[en] Purpose: To determine the etiology of treatment-induced erectile dysfunction among patients who underwent surgery or radiotherapy for prostatic cancer. Methods and Materials: Ninety-eight patients were evaluated for erectile dysfunction after definitive therapy for prostate cancer with Duplex ultrasonography before and after intracorporal prostaglandin injection. Patients were classified as having arteriogenic, cavernosal, mixed (arteriogenic/cavernosal), or neurogenic impotence based upon the results of the Duplex studies. Results: Among patients who underwent radical prostatectomy (RP), 31 (52%) had cavernosal dysfunction, 19 (32%) had arteriogenic dysfunction, 3 (5%) were classified as mixed, and 7 (12%) as neurogenic dysfunction. Among patients treated with radiotherapy (RT), 24 (63%) had arteriogenic dysfunction, 12 (32%) had cavernosal dysfunction, 1 (2.5%) were classified as mixed, and 1 (2.5%) as neurogenic dysfunction. A multivariate analysis identified prior RT as the only predictor of an arteriogenic etiology (p < 0.001) and prior RP as the only predictor of a cavernosal etiology (p < 0.04) for erectile dysfunction among these patients. In the RP and RT groups, the median erectile responses were 70 and 65%, respectively. Arterial peak flows <25 cc/min predicted for a suboptimal erectile response with intracavernosal prostaglandin injections. Among 47 patients with arterial peak flows <25 cc/min, 21 (55%) had erectile responses of <70%, while for 51 patients with arterial peak flows ≥25 cc/min, 31 (39%) had erectile responses of <70% (p < 0.039). Conclusions: While the etiology of erectile dysfunction after definitive therapy for prostatic cancer is likely a multifactorial phenomenon, these data suggest that the predominant etiology among patients who undergo RT is arteriogenic and among patients who undergo RP is veno-occlussive/cavernosal pathology. This information may have implications for the design of more effective therapies to address erectile dysfunction in this patient population

[en] Purpose: Several reports have documented the prognostic value of a post-irradiation nadir PSA of ≤1 ng/ml in prostatic cancer patients. The purpose of this study was to determine which pre-treatment and treatment-related variables impact upon achieving such nadir levels. Materials and Methods: Between January 1987 and June 1995, 740 patients with clinically localized prostate cancer were treated with 3-dimensional conformal radiotherapy (3D-CRT). 214 (29%) patients were treated with neo-adjuvant androgen ablation prior to therapy and were excluded from this analysis. Among the 526 evaluable patients, the clinical stage were as follows: T₁C=128 (24%); T₂A=76 (14%); T₂B=116 (22%); T₂C=99 (19%) and T₃=107 (21%). The prescription dose to the planning target volume (PTV) was 64.8-68.4 Gy in 87 patients (17%); 70.2 Gy in 191 (36%); 75.6 Gy in 209 (40%) and 81 Gy in 39 (7%). The median pre-treatment PSA value was 11.2 ng/ml (range 0.3-114). The median follow-up was 20 months (range: 6-76 months). Results: 242 patients (46%) had PSA levels which declined to ≤1.0 ng/ml. The median time to a nadir level of ≤1.0 was 15.6 months (range: 1-43 months) from completion of 3D-CRT. 154 (29%) patients continued to show declining PSA levels within the first 2 years after therapy, and 130 patients (25%) failed to nadir at PSA levels of ≤1.0 ng/ml. Among patients with nadir PSA levels ≤1, the 3 year PSA relapse-free survival was 91% compared to 29% for patients with nadir PSA levels >1 ng/ml (p<0.0001). A Cox-regression analysis demonstrated that nadir PSA ≤1 was the strongest predictor of PSA relapse-free survival (p<0.001) followed by Gleason score ≤ 6 (p<0.001) and stage< T3 (p=0.004). Among patients who received doses of ≥75.6 Gy, the likelihood of achieving PSA nadir levels ≤1.0 at 24 and 36 months was 86% and 93%, respectively, compared to 74 and 80%, respectively, among those who received lower doses (p<0.001). Doses of ≥75.6 Gy was the strongest independent predictor for a nadir PSA level of ≤1.0 (p<0.001) followed by pre-treatment PSA levels ≤10 ng/ml (p<0.001) and stage (p=0.01), while the Gleason score had no significant impact. Conclusion: Nadir PSA levels of ≤ 1.0 ng/ml after radiotherapy for localized prostate cancer is the strongest predictor of PSA relapse-free survival. Higher radiation doses are associated with an increased likelihood of achieving post-treatment nadir PSA levels of ≤1.0 ng/ml. Further follow-up is needed to determine whether higher doses will also translate into improved long-term outcome for these patients

