A new immunodeficient hyperglycaemic mouse model based on the Ins2Akita mutation for analyses of human islet and beta stem and progenitor cell function.

AIMS/HYPOTHESIS: To develop and validate a new immunodeficient mouse strain that spontaneously develops a non-autoimmune hyperglycaemia to serve as a diabetic host for human islets and human beta stem and progenitor cells without the need for induction of hyperglycaemia by toxic chemicals with their associated side effects. METHODS: We generated and characterised a new strain of immunodeficient spontaneously hyperglycaemic mice, the NOD-Rag1null Prf1null Ins2Akita strain and compared this strain with the NOD-scid Il2rgammanull (also known as Il2rg) immunodeficient strain rendered hyperglycaemic by administration of a single dose of streptozotocin. Hyperglycaemic mice were transplanted with human islets ranging from 1,000 to 4,000 islet equivalents (IEQ) and were monitored for normalisation of blood glucose levels. RESULTS: NOD-Rag1null Prf1null Ins2Akita mice developed spontaneous hyperglycaemia, similar to Ins2Akita-harbouring strains of immunocompetent mice. Histological examination of islets in the host pancreas validated the spontaneous loss of beta cell mass in the absence of mononuclear cell infiltration. Human islets transplanted into spontaneously diabetic NOD-Rag1null Prf1null Ins2Akita and chemically diabetic NOD-scid Il2rgammanull mice resulted in a return to euglycaemia that occurred with transplantation of similar beta cell masses. CONCLUSIONS/INTERPRETATION: The NOD-Rag1null Prf1null Ins2Akita mouse is the first immunodeficient, spontaneously hyperglycaemic mouse strain described that is based on the Ins2Akita mutation. This strain is suitable as hosts for human islet and human beta stem and progenitor cell transplantation in the absence of the need for pharmacological induction of diabetes. This strain of mice also has low levels of innate immunity and can be engrafted with a human immune system for the study of human islet allograft rejection.

Does hormonal manipulation in conjunction with permanent interstitial brachytherapy, with or without supplemental external beam irradiation, improve the biochemical outcome for men with intermediate or high-risk prostate cancer?

OBJECTIVE: To determine whether hormonal manipulation improves the biochemical outcome for men with intermediate or high-risk prostate cancer and undergoing permanent brachytherapy with or without supplemental external beam radiation therapy. PATIENTS AND METHODS: From April 1995 to August 2000, 350 patients with intermediate-risk (225 men; a Gleason score of >or= 7 or a prostate specific antigen, PSA, level of >or= 10 ng/mL or clinical stage >or= T2b) or high-risk features (125 men; two or three of a Gleason score of >or= 7 or PSA >or= 10 ng/mL or clinical stage >or= T2b) underwent transperineal ultrasonography-guided permanent brachytherapy. No patient underwent pathological lymph node staging. Of these patients, 293 received supplemental external beam radiation therapy (EBRT), 141 received hormonal manipulation, with 82 having hormonal therapy for 4 months) regimens, supplemental EBRT, isotope and dosimetric variables. RESULTS: For intermediate-risk patients, the 6-year actuarial BDF survival rates were 98%, 96% and 100% for hormone naïve, cytoreductive and adjuvant treatment, respectively (P = 0.693); for high-risk patients the respective values were 79%, 94% and 92% (P = 0.046). When stratified by pretreatment PSA, hormonal manipulation improved the outcome for patients with a PSA of >or= 10 ng/mL (P = 0.019), but not for those with < 10 ng/mL (P = 0.661). Hormonal status was not statistically significant in predicting biochemical outcome when stratified by Gleason score. The follow-up in hormone-naïve patients was significantly longer than that in hormonally manipulated patients, at 55 (20) vs 43 (15) months (P < 0.001). In a multivariate analysis only the Gleason score predicted failure in intermediate-risk patients, while pretreatment PSA, the use of hormonal manipulation and Gleason score predicted the outcome in high-risk patients (P = 0.035). For both hormone-naïve and hormonally manipulated BDF patients, the median PSA level after implantation was < 0.1 ng/mL. CONCLUSION: In patients treated by permanent prostate brachytherapy, hormonal manipulation improved the biochemical outcome for those at high-risk and those with an initial PSA of >or= 10 ng/mL, but not for those with intermediate-risk features. The use of hormonal therapy for> 4 months conferred no additional biochemical advantage over short-course regimens. Because the follow-up in hormone-naïve patients was longer than that for those receiving hormonal manipulation, additional follow-up will be mandatory to confirm the durability of these findings.

Perineural invasion is not predictive of biochemical outcome following prostate brachytherapy.

