A prospective randomized comparison of stranded vs. loose 125I seeds for prostate brachytherapy.

PURPOSE: To compare seed loss and dosimetric parameters between stranded and loose 125I seeds (LS) for prostate brachytherapy. METHODS AND MATERIALS: Sixty-four patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1c or T2a prostate carcinoma were prospectively randomized to brachytherapy (144Gy) with RAPID Strand 125I seeds (RS) vs. LS (Oncura, Plymouth Meeting, PA) The treatment plan for each patient was devised before randomization, and was not modified based on the randomization. Each patient underwent magnetic resonance, computed tomography, and plain film radiographs on the day of the implant (Day 0) and 30 days later (Day 30). RESULTS: Overall, 21 of 62 patients (30%) experienced seed loss. Seed loss occurred in 15 of 32 of LS patients (47%) vs. 6 of 30 RS patients (23%; p=0.053). Mean seed loss was 1.09 in the LS patient vs. 0.43 in RS patients (p=0.062). Eight LS patients (25%) lost multiple seeds, compared to 3 stranded patients (10%). Despite the lesser degree of seed loss in patients who received stranded seeds, they had a paradoxical trend toward lower V100 and D90 values. CONCLUSION: This prospective randomized trial showed a strong trend toward a decrease in postimplant seed loss with stranded seeds. Improved seed retention may be more advantageous in a setting of less generous periprostatic coverage. The lowered risk seed migration seen with stranded seeds would presumably also decrease the likelihood of lung or cardiac seed embolization.

Rectal fistulas after prostate brachytherapy.

PURPOSE: To compare the rectal and prostatic radiation doses for a prospective series of 503 patients, 44 of whom developed persistent rectal bleeding, and 2 of whom developed rectal-prostatic fistulas. METHODS AND MATERIALS: The 503 patients were randomized and treated by implantation with 125I vs. 103Pd alone (n = 290) or to 103Pd with 20 Gy vs. 44 Gy supplemental external beam radiotherapy (n = 213) and treated at the Puget Sound Veterans Affairs Medical Center (n = 227), Schiffler Cancer Center (n = 242) or University of Washington (n = 34). Patients were treated between September 1998 and October 2001 and had a minimum of 24 months of follow-up. The patient groups were treated concurrently. Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urological Association and Radiation Therapy Oncology Group criteria, at 1, 3, 6, 12, 18, and 24 months. Patients who reported Grade 1 or greater Radiation Therapy Oncology Group rectal morbidity were interviewed by telephone to clarify details regarding their rectal bleeding. Those who reported persistent bleeding, lasting for >1 month were included as having Grade 2 toxicity. Three of the patients with rectal bleeding required a colostomy, two of whom developed a fistula. No patient was lost to follow-up. The rectal doses were defined as the rectal volume in cubic centimeters that received >50%, 100%, 200%, or 300% of the prescription dose. The rectum was considered as a solid structure defined by the outer wall, without attempting to differentiate the inner wall or contents. RESULTS: Persistent rectal bleeding occurred in 44 of the 502 patients, 32 of whom (73%) underwent confirmatory endoscopy. In univariate analysis, multiple parameters were associated with late rectal bleeding, including all rectal brachytherapy indexes. In multivariate analysis, however, only the rectal volume that received >100% of the dose was significantly predictive of bleeding. Rectal fistulas occurred in 2 patients (0.4%), both of whom had received moderate rectal radiation doses and extensive intervention for rectal bleeding. CONCLUSION: Partly on the basis of data from others and data presented here, we believe that the incidence of rectal fistulas can be much lower than in our series. High rectal radiation doses should be avoided a priori, to minimize the likelihood of rectal bleeding, and hence the likelihood that invasive procedures will be performed.

20 Gy versus 44 Gy supplemental beam radiation with Pd-103 prostate brachytherapy: preliminary biochemical outcomes from a prospective randomized multi-center trial.

