Michel Ghilezan

High-Dose-Rate Monotherapy: Safe and Effective Brachytherapy for Patients With Localized Prostate Cancer

PURPOSE High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low- and intermediate-risk prostate cancer patients. METHODS AND MATERIALS There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography-defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3. RESULTS The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%. CONCLUSIONS High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer.

High-dose-rate prostate brachytherapy: an excellent accelerated-hypofractionated treatment for favorable prostate cancer.

Purpose:The radiobiology of prostate cancer appears to favor large fractions. Accelerated hypofractionation treatments may therefore be used to improve the therapeutic ratio, particularly when the doses to rectum and bladder are kept below the prostate dose. The 5-year experience at William Beaumont Hospital (WBH) and the California Endocurietherapy Center (CET) with accelerated-hypofractionated high-dose-rate (HDR) monotherapy in favorable prostate cancer is presented. Materials and Methods:Between 1993 and 2004, 454 patients were treated with brachytherapy of which 248 treated with HDR and 206 patients treated with low-dose-rate Palladium (LDR-Pd103). The WBH-HDR dose was 38 Gy, in 4 fractions, twice a day. The CET-HDR dose was 42 Gy in 6 fractions in 2 separate implants 1 week apart. The WBH-LDR dose was 120 Gy. Results:Median follow-up was 4.8 years. The 5-year Phoenix biochemical control (BC) was 89%, 91%, and 88% for WBH-LDR, WBH- HDR, and CET-HDR, respectively. The majority of complications were grade 1. HDR was associated with less acute grade 1 to 3 dysuria 60% versus 39%, (P < 0.001), urinary frequency/urgency 90% to58% (P < 0.001), and rectal pain 17% to 6.5% (P < 0.001). Long-term urinary frequency/urgency 54% versus 43%, (P = 0.03) and dysuria 22% versus 15% were less with HDR. The 5-year actuarial impotence rate was 30% for LDR and 20% for HDR (P = 0.23). Conclusions:Although the same 5-year BC rates were achieved with HDR (248 patients) and LDR (206 patients) monotherapy, HDR brachytherapy was associated with less acute and chronic genitourinary and gastrointestinal toxicities. As another accepted standard of care, accelerated hypofractionated HDR monotherapy is target specific and efficient radiobiologically than EBRT which has many smaller doses per fraction. It could be considered today as the best option in accelerated hypofractionated prostate cancer treatment.

High-Dose-Rate Brachytherapy as Monotherapy Delivered in Two Fractions Within One Day for Favorable/Intermediate-Risk Prostate Cancer: Preliminary Toxicity Data

PURPOSE To report the toxicity profile of high-dose-rate (HDR)-brachytherapy (BT) as monotherapy in a Human Investigation Committee-approved study consisting of a single implant and two fractions (12 Gy × 2) for a total dose of 24 Gy, delivered within 1 day. The dose was subsequently increased to 27 Gy (13.5 Gy × 2) delivered in 1 day. We report the acute and early chronic genitourinary and gastrointestinal toxicity. METHODS AND MATERIALS A total of 173 patients were treated between December 2005 and July 2010. However, only the first 100 were part of the IRB-approved study and out of these, only 94 had a minimal follow-up of 6 months, representing the study population for this preliminary report. All patients had clinical Stage T2b or less (American Joint Committee on Cancer, 5th edition), Gleason score 6-7 (3+4), and prostate-specific antigen level of ≤12 ng/mL. Ultrasound-guided HDR-BT with real-time dosimetry was used. The prescription dose was 24 Gy for the first 50 patients and 27 Gy thereafter. The dosimetric goals and constraints were the same for the two dose groups. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. The highest toxicity scores encountered at any point during follow-up are reported. RESULTS The median follow-up was 17 months (range, 6-40.5). Most patients had Grade 0-1 acute toxicity. The Grade 2 acute genitourinary toxicity was mainly frequency/urgency (13%), dysuria (5%), hematuria, and dribbling/hesitancy (2%). None of the patients required a Foley catheter at any time; however, 8% of the patients experienced transient Grade 1 diarrhea. No other acute gastrointestinal toxicities were found. The most common chronic toxicity was Grade 2 urinary frequency/urgency in 16% of patients followed by dysuria in 4% of patients; 2 patients had Grade 2 rectal bleeding and 1 had Grade 4, requiring laser treatment. CONCLUSIONS Favorable-risk prostate cancer patients treated with a single implant HDR-BT to 24-27 Gy in two fractions within 1 day have excellent tolerance with minimal acute and chronic toxicity. Longer follow-up is needed to confirm these encouraging early results.