[en] Purpose: Three-dimensional conformal radiotherapy (3D-CRT) has been associated with a reduction in acute and late toxicity among patients treated for localized prostatic cancer. The purpose of this study is to assess the acute and late toxicity of 3D-CRT delivered to patients in the postprostatectomy setting and to analyze which factors predict for durable biochemical control in this group of patients. Methods and Materials: Between 1988 and 1994, 42 patients were treated after prostatectomy with three-dimensional conformal radiotherapy. The median time from prostatectomy to radiotherapy was 11 months. Indications for treatment included a rising serum PSA level in 28 patients (65%) and positive surgical margins without a rising PSA level in 14 (35%). Twenty-five patients (60%) had pathologic stage T3 disease, and 32 (74%) had tumor at or close to the surgical margins. The median dose was 64.8 Gy, and the median follow-up time was 2 years. Results: 3D-CRT in the postprostatectomy setting was well tolerated. Three patients (7%) experienced Grade II acute genitourinary toxicity and nine patients (21%) experienced Grade II acute gastrointestinal toxicity during treatment. No patient experienced Grade III or higher acute morbidity. The 2-year actuarial risk for Grade II late genitourinary and gastrointestinal late complications were 5 and 9%, respectively. In patients with existing incontinence, the incidence of worsening stress incontinence 6 months after treatment was 17%, which resolved within 12 months to its preradiotherapy level in four of six cases (66%). The overall 2-year postirradiation PSA relapse-free survival rate was 53%. The 2-year PSA relapse-free survival was 66% for patients with undetectable PSA levels in the immediate postoperative period compared to 26% for those with detectable levels of PSA after surgery (p < 0.006). Furthermore, for patients with preradiotherapy PSA levels of ≤1.0 ng/ml, the 2-year PSA relapse-free survival was 74% compared to 17% of those with preradiotherapy PSA levels of >1.0 ng/ml (p < 0.002). The resection margin status, presence of seminal vesicle involvement, Gleason score, and the preprostatectomy PSA level did not impact on PSA relapse-free survival. A cox proportional hazards regression analysis demonstrated that a preradiotherapy PSA value of >1 ng/ml (p < 0.002) was the most important covariate predicting for a rising PSA after radiotherapy. Conclusions: After prostatectomy, three-dimensional conformal radiotherapy is associated with minimal treatment-related morbidity. Patients with postprostatectomy, preradiotherapy PSA levels ≤ 1.0 ng/ml, and those patients who had undetectable PSA levels in the immediate postoperative period are more likely to benefit from local adjuvant therapy

[en] Purpose: To determine the efficacy of an alpha-1 adrenoreceptor blocking agent for acute urinary symptoms in patients treated with radiotherapy for localized prostate cancer. Methods and Materials: Between 1987 and 1995, 743 patients with clinically localized prostate cancer were treated with 3D-CRT. A total of 275 (37%) patients developed Grade 2 acute urinary symptoms as defined by the RTOG morbidity scoring system. Terazosin hydrochloride (THC), a selective alpha-1 adrenoceptor blocking agent, was given to 119 (43%) patients for treatment of their urinary symptoms, whereas nonsteroidal anti-inflammatory medications (NSAID) were administered to 71 patients (26%). Thirty-one patients (11%) were treated with other medications, and 54 (20%) did not seek pharmacologic intervention for their urinary symptoms. Patients were monitored weekly to assess changes in urinary urgency, frequency, and nocturia. Results: Treatment with THC resulted in a significant resolution of urinary symptoms in 79 of 119 patients (66%), while 26 (22%) had moderate improvement, and 14 (12%) had minimal to no response to this drug. In contrast, only 11 of 71 (16%) of the patients treated with NSAIDs experienced significant symptom relief, 20 (28%) had moderate improvement, and 40 (56%) had minimal to no response. The difference in the significant symptomatic improvement between THC and NSAID therapy (66% vs. 16%) was highly significant (p < 0.001). For patients treated with THC, a higher likelihood of significant symptom relief was observed in patients who did not receive neoadjuvant androgen ablation (p = 0.04) and in those who were younger than 65 years of age (p = 0.02). Conclusion: Alpha-1 selective adrenoceptor blocking agents are effective in ameliorating the acute urinary symptoms in patients receiving radiotherapy for localized prostate cancer. Although this was not a randomized prospective study, the data suggest that NSAIDs were less effective in relieving radiation-induced urinary symptoms