BACKGROUND AND PURPOSE: While favorable results are achieved with combined modality irradiation, there has never been a rigorous study of the need for supplemental beam. The study reported here compares clinical outcomes with substantially different external beam radiation doses. Similar to classic randomized Wilm's tumor studies from the 1980s, the intention of the trial design was to decrementally test the need for beam radiation. PATIENTS AND METHODS: As of June 2000, 165 of a planned 600 patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma, Gleason grade 7-10 and/or PSA 10-20 ng/ml, were treated on a randomized protocol comparing 44 versus 20 Gy pre-implant supplemental beam radiation, combined with Pd-103, 90 versus 115 Gy, respectively (NIST-1999). Freedom from biochemical failure was defined as a serum PSA0.5 ng/ml were scored as failures at the time at which their PSA nadired. The follow-up period for non-failing patients ranged from 0.5 to 4.9 years (median: 2.9 years). Accrual of 566 patients was achieved in October 2004. The study was closed at that time because of slowing accrual, due in part to the findings reported here. RESULTS: The overall actuarial freedom from biochemical progression at 3 years is 85%, with 59 patients followed beyond 3 years. A total of 21 patients have developed biochemical failure, 12 treated with 20 Gy and nine treated with 44 Gy. There were no clinically evident local failures. The actuarial biochemical freedom-from-failure rate at 3 years was 83% for 20 Gy patients versus 88% for 44 Gy patients (P=0.64). For 112 patients with a pre-treatment PSA<10 ng/ml, the 3-year freedom from progression was 84% in patients receiving 20 Gy beam radiation versus 94% in those who received 44 Gy beam (P=0.16). For 47 patients with a pre-treatment PSA>10 ng/ml, the 3-year freedom from progression was 82% in patients receiving 20 Gy beam radiation versus 72% in those who received 44 Gy beam (P=0.38). CONCLUSIONS: The randomized data presented here suggests that the likelihood of biochemical cure is similar with standard (44 Gy) or lower dose (20 Gy) supplemental beam radiation. Since the biological effect of 20 Gy external beam radiation is likely to be small, we interpret these preliminary results to suggest that supplemental beam radiation is unnecessary, in the setting of a high degree of prostate coverage by the brachytherapy prescription dose. With closure of this study, we have begun treating intermediate and high risk patients on a prospective randomized comparison of Pd-103 with 20 versus 0 Gy supplemental beam radiation.

Brachytherapy for carcinoma of the prostate: techniques, patient selection, and clinical outcomes.

Brachytherapy for prostate carcinoma has developed as either low dose rate permanent implants or high dose rate afterloading. Both approaches offer unsurpassed dose escalation and, particularly with permanent implants, the convenience of a single outpatient treatment. These therapies have now entered the mainstream of treatment options and are in the refinement phase of development. Techniques of implantation, treatment planning approaches, innovative fractionation schemes, and appropriate patient selection are the subject of current investigation. Treatment results are available beyond 10 years and appear equivalent or superior to other modalities. Although short term morbidity can be significant with brachytherapy, most current series report low long-term urinary and rectal complications. Meaningful quality of life studies and randomized cooperative group trials are now underway and should help define the role of brachytherapy in the near future.

Risk factors for acute urinary retention requiring temporary intermittent catheterization after prostate brachytherapy: a prospective study.

PURPOSE: We prospectively investigated prognostic factors for men undergoing transperineal radioactive seed implantation for prostate cancer at the University of Washington. METHODS AND MATERIALS: Between February and April, 1998, 62 consecutive unselected patients were prospectively followed after brachytherapy for early-stage prostate adenocarcinoma. Pretreatment variables included age, American Urological Association (AUA) score, uroflowimetry, and prostate volume by ultrasound. Nonrandomized variables included hormonal therapy, seed type, and use of pelvic radiotherapy. Patients were contacted by phone at one week postoperatively and at one-month intervals thereafter. Follow-up continued until all patients provided the date of last catheterization. RESULTS: Urinary retention rate at one week was 34% (21 of 63 patients). At one month, 29%; at three months, 18%; and at six months, 10%. Preoperative flow rate and post-void residual did not predict for retention (p =.48 and p =.58). Use of alpha blockers, hormonal therapy, type of seed (103Pd or 1251), or external beam radiotherapy had no impact on risk of retention at any followup point. Preimplant volume and AUA score predicted for retention on univariate analysis, but on multivariate analysis only postimplant volume remained significant (p =.02) for predicting retention risk and duration. CONCLUSION: Patients with large prostate size (>36 g) and higher AUA score (>10) appear to be at greater risk of risk of retention as well as duration of retention as defined in our study. Further investigation will be needed to clarify the risk of urinary retention for men undergoing brachytherapy.