PURPOSE: The purpose of this article is to evaluate whether the presence of perineural invasion (PNI) in the biopsy specimen is predictive of 5-year biochemical disease-free outcome after prostate brachytherapy. MATERIALS AND METHODS: Four hundred twenty-five patients underwent transperineal ultrasound-guided prostate brachytherapy using either 103Pd or 125I for clinical T1b/T3a NXMO (1997 American Joint Committee on Cancer) adenocarcinoma of the prostate gland from April 1995 to October 1999. No patient was lost to follow-up, and no patient underwent pathological lymph node staging. Two hundred twenty-one patients were implanted with 103Pd, and 204 patients were implanted with 125I. Of this cohort, 190 patients were implanted without supplemental beam radiation, and 235 received moderate-dose external-beam radiation therapy followed by a prostate brachytherapy boost. One hundred sixty-three patients received hormonal manipulation in conjunction with the brachytherapy implant (86 of these patients received moderate-dose external-beam radiation therapy before brachytherapy), and 262 patients were hormone naïve. Perineural invasion, defined as carcinoma tracking along or around a nerve within the perineural space, was identified in 105 patients (24.7% of the population). The median patient age was 68 years (range, 48-81 years). The mean follow-up was 37.1 +/- 15.2 months, and the median follow-up was 35.4 months (range, 6-74 months). Follow-up was calculated from the date of implantation. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology (ASTRO) consensus definition. RESULTS: When Kaplan-Meier survival analysis was performed, the presence of PNI did not predict failure. When PNI was entered into a Cox regression analysis with evaluated clinical predictors of failure (age, clinical T stage, pretreatment prostate-specific antigen level, and Gleason score) or treatment parameters (use of neoadjuvant hormonal therapy, supplemental external-beam radiation therapy, and choice of isotope), PNI did not add to the predictive strength of these variables. The median disease-free prostate-specific antigen level was 0.1 ng/mL for the entire cohort. CONCLUSIONS: Our results indicate that actuarial 5-year biochemical outcomes with a prostate brachytherapy approach that utilizes generous periprostatic margins is not dependent on the presence of PNI. In addition, PNI should not be used as an independent prognosticator in determining the need for combined-modality therapy in patients undergoing prostate brachytherapy.

Short-term sexual function after prostate brachytherapy.

Sexual function was evaluated in 34 patients with low-risk prostate cancer (PSA < or = 10, Gleason score < or = 6, clinical stage T1/T2) undergoing brachytherapy in a phase III prospective randomized trial comparing iodine-125 ((125)I) to palladium-103 ((103)Pd). 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 > or = 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.

Effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation.

PURPOSE: The aim of this study was to assess retrospectively the influence of prostate size and the effect of isotope selection on implant quality in patients undergoing transperineal ultrasound-guided permanent prostate brachytherapy. PATIENTS AND METHODS: Two hundred forty-eight consecutive patients without prior transurethral resection of the prostate gland underwent permanent seed implantation using either iodine 125 or palladium 103 as monotherapy or a boost following moderate doses of external-beam radiation therapy from January 1998 through November 1999. Postimplant dosimetry was obtained on day 0 using thin slice computed tomography (CT) scans. Dosimetric quality was reported in terms of the following parameters: D90, V100, V150, and V200, where D90 is defined as the minimum dose covering 90% of the prostate volume, and V100, V150, and V200 are defined as the percentage volume of the prostate receiving at least 100%, 150%, and 200% of the prescribed minimal peripheral dose (mPD), respectively. In addition, the urethral dose was evaluated. Preimplant prostate size was divided into the following categories: <20, 20-30, 30-40, 40-50, and >50 cm3. Prostate volume was determined via transrectal ultrasound volumetric study. In addition, within each of the five size categories, the effect of isotope on implant quality was evaluated. RESULTS: No statistically significant volume dependence in D90, V100, or urethral doses was discerned, whereas V150 and V200 were volume dependent. Between isotopes, the following differences in dosimetric quality were statistically significant: V100, V150, V200, and mean and medial urethral dose. 125I implants had higher values of V100 (95% vs. 94%, p = .004) and urethral dose (118% vs. 110% of mPD, p < .001), and 103Pd implants had higher V150 and V200 (57% vs. 51% and 31% vs. 22%, respectively). Only the isotopic differences in V200 persisted for all the volumetric subgroups. There was no significant overall volume dependence based on neoadjuvant hormone use or nonuse for any of the quality parameters analyzed. CONCLUSIONS: The most important indicators of the quality of dosimetric coverage, V100 and D90, were not dependent on preimplant prostate volume or use of neoadjuvant hormones. The mean, median, and maximum urethral doses also showed no dependence on prostate size. Although there were isotopic differences in day 0 dosimetric parameters following permanent prostate brachytherapy, we do not consider the magnitude of any of these differences to be clinically significant.