[en] Purpose: We have previously shown that adjuvant brachytherapy (BRT) improves local control in soft tissue sarcoma (STS) of the extremity and superficial trunk. A detailed assessment of the morbidity of this approach has not been examined. The purpose of this study was to evaluate the toxicity associated with adjuvant BRT in terms of wound complications, bone fracture, and peripheral nerve damage. Methods and Materials: Between July 1982 and June 1992, 164 adult patients with STS of the extremity or superficial trunk were randomized intraoperatively to receive or not to receive BRT after complete resection. BRT was delivered with ¹⁹²Ir to a total dose of 42-45 Gy. The BRT and no-BRT arms were balanced with regard to age, sex, presentation (primary vs. recurrent), site, grade, size, and depth. Morbidity was assessed in terms of significant wound complication, bone fracture, and peripheral nerve damage (grade ≥ 3). The significant wound complications were defined as those wound problems requiring operative revision for coverage or threatened limb loss, persistent seroma requiring repeated aspirations and/or drainage, wound separation > 2 cm, hematoma > 25 ml, and/or purulent wound discharge. The median follow-up was 100 months. Results: The significant wound complication rate was 24% in the BRT group and 14% in the no-BRT group, (p = 0.13). The rate of wound reoperation, however, was significantly higher in the BRT arm (10% vs. 0%; p = 0.006). Examination of other covariables that may have contributed to wound reoperation revealed the width of the excised skin (WES) to be a significant factor [1% (WES ≤ 4 cm) vs. 10% (WES > 4 cm), p = 0.02]. Bone fracture only occurred in patients receiving BRT (n = 3, 4%), although this was not statistically significant (p = 0.2). The rate of peripheral nerve damage, however, was similar in both arms (7% vs. 7%). Conclusion: The overall morbidity associated with adjuvant BRT was not significantly higher than that with surgery alone. However, BRT and WES > 4 cm were associated with significantly higher wound reoperation rate. This has significant implications for strategies designed to maximize wound coverage in patients who receive BRT

[en] Purpose: The objective of this report is to re-evaluate the role of the Anderson nomograms in treatment planning for permanent prostate implants. The incentive for revisiting this topic concerns three issues: (1) Although nomograms continue to be used in many centers for ordering seeds, few centers use them during treatment planning; (2) Whereas nomograms were designed to deliver a minimum peripheral dose for a uniform distribution of seeds in the gland, many practitioners use peripheral seed loading patterns to reduce urethral toxicity; and (3) As preoperative and intraoperative treatment planning is becoming standard, the apparent role of nomograms is diminished. The nomogram method is reviewed in terms of: (1) total activity predicted, (2) target coverage (as planned in the operating room and as calculated from postimplant computed tomography studies), and (3) reproducibility (i.e., patient-to-patient and planner-to-planner variability). In each case, the computer-optimization system for intraoperative planning currently in use at our institution was taken as the 'gold standard'. Methods and Materials: We compared for the same patient the results of nomogram planning to those yielded by genetic algorithm (GA) optimization in terms of total activity predicted (n=20 cases) and percent target coverage (n=5 cases). Furthermore, we examined retrospectively the dosimetry of 61 prostate implants planned with the GA (n=27) and the current implementation of Anderson nomograms (n=34). Results: Nomogram predictions of the total activity required are in good agreement (within 10%) with the GA-planned activity. However, computer-optimized plans consistently yield superior plans, as reflected in both pre- and postimplant analyses. We find also that user (specifically, treatment planner) implementation of the nomograms may be a major source of variability in nomogram planning - a difficulty to which robust computer optimization is less prone. Conclusions: Nomograms continue to be useful tools for predicting the total required activity for volume implants, and thus for performing an independent check of this quantity. Not unexpectedly, computer optimization remains the preferred planning method. Generally, nomogram-guided implants do not incorporate structures other than the treatment volume into the planning process. Further yet, they deliver a lower dose than that prescribed and result in greater variability among plans than computer-optimized treatments. In summary, nomograms (1) remain an efficient quality assurance tool for computer-generated plans, (2) serve as a good predictor of the number of seeds required for ordering purposes, and (3) provide a simple and dependable backup planning method in case the intraoperative planning system fails