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.

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.

Perirectal seeds as a risk factor for prostate brachytherapy-related rectal bleeding.

PURPOSE: To correlate rectal wall doses and perirectal seed numbers with late rectal bleeding after prostate brachytherapy. METHODS AND MATERIALS: We studied 148 patients randomized to implantation with I-125 vs. Pd-103 at the VA Puget Sound HCS from 1998 through 2001 and for whom postimplant dosimetry was available. Implants were performed by standard techniques, using a modified peripheral loading pattern. A postimplant computed tomography (CT) scan (3 mm slice thickness) was obtained 1-4 h after implantation. Rectal doses were expressed as the R100, R200, and R300, defined as the rectal volume (cc) that received more than 100%, 200%, or 300% of the prescription dose, respectively. The rectum was considered to be a solid structure defined by the outer wall, without attempting to differentiate the inner wall or contents. In addition to conventional dose parameters, each patient's postimplant CT scan was reviewed for the number of seeds within 0, 0.1-2, and 2.1-4 mm of the outer rectal wall. The proximal edge of the seed was used for distance determinations from the outer rectal wall. Patients who reported Grade 1 or higher Radiation Therapy Oncology Group morbidity were contacted by telephone to obtain more details regarding their rectal bleeding. Those who reported persistent bleeding lasting for more than 1 month were categorized as Grade 2. RESULTS: Patients had a wide range of rectal wall doses, with R100 values ranging from 0.0 to 10.4 cc (median, 0.95 cc). Similarly, the number of perirectal seeds within 0.0 to 2.0 mm of the rectum varied widely, ranging from 0 to 12 seeds (median: 1 seed). Seven patients (7 of 144 = 5%) developed persistent rectal bleeding, one of whom required a colostomy. Both rectal radiation doses and the number of perirectal seeds were higher in patients with persistent rectal bleeding. The number of perirectal seeds < or =2.0 mm of the rectal wall was higher in patients with rectal bleeding (p = 0.037), but the number of seeds 2-4 mm from the wall were not related (p = 0.72). In multivariate regression analysis including prostatic D90 (the dose that covers 90% of the postimplant prostate), preimplant transrectal ultrasound volume, R300, and the number of seeds < or =2 mm from the rectal wall as independent variables, only the R300 was statistically significantly associated with the likelihood of persistent rectal bleeding (p = 0.025). CONCLUSION: A limited number of errant perirectal sources in itself does not appear to place patients at increased risk of rectal bleeding, providing that the overall rectal wall doses are within acceptable values.

Factors predictive of rectal bleeding after 103Pd and supplemental beam radiation for prostate cancer.

PURPOSE: To evaluate the contribution of various clinical and radiation treatment parameters to the likelihood of late rectal bleeding after brachytherapy plus supplemental beam radiation (EB). METHODS: A total of 161 intermediate risk patients, with Gleason score 7 or higher and/or PSA 10-20 ng/ml randomized to implantation with (103)Pd (90 versus 115 Gy) with 44 versus 20 Gy EB (2 Gy/day) were studied. 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). Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. A postimplant CT scan (3 mm slice thickness) was obtained 1-4 h after implantation. Dose volume histograms of the prostate and rectum were calculated using the outer prostatic and rectal margins identified on CT scan by one investigator (KW). Rectal doses were expressed as the R100, R200, and R300, defined as the rectal volume (cc) that received at least 100%, 200%, or 300% of the prescription dose, respectively. External beam doses were expressed as EB75% (cc)-the volume of rectum that received 75% of the beam prescription dose. Treatment-related rectal morbidity was monitored by mailed questionnaires, using Radiation Therapy Oncology Group (RTOG) criteria, at 1, 3, 6, 12, 24, and 36 months. Patients who reported Grade 1 or higher RTOG morbidity were contacted by telephone to obtain more details regarding their rectal bleeding. RESULTS: In univariate analysis, rectal bleeding was statistically related to the R100, R200, and R300 values, with p-values of 0.0055, 0.0007, and 0.012, respectively. Bleeding was not related to gap times, prostate size, patient age, V100 or D90 values. The EB75% values were similar in 44 Gy patients with or without late bleeding. CONCLUSION: Considering the potential severity of rectal morbidities and their relationship to implant dose, we urge our colleagues to routinely monitor the rectal implant doses of their own patients to make sure that such doses are kept within an accepted range.