Five-year biochemical outcome following permanent interstitial brachytherapy for clinical T1-T3 prostate cancer.

PURPOSE: To evaluate 5-year biochemical disease-free outcome for men with clinical T1b-T3a NxM0 1977 American Joint Committee on Cancer (1997 AJCC) adenocarcinoma of the prostate gland who underwent transperineal ultrasound-guided permanent prostate brachytherapy. METHODS AND MATERIALS: Four hundred twenty-five patients underwent transperineal ultrasound-guided prostate brachytherapy using either 103Pd or 125I, for clinical T1b-T3a NxM0 (1997 AJCC) adenocarcinoma of the prostate gland, from April 1995 to October 1999. No patient underwent pathologic lymph-node staging. One hundred ninety patients were implanted with either 103Pd or 125I monotherapy; 235 patients received moderate-dose external beam radiation therapy (EBRT), followed by a prostate brachytherapy boost; 163 patients received neoadjuvant hormonal manipulation, in conjunction with either 103Pd or 125I monotherapy (77 patients) or in conjunction with moderate-dose EBRT and a prostate brachytherapy boost (86 patients). The median patient age was 68.0 years (range, 48.2-81.3 years). The median follow-up was 31 months (range, 11-69 months). Follow-up was calculated from the day of implantation. No patient was lost to follow-up. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology (ASTRO) consensus definition. RESULTS: For the entire cohort, the 5-year actuarial biochemical no evidence of disease (bNED) survival rate was 94%. For patients with low-, intermediate-, and high-risk disease, the 5-year biochemical disease-free rates were 97.1%, 97.5%, and 84.4%, respectively. For hormone-naive patients, 95.7%, 96.4%, and 79.9% of patients with low-, intermediate-, and high-risk disease were free of biochemical failure. Clinical and treatment parameters predictive of biochemical outcome included: clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, risk group, age > 65 years, and neoadjuvant hormonal therapy. Isotope choice was not a statistically significant predictor of disease-free survival for any risk group. The median postimplant PSA was < or = 0.2 for all risk groups, regardless of hormonal status. The mean posttreatment PSA, however, was significantly lower for men implanted with 103Pd (0.14 ng/mL) than for those implanted with 125I (0.25 ng/mL), p < or = 0.001. CONCLUSION: With a median follow-up of 31 months, permanent prostate brachytherapy results in a high probability of actuarial 5-year biochemical disease-free survival (DFS) for patients with clinical T1b-T3a (1997 AJCC) adenocarcinoma of the prostate gland, with an apparent plateau on the PSA survival curve.

Five-year biochemical outcome after prostate brachytherapy for hormone-naive men < or = 62 years of age.

PURPOSE: To evaluate 5-year biochemical disease-free outcome for hormone naïve men 62 years of age or less who underwent transperineal ultrasound-guided permanent prostate brachytherapy. METHODS AND MATERIALS: 76 patients underwent transperineal ultrasound guided prostate brachytherapy using either (103)Pd or (125)I for clinical T1b--T2b NxM0 (1997 AJCC) adenocarcinoma of the prostate gland from April 1995 to October 1999. No patient was lost to follow-up, and no patient underwent pathologic lymph-node staging. 47 patients were implanted with either (103)Pd or (125)I monotherapy, and 29 patients received moderate-dose external-beam radiation therapy followed by a prostate brachytherapy boost. No patient received hormonal manipulation. The median patient age was 58 years (range, 48--62 years). The median follow-up was 37 months (range, 14--70 months). Follow-up was calculated from the day of implantation. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology (ASTRO) consensus definition. RESULTS: The actuarial 5-year biochemical disease-free survival rate was 98.7%. For patients with low-, intermediate-, and high-risk disease, 97.7%, 100%, and 100%, respectively, were free of biochemical failure. The median posttreatment prostate-specific antigen (PSA) for the entire group was 0.2 ng/mL. When stratified by risk group, the median posttreatment PSA was 0.2, 0.15, and 0.1 for patients with low-, intermediate-, and high-risk disease, respectively. CONCLUSION: With a median follow-up of 37 months, hormone naïve patients < or = 62 years of age have a high probability of 5-year biochemical disease-free survival following permanent prostate brachytherapy with an apparent plateau on the PSA curve.

A comparison of radiation dose to the bulb of the penis in men with and without prostate brachytherapy-induced erectile dysfunction.

