Mark Hurwitz

THE CLINICAL UTILITY OF THE PERCENT OF POSITIVE PROSTATE BIOPSIES IN PREDICTING BIOCHEMICAL OUTCOME FOLLOWING EXTERNAL-BEAM RADIATION THERAPY FOR PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSEnAn investigation was performed of the clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following external-beam radiation therapy (RT) for men with PSA-detected or clinically palpable prostate cancer.nnnMETHODS AND MATERIALSnA Cox regression multivariable analysis was used to determine whether the percent of positive prostate biopsies provided clinically relevant information about PSA outcome following external beam RT in 473 men while accounting for the previously established risk groups based on the pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T stage.nnnRESULTSnControlling for the known prognostic factors, the percent of positive prostate biopsies added clinically significant information (p = 0.02) regarding time to PSA failure following RT. Specifically, 76% of the patients in the intermediate risk group (1992 AJCC T(2b) or biopsy Gleason 7 or PSA > 10 ng/mL and < or = 20 ng/mL) could be classified into either an 30% or 85% 5-year PSA control cohort using the preoperative prostate biopsy data.nnnCONCLUSIONnThe previously validated stratification of PSA outcome following radical prostatectomy (RP) using the percent of positive prostate biopsies in intermediate-risk patients is also clinically significant for men treated with external beam RT. The percent positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome following RP or external beam RT.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer

PURPOSEnTo investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT).nnnMETHODS AND MATERIALSnThe study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test.nnnRESULTSnCox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033).nnnCONCLUSIONnA decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

Updated Results of Magnetic Resonance Imaging Guided Partial Prostate Brachytherapy for Favorable Risk Prostate Cancer: Implications for Focal Therapy

PURPOSEnWe report updated results of magnetic resonance imaging guided partial prostate brachytherapy and propose a definition of biochemical failure following focal therapy.nnnMATERIALS AND METHODSnFrom 1997 to 2007, 318 men with cT1c, prostate specific antigen less than 15 ng/ml, Gleason 3 + 4 or less prostate cancer received magnetic resonance imaging guided brachytherapy in which only the peripheral zone was targeted. To exclude benign prostate specific antigen increases due to prostatic hyperplasia, we investigated the usefulness of defining prostate specific antigen failure as nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. Cox regression was used to determine the factors associated with prostate specific antigen failure.nnnRESULTSnMedian followup was 5.1 years (maximum 12.1). While 36 patients met the nadir +2 criteria, 16 of 17 biopsy proven local recurrences were among the 26 men who also had a prostate specific antigen velocity greater than 0.75 ng/ml per year (16 of 26 vs 1 of 10, p = 0.008). Using the nadir +2 definition, prostate specific antigen failure-free survival for low risk cases at 5 and 8 years was 95.1% (91.0-97.3) and 80.4% (70.7-87.1), respectively. This rate improved to 95.6% (91.6-97.7) and 90.0% (82.6-94.3) using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. For intermediate risk cases survival was 73.0% (55.0-84.8) at 5 years and 66.4% (44.8-81.1) at 8 years (the same values as using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year).nnnCONCLUSIONSnRequiring a prostate specific antigen velocity greater than 0.75 ng/ml per year in addition to nadir +2 appears to better predict clinical failure after therapies that target less than the whole gland. Further followup will determine whether magnetic resonance imaging guided brachytherapy targeting the peripheral zone produces comparable cancer control to whole gland treatment in men with low risk disease. However, at this time it does not appear adequate for men with even favorable intermediate risk disease.

Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy

PURPOSEnLarger prostate gland volumes have been associated with long-term urinary morbidity in prostate interstitial radiation therapy utilizing ultrasound image guidance technique. This study was performed to identify the clinical and technical predictors of acute urinary retention following magnetic-resonance (MR)-guided prostate interstitial brachytherapy.nnnMETHODS AND MATERIALSnFifty patients underwent MR-guided prostate brachytherapy between December 1997 and March 1999. Patient selection was limited to men with stage T1cNXM0 disease, PSA of less than10 ng/mL, biopsy Gleason score not more than 3 + 4, and endorectal coil MR stage T2 disease. Dosimetry plans were developed in the operating room and (125)Iodine sources were implanted using MR real-time guidance. The peripheral zone (PZ) of the prostate gland was defined as the clinical target volume (CTV) and the minimum prescribed dose to the CTV was 137 Gy. The volumes of the PZ, transition zone (TZ), and total prostate gland volume were also determined by MR. Individual source strength ranged from 0.35 to 0.54 microGym(2)/h (NIST 99, median 0.46 microGym(2)/h) and the total implanted activity ranged from 17.0 to 43.1 mCi (median, 28.1 mCi) using 43-120 seeds (median, 79). The seeds were placed using MR-compatible biopsy needles (14-28, median, 19).nnnRESULTSnThe ability of clinical (MR defined prostate, PZ, and TZ volumes) and technical (number of catheters, number of seeds implanted, and total activity) factors to predict AUR for 50 men undergoing MR-guided prostate interstitial brachytherapy were evaluated using univariable and logistic regression multivariable analyses. Six men (12%) experienced AUR within 24 h after removal of the Foley catheter subsequent to prostate brachytherapy. The total number of seeds (p = 0.05), MR determined prostate volume (p < 0.01), and the MR-determined TZ volume (p < 0.01) were significant predictors of AUR on univariable analysis. Utilizing a multivariable logistic regression analysis, the TZ volume was the only significant predictor of AUR (p < 0.01). The prostate volume is highly correlated to the TZ volume (Spearman correlation coefficient of 0. 91) and was thus significant in the univariable analysis; however, the prostate volume did not add prognostic value in multivariable analysis.nnnCONCLUSIONnBenign prostatic hyperplasia (BPH) resulting in an enlarged TZ volume, is the most important predictor of AUR following MR-guided prostate interstitial radiation therapy. Although AUR was significant (60%) in men with moderate BPH (TZ volume >/= 50 cc), it was also self-limiting.

Comparing PSA outcome after radical prostatectomy or magnetic resonance imaging-guided partial prostatic irradiation in select patients with clinically localized adenocarcinoma of the prostate.

OBJECTIVESnTo determine whether high-dose radiation delivered to a subvolume of the prostate gland (peripheral zone) using intraoperative magnetic resonance imaging-guided brachytherapy provided comparable 5-year prostate-specific antigen (PSA) control rates to radical prostatectomy (RP) in select patients compared prospectively but in a nonrandomized setting.nnnMETHODSnBetween 1997 and 2002, 322 and 196 patients with clinical Stage T1c, PSA less than 10 ng/mL, biopsy Gleason score 3 + 4 or less, and without perineural invasion underwent RP or intraoperative magnetic resonance imaging-guided brachytherapy, respectively, and had a 2-year minimal follow-up. Cox regression multivariable analysis was used to evaluate whether the initial therapy, pretreatment PSA level, biopsy Gleason score, percentage of positive biopsies, or prostate gland volume were predictors of the time to post-therapy PSA failure. PSA failure was estimated using the Kaplan-Meier method and defined using the American Society for Therapeutic Radiology Oncology consensus definition.nnnRESULTSnOnly the percentage of positive prostate biopsies (P(Cox) = 0.02) was a significant predictor of the time to post-treatment PSA failure. However, the distribution of this parameter between RP and brachytherapy-treated patients was not significantly different (P(chi-square) = 0.25). The initial therapy did not predict for the time to post-therapy PSA failure (P(Cox) = 0.18). The 5-year estimate of PSA control was 93% versus 95% (P(log-rank) = 0.16) for the RP and brachytherapy patients, respectively.nnnCONCLUSIONSnDespite only partial prostatic irradiation using intraoperative magnetic resonance imaging-guided brachytherapy, similar 5-year estimates of PSA control were found for both brachytherapy and RP-managed patients.