Late urinary function after prostate brachytherapy.

PURPOSE: To determine the relationship between short term and longer term morbidity following prostate brachytherapy. METHODS AND MATERIALS: Patients completed the American Urological Association (AUA) questionnaire at the time of initial clinical evaluation. Most patients underwent pre-implant uroflowmetry and postvoid residual (PVR) via transcutaneous ultrasound. Seventeen patients were treated with palladium-103 (29%) and 44 were treated with iodine-125 (71%). Follow-up ranged from 31 to 35 months. RESULTS: Twenty-one of 52 patients (43%) developed postimplant urinary retention, almost always within 24 h of the procedure, and were generally managed by intermittent self-catheterization. By 2 years, all cases of retention had resolved spontaneously, and no patient required a surgical procedure to relieve urinary obstruction. Preimplant AUA score, age, and transrectal ultrasound volume did not correlate with time in retention. There was no clear relationship between long-term changes in AUA scores and preimplant transrectal ultrasound volume, age, preimplant AUA scores, postvoid residual, maximum urinary flow rates, or use of beam radiation or hormonal therapy. CONCLUSIONS: Although there is no shortage of unsubstantiated claims regarding predisposing factors to postimplant morbidity, the risk of urinary retention and long-term urinary dysfunction is probably multifactorial in nature and only crudely defined by known clinical variables.

Morbidity effect of the time gap between supplemental beam radiation and Pd-103 prostate brachytherapy.

PURPOSE: To determine if gap time variations between prostate brachytherapy and supplemental beam radiation (EBRT) affect postimplant morbidity. MATERIALS AND METHODS: Ninety-one patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma, Gleason grade 7-9, or PSA 10-20 ng/ml, were randomized to implantation with 90 Gy Pd-103 versus 115 Gy (NIST-1999) with 44 Gy versus 20 Gy preimplant supplemental beam radiation, respectively. Pd-103 implantation was performed by standard techniques, using a modified peripheral loading pattern. 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. A post-implant computed tomography (CT) scan was obtained on the same day. Dosimetric parameters analyzed included the V100 - the percent of the postimplant prostate or rectal volume covered by the prescription dose, and the D90 - the dose that covers 90% of the post-implant prostate or rectal volume. For EBRT rectal D90s, the rectal volume included slices 0.9 cm above and below the seminal vesicles and apex, respectively. Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urologic Association (AUA) and Radiation Therapy Oncology Group (RTOG) criteria at 1, 3, 6, 12, 18, and 24 months. Use of alpha-blockers to relieve obstructive symptoms was not controlled for, but was noted at each follow-up point. Median follow-up at the time of this analysis was 21 months, with a range of 18-26 months. RESULTS: Variability in the total radiation delivery time within each treatment arm was due almost exclusively to gap time variability. Patients receiving 20 Gy EBRT completed their beam radiation over an average of 12 days (+/-1 day). Patients receiving 44 Gy did so over an average of 31 days (+/- 2 days). The median gap interval for patients receiving 20 Gy EBRT was 5 days (range: 1-40 days) versus 9 days (range: 0-15 days) for patients receiving 44 Gy EBRT. Urinary morbidity, measured by a change in the AUA score from baseline (DeltaAUA) was greater at 1-month postimplant in patients who had shorter gap intervals. The effect of gap time on AUA score changes was lost by 6 months. When looking at the treatment arms separately, the dependence on gap interval was limited to those patients receiving 44 Gy beam radiation. No patient has developed RTOG grade 3 rectal morbidity, and no patient has required invasive therapy for rectal bleeding. There was no relationship between gap interval and rectal morbidity at any time point. There was no relationship between beam doses and RTOG rectal morbidity scores. CONCLUSIONS: The findings reported here are suggestive that short gap times are safe.

Transperineal TRUS-guided prostate brachytherapy using loose seeds versus RAPIDStrand: a dosimetric analysis.