Adaptive Radiation Therapy for Prostate Cancer

Adaptive radiotherapy has been introduced to manage an individuals treatment by, including patient-specific treatment variation identified and quantified during the course of radiotherapy in the treatment planning and delivering optimization. Early studies have demonstrated that this technique could significantly improve the therapeutic ratio by safely reducing the large target margin that has to be used in conventional radiotherapy for prostate cancer treatment. Clinical application of off-line image-guided adaptive radiotherapy for prostate cancer has demonstrated encouraging clinical outcome. Long-term clinical follow-up has shown significant improvement in terms of tumor control and low toxicity profile, emphasizing the beneficial effect of image-guidance and adaptive treatment. Continuous development in adaptive radiotherapy has made possible additional increases in target dose by further reducing target margin when using online image-guided adaptive intensity-modulated radiation therapy. However, clinical implementation of new techniques should be explored cautiously and should include a comprehensive management strategy to address uncertainties in target definition and delineation in the preclinical implementation studies.

LACK OF BENEFIT FOR THE ADDITION OF ANDROGEN DEPRIVATION THERAPY TO DOSE-ESCALATED RADIOTHERAPY IN THE TREATMENT OF INTERMEDIATE- AND HIGH-RISK PROSTATE CANCER

PURPOSE Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA ≥20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason ≥8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

PSA bounce after prostate brachytherapy with or without neoadjuvant androgen deprivation

PURPOSE To assess the impact of PSA bounce (PB) on biochemical failure (BF) and clinical failure (CF) in brachytherapy patients treated with or without neoadjuvant androgen deprivation (AD). METHODS AND MATERIALS From 1987 to 2003, 691 patients with clinical stage T1-T3N0M0 prostate cancer were treated with external beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy boost (n=407), HDR brachytherapy alone (n=93), or permanent seed implant (n=191). Three hundred seventeen patients (46%) received neoadjuvant/adjuvant AD with RT. BF was scored using 3 definitions (ASTRO--3 rises, nadir+2 ng/ml, and threshold 3 ng/ml) based on current and absolute nadir (AN) methodologies. PB was defined as any increase in PSA followed by a decrease to the prior baseline or lower. The median followup was 4.0 years. RESULTS Forty-six patients (7%) experienced CF at 5 years. PB of >or=0.1, >or=1.0, and >or=2.0 ng/ml at any time after RT occurred in 330 (48%), 60 (9%), and 22 patients (3%) respectively. The use of an AN definition reduced the likelihood of scoring PB as BF across all levels. The patients receiving AD experienced significantly longer bounce duration. Bounce <1.0 ng/ml showed no association with CF. For bounce >or=1.0 ng/ml, 10% demonstrated CF vs. 6% without bounce of this amplitude (p=0.27). Bounces >or=1.0 ng/ml were more likely to be scored as BFs for definitions based on current nadir (3 rises: 20% vs. 13%, nadir+2: 43% vs. 11%, 3 at/after nadir: 57% vs. 12%) than those based on AN (3 rises: 8% vs. 10%, nadir+2: 18% vs. 11%, 3 at/after nadir: 13% vs. 11%). CONCLUSIONS Bounces >or=1.0 ng/ml are rare after brachytherapy with or without neoadjuvant AD, occurring in less than 10% of patients. Low PBs have little impact on BF, but as PB amplitude increases, the BF rate increases. BF definitions based on AN are less sensitive to PB after brachytherapy.