[en] Over the last 20 years it has become well recognized that higher radiation dose levels are critical for tumor ablation among patients with localized prostate cancer. From single institution prospective dose escalation studies to randomized trials, the evidence demonstrates improved PSA free survival outcomes reflecting enhanced local tumor control. The long-term results of the Phase III ASCENDERT trial demonstrated that among higher risk patients, further escalation of the radiation dose accomplished with a combination of brachytherapy and external beam radiotherapy was associated with a superior PSA-free survival outcome at 9 years compared to outcomes of patients treated with a dose-escalated of regimen of external beam radiotherapy of 78 Gy. Brachytherapy has an important advantage given its biologic characteristics of high- dose deposition near the tumor providing the opportunity for focal dose intensification associated with exquisite conformality. Indeed, there is a greater degree of dose heterogeneity with implanted volumes where high dose regions can be easily shifted toward dominant regions of disease. Dose levels of 150-300% of the prescription dose can be delivered with reduced exposure to surrounding normal tissues compared to external beam techniques. (author)

[en] Purpose: To report the 5-year prostate-specific antigen (PSA) relapse-free survival outcome and incidence of long-term morbidity for patients with localized prostate cancer treated with CT-planned permanent I-125 prostate implantation using a transperineal technique (TPI). Methods and Materials: Between 1989-1996, 248 patients with clinically localized prostate cancer were treated with TPI. The median age was 65 years (range: 45-80 years). The clinical stage was T1c in 143 patients (58%), Stage T2a in 102 (41%), and T2b in 3 (1%). Thirty patients (12%) had Gleason scores <6, 158 patients (64%) had Gleason scores of 6, and 60 (24%) had scores ≥7. The median pretreatment PSA was 7 ng/mL (range: 1-58 ng/mL). The median prescribed implant dose was 150 Gy. Patients were characterized as having favorable risk disease if their pretreatment PSA level was ≤10.0 ng/mL and Gleason score ≤6; those with one and two adverse prognostic features (PSA > 10 ng/mL and Gleason score >6) were classified as having intermediate and unfavorable risk disease, respectively. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was scored according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up was 48 months (range: 12-126 months). Results: Thirty-eight patients (15%) developed a PSA relapse, and the overall 5-year PSA relapse-free survival (PRFS) rate was 71%. The 5-year PRFS rates for favorable-risk (n = 146), intermediate-risk (n = 85), and unfavorable-risk (n = 17) patients were 88%, 77%, and 38%, respectively (p < 0.0001). The 5-year PRFS rates among patients treated with a 2-month course of neoadjuvant androgen deprivation (NAAD) prior to TPI compared to patients treated with TPI only were 100% and 77%, respectively (p = 0.03). Multivariate analysis identified pretreatment PSA > 10 ng/mL and Gleason score >6 as independent predictors for biochemical relapse after TPI. The 5-year actuarial likelihood of late Grade 2 urinary toxicity was 41%. The 5-year likelihood of urethral stricture development was 10%, and the median time to stricture development was 18 months. One patient (0.4%) in the early phase of this clinical experience developed a Grade 4 urethral complication. The actuarial incidence of late Grade 2 rectal bleeding was 9%. One patient (0.4%) developed a Grade 4 rectal complication. Conclusions: Especially for favorable risk disease, the 5-year biochemical outcome with this approach was excellent and appears to be comparable to other therapeutic interventions. Grade 2 urinary symptoms were common in these patients but gradually resolved in most. Improved treatment planning approaches that further constrain the urethral dose without compromising the target volume dose will likely decrease the incidence of Grade 2 and 3 urinary symptoms after TPI