PURPOSE: An analysis of the effect of stranded (125)I and loose (predominantly (103)Pd) sources on dosimetric outcomes of brachytherapy of the prostate. METHODS AND MATERIALS: Between September 1998 and December 2003, 473 patients were treated with brachytherapy for biopsy-proven carcinoma of the prostate. Of these, 337 (71%) procedures were performed using free seeds placed with a Mick applicator. Beginning in April 2002, a program of stranded (125)I sources (RAPIDStrand) was implemented; 136 (29%) patients were treated via this approach. Dosimetric variables were collected, as were events of urinary retention. RESULTS: Mean V100 values for the stranded (125)I approach were greater than those for free seeds (p < 0.0005), whether (125)I or (103)Pd (p < 0.005). Use of the strand was the most significant determinant of V100 of all variables examined. The stranded (125)I approach was also associated with higher mean D90 values and lower V150-urethral doses. CONCLUSIONS: Use of stranded (125)I was associated with superior dosimetric outcomes in this group of patients.

Chemotherapy followed by syngeneic dendritic cell injection in the mouse: findings and implications for human treatment.

A growing number of studies have described an apparent synergy between systemic chemotherapy administration and the intratumoral injection of dendritic cells (DCs) in the successful treatment of murine tumors. A review of several of these studies is undertaken here and possible combinations of DC therapy and conventional cancer therapies are discussed with the goal of contemplating the exploitation of current findings and theory toward the treatment of human patients with cancer. The methods and results of several murine studies are described in detail and additional reference is made to other relevant murine studies. Hypothetical routes of synergy between DC therapy, chemotherapy, and ablative therapies are explored, and the potentially significant role played by the regulatory immune system is discussed. Given the results of preclinical studies and the current understanding of cancer immunity, it is possible to consider a human treatment that calls for focal ablation of cancer followed by intratumoral DC injection, in the setting of chemotherapy-based regulatory T-cell depletion.

I-125 versus Pd-103 for low-risk prostate cancer: long-term morbidity outcomes from a prospective randomized multicenter controlled trial.

BACKGROUND: We tested the hypothesis that the shorter half-life of Pd-103 versus I-125 results in different late radiation-related morbidities following prostate brachytherapy. METHODS: As of June 14th, 2002, 352 of a planned total of 600 patients with 1997 American Joint Committee on Cancer (AJCC) clinical stage T1c-T2a prostatic carcinoma (Gleason grade 2-6, PSA 4-10 ng/mL) had been randomized to implantation with I-125 (144 Gy, TG-43) or Pd-103 (125 Gy, NIST-99). Treatment-related morbidity was monitored by questionnaires based on standard American Urologic Association (AUA) and Radiation Therapy Oncology Group (RTOG) criteria that were mailed at 1, 3, 6, 12, 18, and 24 months after implant. The use of alpha-blockers to relieve obstructive symptoms was not controlled for but was noted at each follow-up point. All patients reported here had a minimum follow-up of 2 years. Dosimetric parameters analyzed included the V100, which was defined as the percentage of the postimplant prostate volume covered by 100% of the prescription dose. Rectal doses were expressed as the R100, defined as the rectal volume (cc) that received at least 100% of the prescription dose. Statistical comparisons were by Student's unpaired t-test at specified follow-up times. RESULTS: The AUA scores peaked at the 1-month postimplant time point for both isotopes and gradually declined. The difference in AUA scores between patients who received I-125 versus those who received Pd-103 was greatest at 1 and 6 months following implantation. At 1 month, I-125 patients had a mean AUA score of 14.8 (+/-9.5) compared with 18.6 (+/-9.8) for the Pd-103 patients (P = 0.0009). By 6 months, mean AUA scores for the I-125 patients had decreased to 12.0 (+/-9.1) compared with 9.9 (+/-8.7) for the Pd-103 patients (P = 0.04). The use of alpha-blockers was similar between groups at all time points. Radiation proctitis (persistent bleeding) occurred in 29 of 314 patients (9%). There was an overall trend toward more proctitis in I-125 patients (P = 0.21). However, only four of the 163 patients (2%) with an R100 below the recommended 1.0 cc developed bleeding, which did not differ between isotopes (P = 0.49). DISCUSSION: Patients treated with Pd-103 had more intense radiation prostatitis in the first month after implantation, but they recovered from their radiation-related symptoms sooner than I-125 patients, consistent with palladium's shorter half-life. The trend toward more proctitis in the I-125 patient group likely reflects their higher R100 values due to less rapid dose fall-off that can be overcome with judicious treatment planning and implant execution.

Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer.

PURPOSE: No effective treatment is currently available for metastatic prostate cancer. Dendritic cell (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. We describe progress in the development of DC based prostate cancer vaccine. MATERIALS AND METHODS: The literature was reviewed for major contributions to a growing number of studies that demonstrate the potential of DC based immunotherapeutics for prostate cancer. Background topics relating to DC based immunotherapy theory and practice are also addressed. RESULTS: DCs have been recognized as the most efficient antigen presenting cells that have the capacity to initiate naive T cell response in vitro and in vivo. During their differentiation and maturation pathways, dendritic cells can efficiently capture, process and present antigens for T cell activation. These characteristics make DC an attractive choice as the cellular adjuvant for cancer vaccines. Advances in DC generation, loading, and maturation methodologies have made it possible to generate clinical grade vaccines for various human trials. More than 100 DC vaccine trials, including 7 studies of patients with advanced prostate cancer have been reported to date. These vaccines were generally well tolerated with no significant adverse toxicity reported. Clinical responders have been identified in these studies. CONCLUSIONS: The new prospects opened by DC based vaccines for prostate cancer are fascinating. When compared to conventional treatments, DC vaccinations have few side effects. Improvements in patient selection, vaccine delivery strategies, immune monitoring and vaccine manufacturing will be crucial in moving DC based prostate cancer vaccines closer to the clinics.

The prognostic significance of Gleason pattern 5 in prostate cancer patients treated with Pd 103 plus beam radiation therapy.

BACKGROUND: There is little clinical information specifically regarding the clinical significance of Gleason pattern 5 in prostate biopsies. Accordingly, we have analyzed the effect of pattern 5 cancer on the prognosis of prostate cancer treated with Pd-103 brachytherapy. METHODS: Intermediate-risk patients with a Gleason score of 7 or higher and/or a prostate-specific antigen level of 10-20 ng/mL and whose biopsy slides were available for review were treated on a randomized trial. The regimens consisted of implantation with Pd 103 (90 vs 115 Gy [National Institute of Standards and Technology; NIST-1999]), combined with 44 Gy versus 20 Gy of supplemental beam radiation, 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). Isotope implantation was per formed by standard techniques, using a modified peripheral loading pattern. All prostate biopsy specimens were reviewed for Gleason score by one investigator (L. T.). Along with assignment of a Gleason score based on established criteria, the presence of any pattern 5 cancer was separately noted and photographed for future review. Freedom from biochemical failure was defined as a serum prostate-specific antigen level < or = 0.5 ng/mL at last follow-up. Four of the 156 patients had insufficient PSA follow-up for inclusion, leaving 152 patients for cancer control analysis. RESULTS: Overall actuarial biochemical freedom from failure was 86% at 3 years, with 20 patients having experienced biochemical failure. Patients with or without Gleason pattern 5 cancer in their biopsy specimen had similar overall biochemical control. There was no obvious trend toward poorer overall biochemical cancer control in patients with pattern 5 cancer, regardless of whether the pretreatment prostate-specific antigen was less than or greater than 10 ng/mL. Of the 17 patients with biochemical failure, clinically evident bone metastases has developed in five. Three of these five patients who had a positive bone scan had pattern 5 cancer in their biopsy. CONCLUSIONS: Although the presence of pattern 5 disease may be a risk factor for early systemic failure, we are encouraged that high-dose, brachytherapy-based treatment seems to provide a high likelihood of biochemical cancer control, even in patients with the highest-grade cancer.

I-125 versus Pd-103 for low-risk prostate cancer: morbidity outcomes from a prospective randomized multicenter trial.