Radiation therapy induces circulating serum Hsp72 in patients with prostate cancer

BACKGROUND AND PURPOSEnHsp72 found in the extracellular milieu has been shown to play an important role in immune regulation. The impact of common cancer therapies on extracellular release of Hsp72 however, has been to date undefined.nnnMATERIALS AND METHODSnSerum from 13 patients undergoing radiation therapy (XRT) for prostate cancer with or without hormonal therapy (ADT) was measured for levels of circulating serum Hsp72 and pro-inflammatory cytokines (IL-6 and TNF-alpha) using the classical sandwich ELISA technique and the relative expression of CD8(+) T lymphocytes and natural killer (NK) cells was measured using flow cytometry. Mouse orthotopic xenograft of human prostate cancer tumors (DU-145 and PC-3) were used to validate and further characterize the response noted in the clinical setting. The biological significance of tumor released Hsp72 was studied in human dendritic cells (DC) in vitro.nnnRESULTSnCirculating serum Hsp72 levels increased an average of 3.5-fold (median per patient 4.8-fold) with XRT but not with ADT (p=0.0002). Increases in IL-6 (3.3-fold), TNF-alpha (1.8-fold), CD8(+) CTL (2.1-fold) and NK cells (3.2-fold) also occurred. Using PC-3 and DU-145 human prostate cancer xenograft models in mice, we confirmed that XRT induces Hsp72 release primarily from implanted tumors. In vitro studies using supernatant recovered from irradiated human prostate cancer cells point to exosomes containing Hsp72 as a possible stimulator of pro-inflammatory cytokine production and costimulatory molecules expression in human DC.nnnCONCLUSIONSnThe current study confirms for the first time in an actual clinical setting elevation of circulating serum Hsp72 with XRT. The accompanying studies in mice and in vitro identify the released exosomes containing Hsp72 as playing a pivotal role in stimulating pro-inflammatory immune responses. These findings, if validated, may lead to new treatment paradigms for common human malignancies.

Feasibility and patient tolerance of a novel transrectal ultrasound hyperthermia system for treatment of prostate cancer

This report describes patient tolerance and toxicity of a transrectal ultrasound hyperthermia system used with external beam radiation therapy in treatment of locally advanced prostate cancer. Nine patients with clinical T2B-T3B (4th edition AJCC criteria) disease received external beam radiation therapy, with two hyperthermia treatments scheduled at least 1 week apart during the first 4 weeks of radiation. Five patients also received hormonal therapy. Interstitial and anterior rectal wall thermometry were performed. Median temperature for each treatment (T50) was 40.8 degrees C and mean CEM T90 = 43 degrees C was 3.4 min. Rectal wall temperature was maintained at < or = 40 degrees C. Treatment duration was limited in three of 17 sessions due to positional discomfort which was alleviated with light IV sedation and use of a New Life mattress (Comfortex, Inc. Winoba, MN, USA). Acute toxicity was limited to NCI common toxicity criteria grade 1 and no excess toxicity was noted with full course radiation therapy +/- hormonal therapy. These findings are consistent with those reported in a previous phase I trial assessing this device. Given the favourable toxicity profile demonstrated to date, modification of treatment parameters for this ongoing phase II study have been instituted that should further the efficacy of transrectal ultrasound hyperthermia for treatment of prostate cancer.This report describes patient tolerance and toxicity of a transrectal ultrasound hyperthermia system used with external beam radiation therapy in treatment of locally advanced prostate cancer. Nine patients with clinical T2B-T3B (4th edition AJCC criteria) disease received external beam radiation therapy, with two hyperthermia treatments scheduled at least 1 week apart during the first 4 weeks of radiation. Five patients also received hormonal therapy. Interstitial and anterior rectal wall thermometry were performed. Median temperature for each treatment (T50) was 40.8°C and mean CEM T90 = 43°C was 3.4 min. Rectal wall temperature was maintained at ≤40°C. Treatment duration was limited in three of 17 sessions due to positional discomfort which was alleviated with light IV sedation and use of a `New Life mattress (Comfortex, Inc. Winoba, MN, USA). Acute toxicity was limited to NCI common toxicity criteria grade 1 and no excess toxicity was noted with full course radiation therapy +/− hormonal therapy. These findings are consistent with those reported in a previous phase I trial assessing this device. Given the favourable toxicity profile demonstrated to date, modification of treatment parameters for this ongoing phase II study have been instituted that should further the efficacy of transrectal ultrasound hyperthermia for treatment of prostate cancer.