[en] Purpose: We describe a method of incorporating organ motion into three-dimensional (3D) conformal treatment plans, which predicts the effect of organ motion on the calculated dose to both the clinical target volume (CTV) and nontarget organs. Methods and Materials: The method is based on measurements of organ motion by means of multiple computed tomography (CT) scans from a group of 'reference' patients, in which the data consist of previously drawn contours of the target and nontarget organs. A computer program records the differences in contour position and shape that occur between scans in the reference data, and according to those differences adjusts the contours and dose calculation points of a 'study' patient currently being planned, thus simulating organ motion. Dose-volume histograms (DVHs) are accumulated, and the process is repeated over the set of reference patient scans, resulting in a set of treatment plans that are ranked according to a dose-based endpoint. Two plans are selected corresponding to specified lower and upper confidence limits in the endpoint, and the DVHs from these plans are displayed for comparison with the DVHs from the nominal plan in the absence of motion. Results: As an example of the method's use, it is applied to a 6-field conformal treatment plan for prostate cancer. Confidence limit DVHs of the CTV and rectal wall (in which the plans were ranked by probabilities for tumor control and normal tissue complication, respectively) are presented and compared to those from the nominal plan. Conclusion: The method provides a means of estimating the uncertainty in dose delivered by a treatment plan when organ motion is present. It is generally applicable to any treatment site for which data in the form of multiple CT scans are available, and can be extended to include other treatment uncertainties such as variation in patient positioning

[en] Purpose: To report on the long-term urinary morbidity among prostate cancer patients with a prior history of a transurethral resection of the prostate (TURP) treated with high-dose 3-dimensional conformal radiotherapy (3D-CRT). Methods and Materials: Between 1988 and 1997, 1100 patients with clinically localized prostate cancer were treated with 3D-CRT. Of these, 120 patients (8%) were identified as having had a prior TURP and are the subjects of this analysis. The median age was 71 years (range: 49-83 years). The clinical stages of the patients were T1c: 33 (28%); T2a: 38 (32%); T2b: 15 (13%); and T3: 34 (27%). Neoadjuvant androgen ablation therapy was given to 39 (33%). The median radiation dose prescribed to the planning target volume was 75.6 Gy (range: 64.8-81 Gy). The median elapsed time from TURP to initiation of 3D-CRT was 69 months (range: 4-360 months). The median follow-up time was 51 months (range: 18-109 months). Results: Five patients of the 120 with a prior history of TURP (4%) developed a urethral stricture after 3D-CRT which was corrected with dilatation. The 5-year actuarial likelihood of ≥ Grade 2 late urinary toxicities was 9%. No Grade 4 urinary toxicities were observed in this group of patients. Among 110 patients who were completely continent of urine prior to 3D-CRT, 10 (9%) developed stress incontinence requiring 1 pad daily for protection or experienced occasional leakage (not requiring pad protection). The 5-year incidence of ≥ Grade 1 stress incontinence was 18% in patients who developed acute ≥ Grade 2 GU symptoms during the course of 3D-CRT compared to 7% for patients who experienced Grade 1 or no acute urinary symptoms (p = 0.05). The radiation dose (≥75.6 Gy vs. <75.6 Gy), the number of prior TURP procedures, or the volume of resected tissue at the time of TURP had no significant impact on the long-term urinary morbidity outcome. A multivariate analysis demonstrated that the presence of Grade 2 acute urinary symptoms was the only predictor of ≥ Grade 1 stress incontinence after 3D-CRT in this group of patients. Conclusions: Despite prior TURP, the incidence of ≥ Grade 3 urinary toxicities is low. Nevertheless, especially among patients with a prior history of TURP who experience Grade 2 acute urinary symptoms during radiation treatment, a higher risk of stress incontinence is observed