PURPOSE: To retrospectively evaluate the relationship between the radiation dose to the bulb of the penis and the development of erectile dysfunction (ED) in patients undergoing permanent prostate brachytherapy without external beam radiation therapy. METHODS AND MATERIALS: Twenty-three men who developed ED after transperineal ultrasound-guided permanent prostate brachytherapy for clinical T1/T2 adenocarcinoma of the prostate gland were paired with 23 similar men who maintained potency after implantation. Potency was defined as an erection sufficient for vaginal penetration. The mean and median follow-up for the entire group was 34.6 +/- 13.7 months and 32.8 months, respectively. Patients were implanted with either (125)I (145 Gy TG-43) or (103)Pd (115 Gy, pre-NIST-99). No patient received external beam radiation therapy either before or after brachytherapy. The bulb of the penis was outlined at 0.5-cm intervals on the Day 0 postimplant CT scan. The radiation dose distribution to the bulb of the penis was defined in terms of the minimal dose delivered to 25%, 50%, 70%, 75%, 90%, and 95% of the bulb (D(25), D(50), D(70), D(75), D(90), and D(95)). RESULTS: The radiation dose delivered to the bulb of the penis in men with postbrachytherapy-induced ED was statistically greater for all evaluated dosimetric parameters (D(25), D(50), D(70), D(75), D(90), and D(95)). Multivariate analysis indicated that dose to the bulb of the penis and patient age at the time of implant were predictive of postimplant ED, whereas choice of isotope had no effect. Among potent patients, 19/23 had D(50) < or = 40% of prescribed minimal peripheral dose, whereas for the impotent patients, 19/23 had D(50) >40% of the minimal peripheral dose. Of the impotent patients, 17 utilized sildenafil, with 15 experiencing a favorable response (88%). CONCLUSION: Our data suggest that prostate brachytherapy-induced impotence is highly correlated with the radiation dose delivered to the bulb of the penis. With Day 0 dosimetric evaluation, the radiation dose delivered to 50% of the bulb of the penis should be maintained at 50 Gy or less to maximize post-treatment potency. Fortunately, the majority of the brachytherapy-induced ED population responds favorably to sildenafil.

Relationship between the transition zone index of the prostate gland and urinary morbidity after brachytherapy.

OBJECTIVES: To evaluate whether urinary symptomatology after prostate brachytherapy is related to the preimplant transition zone index (TZI = transition zone volume/prostate gland volume). METHODS: A total of 170 consecutive patients without a prior history of transurethral resection of the prostate gland (TURP) underwent transperineal ultrasound-guided prostate brachytherapy for clinical T1c-T3a carcinoma of the prostate gland. Prostate gland and transition zone dimensions and volumes were measured by prolate ellipsoid calculation from the static ultrasound images. The relationship between TZI and various measures of urinary dysfunction including normalization of International Prostate Symptom Scores (IPSS), catheter dependency, the need for a subsequent TURP, and the duration of alpha-blocker dependency were evaluated. Additional clinical parameters evaluated included the relationship between TZI and patient age, clinical T stage, prostate ultrasound volume, neoadjuvant hormonal manipulation, and preimplant IPSS. For all indices of urinary dysfunction other than serial IPSS, the median patient follow-up was 89.3 weeks. The median follow-up for serial IPSS evaluations was 37.3 weeks with a mean of 11.2 questionnaires per patient. RESULTS: The mean TZI for the 170 patients was 0.23 +/- 0.06 (prostate gland volume 30.3 +/- 8.7 cm(3), transition zone volume 7.3 +/- 3.6 cm(3)). The TZI correlated with the time for IPSS normalization, the maximum IPSS after brachytherapy, and the maximum increase in IPSS. Conversely, the TZI did not correlate with either catheter dependency or alpha-blocker dependency. Two of 170 patients (1.2%) required a postimplant TURP. The TZI in these 2 patients (0.34) was statistically different (P = 0.016) from the mean. CONCLUSIONS: In prostate brachytherapy patients, the preimplant TZI predicted the need for a subsequent transurethral resection. The TZI also correlated with multiple variants of IPSS. Conversely, TZI did not correlate with either catheter dependency or alpha-blocker dependency.

Is brachytherapy comparable with radical prostatectomy and external-beam radiation for clinically localized prostate cancer?

