received Pd-103 (90 Gy) with 46 Gy supplemental external beam radiation (EBRT). Axial CT images were acquired 2 to 4 hours postoperatively for postimplant dosimetry. Because the NVBs cannot be visualized on CT, NVB calculation points were determined according to previously published anatomic descriptions. Bilateral NVB points were considered to lie posterior-laterally, approximately 2 mm from the prostatic capsule. NVB doses were recorded bilaterally, at 0.5-cm intervals from the prostatic base. RESULTS For Pd-103, the average NVB doses ranged from 150 Gy to 260 Gy, or 130% to 226% of the prescription dose. For I-125, the average NVB dose ranged from 200 Gy to 325 Gy, or 140% to 225% of the prescription dose. These was no consistent relationship between the NVB dose and the distance from the prostatic base. To examine the possible effect of minor deviations of our calculation points from the true NVB location, we performed NVB calculations at points 2 mm medial or lateral from the NVB calculation point in 8 patients. Doses at these alternate calculation points were comparable, although there was greater variability with small changes in the calculation point if sources were located outside the capsule, near the NVB calculation point. Three patients who developed early postimplant impotence had maximal NVB doses that far exceeded the average values. CONCLUSIONS In the next few years, we hope to clarify the role of high NVB radiation doses on potency, by correlating NVB dose calculations with a large number of patients enrolled in an ongoing I-125 versus Pd-103 trial for early-stage patients, for whom detailed dosimetric and potency data are being collected prospectively. In the future, we anticipate that NVB doses may be incorporated into dosimetry guidelines to maximize tumor control and minimize treatment-related morbidity.

THE EFFECT OF SUPPLEMENTAL BEAM RADIATION ON PROSTATE BRACHYTHERAPY-RELATED MORBIDITY: MORBIDITY OUTCOMES FROM TWO PROSPECTIVE RANDOMIZED MULTICENTER TRIALS

PURPOSE To detail the effect of supplemental beam radiation on prostate brachytherapy-related morbidity. METHODS AND MATERIALS The 220 patients reported here were a subgroup randomized on two treatment protocols, with a planned total accrual of 1200. Low-risk patients, with Gleason Grade 2-6, prostate-specific antigen (PSA) 4-10 ng/mL, were randomized to implantation with I-125 (144 Gy, TG-43) vs. Pd-103 (125 Gy, NIST-99). Intermediate-risk patients, with Gleason Grade 7 or higher or PSA of 10-20 ng/mL, were randomized to implantation with Pd-103, delivering 90 vs. 115 Gy (NIST-1999), with 44 vs. 20 Gy external beam irradiation (EBRT), respectively. Beam radiation was delivered with a four-field arrangement, designed to cover the prostate and seminal vesicles with a 2-cm margin (reduced to 1.0 cm posteriorly). Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urologic Association (AUA) and Radiation Therapy Oncology Group criteria at 1, 3, 6, 12 and 24 months. Use of alpha-blockers to relieve obstructive symptoms was not controlled for, but was noted at each follow-up time. RESULTS AUA score increases were highest at 1 month in the patients treated with higher prescription doses of Pd-103 (125 Gy Pd-103 alone or 115 Gy Pd-103 with 20 Gy EBRT), consistent with prior reports. By 6 months, most Pd-103 patients had returned to baseline, whereas I-125 patient scores were still declining. Patients treated with lower dose Pd-103 combined with EBRT had lesser elevations of their AUA scores at 1 and 6 months, but differences between those receiving 20 vs. 44 Gy beam radiation were inconsistent. At no point did beam radiation significantly affect postimplant AUA scores or urinary morbidity scores. Rectal morbidity scores were remarkably similar between groups, apart from higher scores at 1 month in patients treated with full dose Pd-103. Rectal morbidity consisted primarily of increased frequency and mucous passage. There have been no instances of rectal ulceration or fistula. The addition of beam radiation significantly increased postimplant rectal morbidity scores only at the 1-month time point. CONCLUSION The addition of supplemental beam radiation had little effect on morbidity. We do not believe that morbidity per se should influence the decision of whether or not to use supplemental beam radiation.