An age-corrected matched-pair study of erectile function in patients treated with adaptive intensity modulated radiation therapy (IMRT) versus high-dose-rate brachytherapy (HDR) in prostate cancer.

225 Background: Increasing age is a likely contributor to erectile dysfunction (ED) after radiotherapy for prostate cancer. A matched-pair (MP) analysis, with age as a criterion, was used to investigate ED after IMRT and HDR monotherapy for prostate cancer. METHODS 430 patients with low (63%) or intermediate risk (37%) prostate cancer with full or partial erectile function were treated between 4/00 and 9/10 with IMRT (n=215) or brachytherapy (n=215). Patients with follow up (FU) <1y were excluded. IMRT dose was 70.2-82.8 Gy (median 75.6) in 1.8 Gy/fx. HDR was given as 9.5 Gy x 4 (median), 13.5 Gy x 2 or 12 Gy x 2. MP, univariate, and multivariate analyses examined ED using CTCAEv4. Match criteria were age (±5y), Gleason (6,7), T stage (T1, T2), and PSA (<4, 4-10, >10). BF was by modified Phoenix criteria (nadir+5 for 2y, nadir+2 after). RESULTS Median FU was 3.4y (range 1-7.1) for IMRT and 3.1y (range 1-10.9) for HDR. There was no difference in PSA (4.8 vs. 4.6, p=0.4), T stage (88% vs. 88% T1, p=1.0) and Gleason score (63% vs. 63% 6, p=1.0) between IMRT and HDR. Despite age matching, IMRT patients were older (median 65 vs. 62 y, p=0.05). Pre-treatment potency grade 0, 1, and 2 were found in 70%, 14% and 15% of IMRT and 69%, 20% and 11% of HDR patients. 5y OS, CSS, and BF were 100%, 100% and 2.4% for IMRT, and 99% (p=0.35), 100% (p=1.0), and 10.6% (p=0.001) for HDR. On subset analysis of pre-treatment grade 0 patients, univariate analysis showed HDR (p<0.001), increasing Gleason (p=0.05) and increasing FU time (p<0.001) correlated with post-treatment ED, while age (p=0.32), PSA (p=0.46) and T stage (p=0.76) did not. On multivariate analysis, increasing FU time correlated with ED (p<0.001), while treatment type (p=0.10) and Gleason (p=0.49) did not. CONCLUSIONS Both IMRT and HDR yield comparable low (25%) rates of 1+ ED for patients with no ED at baseline. Increasing age does not appear to significantly impact ED for both IMRT and HDR. [Table: see text].

Long-Term Outcome and Late Toxicity Analysis for Clinically Localized Prostate Cancer Treated With Permanent Interstitial Brachytherapy

rectum V50) were obtained corresponding to each image data set and the difference was recorded. Results: There were statistically significant differences in all DVH parameters between the 2 image data sets, with the exception of the V100. Excluding one patient in whom there was an 11% decrease in the V100 from 99.5 to 88.5 with and without stylets, the median decrease in prostate V100 was not significant. However, there was a 3.4% decrease for the V125 (p ! 0.001). For urethra V100, the difference was impressive with a mean of 6 and standard deviation (SD) of 12 between the 2 data sets (p ! 0.001). A similar large discrepancy was found for rectum V50 with a mean of 7 and SD of 11.9 (p! 0.001). Conclusions:Significant differenceswerenoted in terms ofDVHparameters between image data sets acquired with and without rigid stylets for the purpose of real-time intraoperative HDR planning for prostate BT. While the difference in terms of prostate coverage may not be clinically relevant, there were large variations in urethral and rectal dosimetry that may result in increased treatment-related toxicity. When using Flexiguide catheters for HDR prostate BT, we recommend performing the intraoperative planning based on an image set with the rigid stylets removed.