PURPOSE: The aim of this study was to summarize the prostate brachytherapy literature and provide a comparative analysis of brachytherapy, radical prostatectomy, and external-beam radiation therapy outcomes for early-stage carcinoma of the prostate gland. MATERIALS AND METHODS: Published literature on brachytherapy, radical prostatectomy, and external-beam radiation therapy for clinically localized carcinoma ofthe prostate gland was reviewed. In addition, MEDLINE searches were performed to ensure completeness of the knowledge base. RESULTS: For patients with low-risk features, the biochemical results of prostate brachytherapy are as favorable as the most positive radical prostatectomy and external-beam radiation therapy series. In most studies, patients with intermediate- and high-risk disease have more durable biochemical outcomes when treated with brachytherapy (with or without external-beam radiation therapy). Long-term urinary morbidity is primarily restricted to patients with a history of transurethral resection. Significant bowel dysfunction is uncommon. Although erectile dysfunction occurs in approximately 50% of patients at 5 years, 80% respond favorably to sildenafil. Multiple postoperative dosimetric studies supported the ability of brachytherapists to adequately encompass the target volume. Compared with radical prostatectomy and external-beam radiation therapy, the total cost of prostate brachytherapy is 20% less. CONCLUSIONS: With prostate-specific antigen-based follow-up as long as 10 years, the results of prostate brachytherapy for low-risk patients are as favorable as the most positive radical prostatectomy and external-beam radiation therapy series. In most reports, intermediate- and high-risk patients have more durable biochemical outcomes when managed by brachytherapy approach (with or without external-beam radiation therapy). Serious complications following brachytherapy are relatively rare.

Utilization of a self-administered questionnaire to assess rectal function following prostate brachytherapy.

A sample of 209 consecutive prostate brachytherapy patients completed a self-administered questionnaire to evaluate bowel changes following treatment. With a median followup of 28 months, less than 20% of patients reported deterioration in bowel function.

A comparison of radiation dose to the neurovascular bundles in men with and without prostate brachytherapy-induced erectile dysfunction.

PURPOSE: The etiology of erectile dysfunction after definitive local therapy for carcinoma of the prostate gland represents a multifactorial phenomenon including neurogenic compromise, venous insufficiency, local trauma, and psychogenic causes. It has been suggested that impotence after prostate brachytherapy is a consequence of excessive radiation dose to the neurovascular bundles (NVB). Herein we evaluate the potential relationship between radiation dose to the NVB and the development of erectile dysfunction following prostate brachytherapy. METHODS AND MATERIALS: The radiation dose to the NVB was evaluated for 33 patients who developed erectile dysfunction (ED) following brachytherapy plus 21 additional patients who were potent before and subsequent to brachytherapy. Of the 54 patient study group, the median follow up was 37 months, and 25 patients were managed with (125)I as a monotherapeutic approach and 29 received (103)Pd as a boost following 45 Gy of external beam radiation therapy. Radiographic localization of the NVB was performed via a two-dimensional geometric model that placed 3-NVB calculation points on the left and right posterolateral side of each 5-mm CT slice. Parameters evaluated included dose-surface histograms, dose parameters via point doses on each slice, the magnitude of the dose in relationship to the distance from the base, and the relationship between NVB radiation dose in patients with and without ED, patient response to sildenafil and case sequence number. RESULTS: In terms of percent prescribed minimum peripheral dose (% mPD), there was no significant difference in mean neurovascular bundle dose between potent and impotent patients, between the isotopes ((125)I or (103)Pd), mono- or boost therapy, or side of the prostate for which the overall average was 217% +/- 55% of mPD. There was also no significant dosimetric difference in terms of response to sildenafil based on a multivariate analysis which included % mPD and various dose thresholds and side of the gland. The dose distribution over the length of the prostate rose smoothly from the base and apex to peak at midgland in (125)I implants while (103)Pd implants had a relatively constant dose over the length of the prostate. Considering the calculation grid as forming a 6-mm wide ribbon along each side of the prostate, the average patient had 70 mm(2) area receiving at least 300% of mPD. CONCLUSION: In this study, no relationship between radiation dose to the NVB and the development of post brachytherapy erectile dysfunction was discernible. Such a difference may become evident with additional follow-up. If long-term brachytherapy-induced erectile dysfunction is related to the radiation dose to the NVB, the ultimate preservation of potency following prostate brachytherapy may be markedly inferior to what has been reported. Nevertheless, the majority of this patient population responded favorably to sildenafil.

Rectal function following prostate brachytherapy.