PURPOSE: The purpose of this study was to test the hypothesis that the shorter half-life of Pd-103 versus I-125 results in a shorter duration of radiation-related symptoms after prostate brachytherapy. METHODS: As of February 2000, 110 of a planned total of 380 patients with 1997 American Joint Commission clinical stage T1c-T2a prostatic carcinoma (Gleason grade 2-6, prostate-specific antigen, 4-10 ng/mL) had been randomly assigned to implantation with I-125 (144 Gy, TG-43) or Pd-103 (125 Gy, NIST-99). Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. 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 point. All patients reported here have a minimum 1-year follow-up. Randomization was carried out at a central enrollment office where eligibility criteria were confirmed and the patient assigned by computerized random number generator to one of the two treatment arms. Patients were assigned to 95 blocks of four. Most statistical comparisons shown here are by Student's unpaired t-test at specific follow-up times, as indicated in the figure legends. Additionally, considering the patients' scores change overtime, repeated measures were incorporated in a mixed model assuming an unstructured covariance matrix. RESULTS: Patients in each arm were well matched by preimplant prostate volume, AUA score, and age. The AUA scores peaked at the 1-month point for both isotopes and then gradually declined. The difference was greatest at 6 months, when I-125 patients had a mean AUA score of 16 (+/- 8), compared with 11 (+/- 10) for the Pd-103 patients. By 12 months, mean AUA scores for the Pd-103 patients had decreased to 12 (+/- 9), compared with 13 (+/- 8) for the I-125 patients. At 6 months after implantation, 41% of Pd-103 patients were still taking alpha-blockers, versus 44% of I-125 patients. The differences between isotopes were more marked in patients with a low pretreatment AUA score or smaller preimplant transrectal ultrasonography volume. Results of the mixed model, incorporating repeated measures for each patient, showed that the effect of isotope choice on AUA score depended on time. This effect was further dependent on baseline AUA score, but not on transrectal ultrasonography volume or on age. Urinary and rectal morbidity was generally low, typically grade 1 or 2. There was a trend to greater morbidity with I-125 than with Pd-103, most markedly at the 6-month time point. DISCUSSION: Patients treated with Pd-103 recovered from their radiation-induced prostatitis sooner than I-125 patients. It appears that patients with minimal pretreatment urinary obstructive symptoms are the most likely to experience implant-related exacerbations of their symptoms and are the most likely to benefit from the more rapid half-life of Pd-103 rather than I-125.

Treatment margins predict biochemical outcomes after prostate brachytherapy.

PURPOSE: Due to the theoretical role of treatment margins (TMs) in cancer, we have correlated biochemical outcomes with post-implant TMs in patients treated with brachytherapy for early stage prostate cancer. METHODS: From November 1998 through September 2003, 492 of a planned total of 600 patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma (Gleason score 5 or 6, PSA 4 to 10 ng/mL) have been randomized to implantation with (125)I (144 Gy, TG-43) versus (103)Pd (125 Gy, NIST-99). This preliminary analysis included only the first 122 analyzable patients, while accrual to the trial finishes. Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. Axial CT images at 3 mm intervals were acquired within four hours postoperatively for post-implant dosimetry. The contoured images and sources were entered into Varian Variseed system 7.1 (Charlottesville, VA). After completion of standard dosimetric calculations, the 100% prescription dose TMs were measured and tabulated around the prostate periphery at the 0.0, 1.0, 2.0 and 3.0 cm planes, going distal from the bladder-prostate interface. Measurements were limited to the transverse planes. Freedom from biochemical failure was defined as a serum PSA < or = 0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Patients whose serum PSA nadired at a value >0.5 ng/mL were scored as failures at the time at which their PSA nadired. The follow-up period for non-failing patients ranged from 2.1-5.0 years (median: 3.3 years). RESULTS: The average 100% prescription dose treatment margin (for individual patients) ranged from -5.0 to 8.7 mm, with an overall average of 2.6 mm (+/-3.1). In univariate analysis, the D(90) was the best predictor of biochemical control for (125)I, while the average TM was the best predictor for (103)Pd. Similarly, in multivariate analysis using the D(90), V(100), and average TM as the independent variables and biochemical control as the dependent variable, the D(90) was most closely related to biochemical control for (125)I patients, while average TM was most closely related for (103)Pd patients. In separate analysis of TM by site, the anterior TMs were the best predictors of biochemical outcomes. CONCLUSION: V(100), D(90), and TMs all appear to have a bearing on biochemical freedom from relapse after prostate brachytherapy. Efforts to better identify and test geographic dosimetric parameters are theoretically appealing, and supported by the clinical data summarized here.