AAPM Task Group 128: Quality assurance tests for prostate brachytherapy ultrasound systems

While ultrasound guided prostate brachytherapy has gained wide acceptance as a primary treatment tool for prostate cancer, quality assurance of the ultrasound guidance system has received very little attention. Task Group 128 of the American Association of Physicists in Medicine was created to address quality assurance requirements specific to transrectal ultrasound used for guidance of prostate brachytherapy. Accurate imaging guidance and dosimetry calculation depend upon the quality and accuracy of the ultrasound image. Therefore, a robust quality assurance program for the ultrasound system is essential. A brief review of prostate brachytherapy and ultrasound physics is provided, followed by a recommendation for elements to be included in a comprehensive test phantom. Specific test recommendations are presented, covering grayscale visibility, depth of penetration, axial and lateral resolution, distance measurement, area measurement, volume measurement, needle template/electronic grid alignment, and geometric consistency with the treatment planning computer.

Fas-Mediated Acute Lung Injury Requires Fas Expression on Nonmyeloid Cells of the Lung

Fas (CD95) is a membrane surface receptor, which, in the lungs, is expressed in macrophages, neutrophils, and epithelial cells. In mice, Fas activation leads to a form of lung injury characterized by increased alveolar permeability. We investigated whether Fas-mediated lung injury occurs primarily as a result of Fas activation in myeloid cells (such as macrophages) or in nonmyeloid cells (such as epithelial cells). Chimeric mice lacking Fas in either myeloid or nonmyeloid cells were generated by transplanting marrow cells from lpr mice (which lack Fas) into lethally irradiated C57BL/6 mice (MyFas− group) or vice versa (MyFas+ group). Additional mice transplanted with marrow cells from their same strain served as controls (Fas+ ctr and Fas− ctr groups). Sixty days after transplantation, the mice received intratracheal instillations of the Fas-activating mAb Jo2 (n = 10/group), or an isotype control Ab (n = 10/group), and were euthanized 24-h later. Only animals expressing Fas in nonmyeloid cells (Fas+ ctr and MyFas−) showed significant increases in lung neutrophil content and in alveolar permeability. These same mice showed tissue evidence of lung injury and caspase-3 activation in cells of the alveolar walls. Despite differences in the neutrophilic response and lung injury, there was no statistical difference in the lung cytokine concentrations (KC and MIP-2) among groups. We conclude that Fas-mediated lung injury requires expression of Fas on nonmyeloid cells of the lungs. These findings suggest that the alveolar epithelium is the primary target of Fas-mediated acute lung injury, and demonstrate that apoptotic processes may be associated with neutrophilic inflammation.

Long-term urinary function after transperineal brachytherapy for patients with large prostate glands

PURPOSE To summarize longer-term postbrachytherapy morbidity in patients with prostate glands >50 cm3. METHODS AND MATERIALS From 1997 to 1998, 33 patients with a transrectal ultrasound-based prostate volume >50 cm3 were treated at the University of Washington by 125I (144 Gy) or 103Pd (115 Gy) implantation for prostate carcinoma. These 33 patients comprised 7% of the total implant patient population. Twelve patients were treated with neoadjuvant androgen ablation before implantation. The (125)I source strength ranged from 0.34 to 0.5 mCi and the 103Pd source strength ranged from 1.1 to 1.4 mCi (pre-NIST-99). The total number of sources implanted was 94-223 (median 155). Despite the typical implant-related volume increase, the postimplant CT-defined prostate volumes were generally well-covered by the prescription isodose (median coverage 92%, range 80-100%). The preimplant urinary obstructive symptoms were quantified by the criteria of the American Urological Association. RESULTS Of the 33 patients, 12 developed acute postimplant urinary retention, all presenting within 24 h of implantation. Patients who developed postimplant retention lasting >1 week were generally treated with intermittent self-catheterization. By 1 month, 85% of patients were catheter free. By 1 year, only 1 patient (4%) remained in urinary retention; the remainder of cases had resolved spontaneously. With follow-up of 1.7-2.6 years, the last American Urological Association scores were higher than the pretreatment scores in 15 patients and lower in 7 patients. No patient developed permanent urinary incontinence. Long-term changes in the American Urological Association scores were unrelated to whether the patient had been in urinary retention after implantation. Two patients developed rectal fistulas; they had preimplant transrectal ultrasound prostate volumes of 53 and 59 cm3, in the low range for this group of patients. No other patient had persistent rectal bleeding suggestive of clinically significant proctitis. The pretreatment serum prostate-specific antigen level was 3.3-15 ng/mL (median 7.2) and the last serum prostate-specific antigen level 0.1-1.6 ng/mL (median 0.2). CONCLUSION Patients with larger prostate volumes appear to have moderate morbidity and a satisfactory technical outcome with brachytherapy. We do not believe the occurrence of two severe rectal complications was related to the prostate volume per se. Our experience and that of others calls into question the validity of using prostate volume as a criterion for patient suitability for prostate brachytherapy.