PURPOSE: Quality of life following therapeutic intervention for carcinoma of the prostate gland has not been well documented. In particular, a paucity of data has been published regarding bowel function following prostate brachytherapy. This study evaluated late bowel function in 209 consecutive prostate brachytherapy patients via a one-time questionnaire administered 16-55 months postimplant. MATERIALS AND METHODS: Two hundred nineteen consecutive patients underwent permanent prostate brachytherapy from April 1995 through February 1998 using either (125)I or (103)Pd for clinical T1c-T3a carcinoma of the prostate gland. Of the 219 patients, 7 had expired. Of the remaining 212 patients (median follow-up, 28 months), each patient was mailed a self-administered questionnaire (10 questions) with a prestamped return envelope; 209 (98.6%) surveys were returned. Clinical parameters evaluated for bowel dysfunction included patient age, diabetes, hypertension, history of tobacco consumption, clinical T-stage, elapsed time since implant, and prostate ultrasound volume. Treatment parameters included utilization of neoadjuvant hormonal manipulation, utilization of moderate dose external beam radiation therapy prior to implantation, choice of isotope ((125)I vs. (103)Pd), rectal dose (average, median and maximum doses), total implanted seed strength, values of the minimum dose received by 90% of the prostate gland (D(90)), and the percent prostate volume receiving 100%, 150%, and 200% of the prescribed minimum peripheral dose (V(100), V(150) and V(200), respectively). Because detailed baseline bowel function was not available for these patients, a cross-sectional survey was performed in which 30 newly diagnosed prostate cancer patients of comparable demographics served as controls. RESULTS: The total rectal function scores for the brachytherapy and control patients were 4.3 and 1.6, respectively, out of a total 27 points (p < 0.001). Of the evaluated clinical parameters, only the preimplant number of bowel movements per day were correlated with the total survey score (p < 0.01). None of the treatment parameters were significantly correlated with the total survey score. Despite the fact that implantation with (103)Pd resulted in lower radiation doses to the rectum, the choice of isotope was not predictive of bowel function scores. A trend toward increased rectal scores was noted for older patients, and a nonsignificant improvement in rectal survey scores was noted with elapsed time from implantation. Only 19.2% (40/208) of the treatment group reported a worsening of bowel function following implantation. Patient perception of overall rectal quality of life, however, was inversely related to the utilization of external beam radiation therapy (p = 0.034). CONCLUSION: To date, no severe changes in late bowel function have been noted following prostate brachytherapy. Although the survey scores indicate bowel function is worse after an implant, the minor changes are not significant enough to bother most individuals. Less than 20% of patients reported that their bowel function was worse following prostate brachytherapy.

Modern prostate brachytherapy.

As computer-aided margin tools become more sophisticated, physicists will be increasingly called upon to convert ultrasound prostate volumes to expanded planning target volumes (PTVs) to treat adequately extracapsular disease. The American Association of Physicists in Medicine Task Group 43 formalism and the new National Institute of Standards and Technology calibration system suitable for single low-energy seeds have been crucial in smoothly implementing changes in established seeds and in incorporating data from new manufacturers. However, the lack of consensus on treatment design and evaluation has led to an uncomfortably wide spectrum of clinical practice, only part of which can be attributed to variations inherent to any surgical procedure due to the practitioner's skill. The relative merits of implanting the prostate and margin with a modified uniform seed-loading approach to create plans with a relatively homogeneous dose distribution and a corresponding low risk of overdosing critical structures are addressed. Likewise, the advantages of performing postoperative dosimetry at the physically optimum time of greater than 2 weeks post implant are contrasted with the clinical advantages of obtaining the dosimetry as soon as possible. Proposed lower limits for quality parameters such D90 and V100 are reviewed. Measures of doses to the urethra, rectum, and neurovascular bundles are presented, along with correlations between various dosimetric parameters and other patient specific data with quality of life metrics involving urinary incontinence, rectal damage, and sexual dysfunction.

Isotope choice and the effect of edema on prostate brachytherapy dosimetry.

In prostate brachytherapy, post implant dosimetry quality parameters may be strongly affected by edema brought on by the trauma of the implant procedure since the amount of edema and the time course of its resolution are highly variable from patient to patient. Edema was simulated from preplans on three prostates which had ultrasound prostate volumes of 18.7, 40.7 and 60.2 cm3 expanded to planning volumes of 32.9, 60.0 and 87.8 cm3, respectively. The preplans were designed so that identical seed distributions for a given prostate gave virtually identical target dose coverage of 99.7+/-0.3% of the planning volume when using either 125I or 103Pd. Simulated CT edema volume expansions of 0%, 10%, 20% and 30% were imposed anisotropically in accordance with clinical observations so that the expansion in the superior-inferior direction was twice that of the transverse dimensions. Dose-volume histograms (DVHs) were analyzed for each prostate as a function of isotope and degree of edema. The 103Pd implants were more greatly affected by fixed amounts of edema than 125I implants, and the slopes of the DVH curves indicate less homogeneity from 103Pd implants. The DVHs were then weighted according to the portion of the isotope decay curve occupied by each edema step for half-lives of edema resolution of 5, 10 and 20 days which are within the range of clinically observed resolution times. The weighted DVHs were summed to give a net DVH corresponding to the overall dynamic effect of edema. A greater fraction of the defined prostate volume received doses in the range of likely therapeutic significance, from 75% to 125% of the prescribed minimal peripheral dose (mPD), from 125I implants than from 103Pd implants. These differences in dosimetric quality arise from two differences in the physical properties of the isotopes: more rapid attenuation of 103Pd photons with distance creates cool spots in an edematous prostate, and the shorter half-life of 103Pd causes a greater fraction of the isotope decay to consist of the prostate in an edematous state. An increase in 103Pd seed strength by about 10% beyond that required to achieve equal coverage with an identical seed distribution using 125I should minimize the differences brought on by edema.