Combined Hyperthermia and Radiotherapy for the Treatment of Cancer

Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an integral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, cardiac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threatening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy.

Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile

Purpose:u2002Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented. Methods and materials:u2002Thirty-seven patients enrolled on a phase II study of external beam radiationu2009±u2009androgen suppression with two transrectal ultrasound hyperthermia treatments were assessed for short- and long-term toxicity. Prostatic and anterior rectal wall temperatures were monitored. Rectal wall temperatures were limited to 40°C (19 patients), 41°C (three patients) and 42°C (15 patients). Univariate logistic regression was used to estimate the log hazard of developing NCI CTC Grade 2 toxicity based on temperature parameters. Hazard ratios, 95% confidence intervals, p-values for statistical significance of each parameter and proportion of variability explained for each of the parameters were calculated. Results:u2002Median follow-up was 42 months. Both short- and long-term GI toxicity were limited to grade 2 or less. Acute grade 2 proctitis was greater for patients with allowable rectal wall temperature of >40°C. Eleven of 18 patients in this group had acute grade 2 proctitis vs three of 19 patients with rectal wall temperatures limited to 40°C (pu2009=u20090.004). Long-term grade 2 GI and GU toxicity occurred in 5% and 19% of patients. No late grade 3 or greater toxicity occurred. Late GI and GU toxicity were not associated with the allowable rectal wall temperature. Conclusion:u2002Transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer is safe and well tolerated.

Lack of radiation dose response for patients with low-risk clinically localized prostate cancer: A retrospective analysis

PURPOSEnThe need for dose escalation for patients with low-risk clinically localized prostate cancer remains controversial. In this study, we report our pooled institutional experience of low-risk patients treated with a range of standard radiation doses to assess outcome in regard to biochemical failure and to determine whether a dose-response relationship exists within this conventional dose range.nnnMETHODS AND MATERIALSnPatients with low-risk clinically localized prostate cancer (T1 or T2a, Gleason grade <or=6, and prostate-specific antigen <or=10 ng/mL) treated at Joint Center for Radiation Therapy-affiliated institutions between October 1989 and September 1997 were retrospectively analyzed for freedom from biochemical failure. The dose was prescribed volumetrically with 95% normalization to between 5760 and 6900 cGy (6100 and 7300 cGy ICRU reference point dose). Patients were stratified into 3 groups with relatively equal numbers of patients (<6660, 6660, and >6660 cGy). To ensure that any differences in biochemical failure between patients at the lower and higher ends of the dose range used were not masked by analysis of the entire cohort, patients receiving <or=6500 cGy or >or=6800 cGy were subsequently analyzed separately. Biochemical failure was defined per the ASTRO consensus definition. The log-rank test was used to assess for differences in follow-up and time to biochemical failure. A Kaplan-Meier plot of time to biochemical failure for the initial 3 subgroups was generated.nnnRESULTSnA total of 264 patients were identified. Sixteen patients whose dose was not recorded in the database were excluded from analysis. The median follow-up was 35 months. No significant differences were found in baseline prostate-specific antigen, Gleason grade, or clinical stage among the groups. The overall actuarial rate of 5-year freedom from biochemical failure was 80.2%. By dose level, the 5-year biochemical failure-free rate was 79.2%, 78.4%, and 84.5% for <6660 cGy, 6660 cGy, and >6660 cGy, respectively. These differences were not significant. Subsequently, 45 patients receiving <or=6500 cGy were compared with 23 patients receiving >or=6800 cGy. The difference between these groups was not significant. The 5-year freedom from biochemical failure rate for the patients receiving <or=6500 cGy was 89.9%.nnnCONCLUSIONnWithin a range of doses considered standard for treatment of low-risk clinically localized prostate cancer during an 8-year period, no improvement in biochemical freedom from failure was noted with the higher doses. The overall 5-year rate of freedom from biochemical failure is consistent with that reported by others with standard and escalated external beam doses used in this low-risk population. A prospective randomized study is necessary to define the optimal dose in this patient population.