RADIATION SAFETY PARAMETERS FOLLOWING PROSTATE BRACHYTHERAPY

PURPOSE To determine the degree and variability of radiation exposure to the general public from patients after I-125 or Pd-103 prostate brachytherapy. METHODS AND MATERIALS Radiation exposure measurements were made from 38 consecutive, unselected patients with stage T1 or T2 prostatic carcinoma who had transperineal I-125 or Pd-103 implants at the University of Washington in 1998. RESULTS The exposure rate at the anterior skin surface following a I-125 implant ranged from 2.2 to 8.9 mrem/hour (average: 5.0). The exposure rate at the anterior skin surface from a Pd-103 implant ranged from 0.5 to 4.9 mrem/hour (average: 1.7). Based on the current Nuclear Regulatory Commission (NRC) regulations the time required to reach the annual limit at the anterior skin surface would be 20 hours for I-125 and 59 hours for Pd-103. For exposure at the lateral skin surface, the times would exceed 500 hours for either isotope. CONCLUSIONS This data suggest that patients need not be concerned about being a radiation risk to the general public following their procedure.

Argon plasma coagulation for rectal bleeding after prostate brachytherapy

PURPOSE To better define the efficacy and safety of argon plasma coagulation (APC), specifically for brachytherapy-related proctitis, we reviewed the clinical course of 7 patients treated for persistent rectal bleeding. Approximately 2-10% of prostate cancer patients treated with 125I or 103Pd brachytherapy will develop radiation proctitis. The optimum treatment for patients with persistent bleeding is unclear from the paucity of available data. Prior reports lack specific dosimetric information, and patients with widely divergent forms of radiation were grouped together in the analyses. METHODS AND MATERIALS Seven patients were treated with APC at the Veterans Affairs Puget Sound Health Care System and the University of Washington from 1997 to 1999 for persistent rectal bleeding due to prostate brachytherapy-related proctitis. Four patients received supplemental external beam radiation, delivered by a four-field technique. A single gastroenterologist at the Veterans Affairs Puget Sound Health Care System treated 6 of the 7 patients. If the degree of proctitis was limited, all sites of active bleeding were coagulated in symptomatic patients. An argon plasma coagulator electrosurgical system was used to administer treatments every 4-8 weeks as needed. The argon gas flow was set at 1.6 L/min, with an electrical power setting of 40-45 W. RESULTS The rectal V100 (the total rectal volume, including the lumen, receiving the prescription dose or greater) for the 7 patients ranged from 0.13 to 4.61 cc. Rectal bleeding was first noticed 3-18 months after implantation. APC (range 1-3 sessions) was performed 9-22 months after implantation. Five patients had complete resolution of their bleeding, usually within days of completing APC. Two patients had only partial relief from bleeding, but declined additional APC therapy. No patient developed clinically evident progressive rectal wall abnormalities after APC, (post-APC follow-up range 4-13 months). CONCLUSIONS Most patients benefited from APC, and no cases of clinically evident progressive tissue destruction were noted. Although APC appears to be efficacious and safe in the setting of the rectal doses described here, caution is in order when contemplating APC for brachytherapy patients.