Influence of prophylactic dexamethasone on edema following prostate brachytherapy.

PURPOSE: This work evaluates the prophylactic administration of dexamethasone as an adjunct to prostate brachytherapy to determine the effect of dexamethasone on postimplant edema, dosimetric quality, catheter dependency, and clinical outcome as assessed by serial American Urological Association (AUA) symptom score determinations. MATERIALS AND METHODS: In a controlled study, 22 unselected patients were placed alternately into either a dexamethasone or control arm. RESULTS: There was no statistically significant difference in volume between the experimental and control groups on either day 0 or day 28. Accordingly, the day 0 dosimetric parameters, short-term catheter dependency, and serial AUA symptom score determinations were equivalent in both patient groups. However, the patients receiving dexamethasone had a markedly smaller volume on day 3, but 9 of 11 experienced rebound edema with a volume on day 14 significantly greater than day 3. CONCLUSIONS: Because of the small number of patients evaluated, additional studies are essential to confirm these findings. At the present time, we do not recommend this dexamethasone schedule as a routine component of prostate brachytherapy.

Temporal resolution of urinary morbidity following prostate brachytherapy.

PURPOSE: To report the short-term urinary morbidity for prostate brachytherapy patients without a preimplant history of a transurethral resection of the prostate gland and who received prophylactic and prolonged alpha-blockers. alpha-blockers may decrease radiation-induced urethritis and increase urinary flow. Multiple clinical and treatment parameters were evaluated to identify factors associated with increased acute urinary morbidity. MATERIALS AND METHODS: One hundred seventy consecutive patients without a prior history of a transurethral resection of the prostate gland underwent transperineal ultrasound guided prostate brachytherapy for clinical T1c-T3a carcinoma of the prostate gland. For all patients, an alpha-blocker was initiated prior to implantation and continued at least until the international prostate symptom score (IPSS) returned to baseline levels. Clinical parameters evaluated for short-term urinary morbidity included patient age, clinical T stage, preimplant IPSS (obtained within 3 weeks of implantation), and prostate ultrasound volume. Treatment parameters included the utilization of neoadjuvant hormonal manipulation, the utilization of moderate dose external beam radiation therapy before implantation, the choice of isotope, the urethral dose, the total implant activity in millicuries, and a variety of dosimetric quality indicators (D(90) and V(100)/V(150)/V(200)). Catheter dependency and the duration of alpha-blocker dependency was also evaluated. On average, 11.2 IPSS surveys were obtained for each patient. RESULTS: One hundred fifty of the 170 patients (88.2%) had the urinary catheter permanently removed on day 0. Only one patient required an urinary catheter for > 5 days. Two patients (1.2%) required a subsequent transurethral resection of the prostate gland because of prolonged obstructive/irritative symptoms. To date, no patient has developed an urinary stricture or urinary incontinence. The IPS score on average peaked at 2 weeks following implantation. This score returned to within 1 point of the antecedent value at a median of 6 weeks and a mean of 13.3 weeks. At 26 and 50 weeks, 85% and 56% of the patients, respectively, continued with alpha-blockers. Of the clinical and treatment parameters evaluated for short-term urinary morbidity, only variants of the IPSS such as the maximum, maximum increase, and preimplant IPSS values correlated with time to return to the referent zone with p < 0.05. CONCLUSION: The return of the IPS score to baseline occurred more rapidly in our series than what has previously been reported. The 1.2% incidence of transurethral resections also compares favorably with the published literature. We believe these results may be due to maintaining the average urethral dose to approximately 115% of the prescribed dose and the prophylactic and long-term use of alpha-blockers.

Radioactive seed embolization to the lung following prostate brachytherapy.

Over the past decade, prostate brachytherapy has been increasingly utilized as definitive management for early stage carcinoma of the prostate gland. One risk of the procedure is pulmonary seed embolization. In this article we report the incidence and timing of seed migration. Pulmonary embolization of radioactive seeds occurs in approximately 20% of patients undergoing prostate brachytherapy. To date, no acute or delayed detrimental effects have been reported which are attributable to the pulmonary embolization of the seeds; nevertheless, it is imperative that patients and health care providers be cognizant of this possible event.

Comparison of seed loading approaches in prostate brachytherapy.

Since uniform seed loading in prostate brachytherapy can produce an intolerably high dose along the urethra, some form of peripheral loading is commonly employed. We define three variants of peripheral loading and compare them in a small, medium, and large prostate in terms of coverage of the planning target volume (PTV), homogeneity, and ability to spare critical structures of excessive dose. Modified uniform loading has at least 2/3 of the seeds occupying sites on a 1 cm cubic grid keyed to the prostate base and the posterior border of the prostate. Nonuniform loading explicitly spares the urethra by using only basal and apical seeds in at least two centrally located needles. Peripheral loading uses higher activity seeds with the posterior implant plane 5 mm anterior to the posterior border of the prostate. The three prostate volumes (18.7, 40.7, and 60.2 cm3 by ultrasound) were expanded to planning volumes (32.9, 60.0, and 87.8 cm3, respectively). The planning volumes (PTVs) were loaded with a 125I seed distribution and activity sufficient to cover 99.7+/-0.3% of the PTV with the prescribed minimal peripheral dose (mPD) of 145 Gy. Activities used ranged from 0.32 to 0.37 mCi/seed (0.41-0.47 U/seed) for the first two approaches and from 0.57 to 0.66 mCi (0.72-0.84 U) for peripheral loading. Modified uniform loading produced the most uniform distribution based on dose-volume histograms and the volume receiving >150% of prescribed dose. All the approaches are capable of constraining the superior-inferior dose profile (the urethral path) to less than 150% of the mPD, but the nonuniform approach with explicit urethral sparing kept the urethral dose below 120% of the mPD. Dose profiles for the three approaches along the posterior-anterior midline axis are comparable near the urethra, but peripheral and nonuniform approaches have extended regions where the dose is >150% of mPD. These regions approach within 10 mm of the rectum or urethra, so these two approaches require greater accuracy in intraoperative execution of the plan. Although each of the three planning approaches can achieve the treatment goals of adequate coverage and critical structure sparing, modified uniform loading has a more homogeneous dose distribution. This approach may be more forgiving of systematic errors in seed placement.

Seed fixity in the prostate/periprostatic region following brachytherapy.

PURPOSE: Although postoperative dosimetric analyses of prostate brachytherapy are commonly reported, the long-term persistence, or fixity, of seeds implanted in the prostate gland and periprostatic region remains unclear, with only a few reports regarding the loss or migration of the seeds in the implanted region and none which correlate lung embolization to pelvic seed loss. METHODS AND MATERIALS: The study population consisted of 175 consecutive patients implanted with either 125I (95 patients) or 103Pd (80 patients) using a mean of 136 seeds in a modified uniform loading approach to cover a planning volume that was 1.64 times the ultrasound prostate volume. An average of 64% of 125I seeds were embedded in braided vicryl suture, and these seeds were used on the periphery and extra prostatic regions. Following CT-based dosimetric analysis on day 0, all patients had orthogonal plain films of the pelvis obtained from day 0 to day 502, with an average of 2.3 film pairs per patient. Routine diagnostic PA and lateral chest X rays were obtained for 156 patients over the same time period. RESULTS: The mean pelvic seed fixity was greater than 98% throughout the time covered by this study. The seed fixity rates for 125I and 103Pd, although nearly equal, were significantly different up to 60 days post implant. The median 125I seed loss per patient was only 1 seed through 180 days while for 103Pd, the median seed loss was 2 seeds at 28 and 60 days and 3 seeds at 180 days. The fraction of patients experiencing no seed loss decreased from 40% at 28 days to 20% at 180 days for 125I and from 24% to 7% for 103Pd over the same time interval. Patient and treatment parameters closely correlated to local seed loss include the number of seeds implanted, the planning volume, and the number of loose seeds, and for 125I, the fraction of seeds in suture. The fraction of seeds placed outside the gland was not correlated with seed loss. Of the seeds lost from the pelvis, about 10% were found to embolize to the lungs. Among the 156 patients with post-implant chest X rays, the fraction of patients with pulmonary seed embolization was 34/156 (21.8%). Of the 20 patients who had post-implant chest X rays obtained within 14 days of brachytherapy, none had seeds detected in the lungs, while of the 136 patients who had chest X rays obtained greater than 30 days following implantation, 25.0% (34 patients) were noted to have seeds visualized in the lungs. CONCLUSIONS: With a median follow-up of 9 months, 125I seeds embedded in a vicryl suture or 103Pd seeds can be safely implanted in the prostate and periprostatic tissue with a high probability of prostate bed seed fixity and a low incidence of radioactive seed embolization to the lungs.