- Email: [email protected]
Beta Value of Linear-Quadratic Model Dependent on Histologic Grade in Prostate Cancer?
Proceedings of the 53rd Annual ASTRO Meeting external beam radiation therapy (EBRT). To date, there are no published data regarding whether higher COX-2 levels are associated with increased risk of BCF following salvage radiation therapy (SRT) for prostate cancer. We sought to evaluate COX-2 expression in radical prostatectomy (RP) specimens and its association with BCF in men treated with SRT for a detectable PSA after RP. Materials/Methods: We identified 151 men with prostate cancer treated with SRT for a detectable PSA after RP between July 1987 to July 2003 at Mayo Clinic Florida, and for whom we had sufficient diagnostic tissue available for immunohistochemical staining and image analysis of COX-2 expression. Staining levels of COX-2 were detected by monoclonal antibody and quantified by an automated imaging system. COX-2 staining intensity was initially recorded as a numerical variable, and then categorized into 3 levels based on sample tertiles: low (\115), moderate (115-130), and high (.130). Relative risks (RRs) and 95% confidence intervals (CIs) from Cox proportional hazards models were used to evaluate the association between COX-2 staining intensity and the primary endpoint of BCF (PSA $ 0.4 ng/mL post-SRT and rising), in single variable models and after multivariable adjustment. Results: Median follow-up was 4.6 years. The estimated incidence of BCF at 8 years was 57%, 62%, and 47.9% in the low, moderate, and high COX-2 intensity groups, respectively. We observed no evidence of an association between COX-2 intensity and BCF when considering COX-2 as a continuous variable (RR: 0.81 [25 unit increase], 95% CI: 0.63 - 1.05, P = 0.11), or as the aforementioned three-level categorical variable (RR [moderate vs. low]: 1.11, 95% CI: 0.66 - 1.86, P = 0.69; RR [high vs. low]: 0.71, 95% CI: 0.42 - 1.18, P = 0.18). These results remained consistent in multivariable analysis adjusting for pathologic tumor stage, Gleason score, pre-SRT PSA, pre-RP PSA, SRT dose, age, time from RP to initiation of SRT, margin status, pre-SRT hormone therapy, and year of start of SRT. Conclusions: This is the first study to examine the association of COX-2 expression in prostate cancer and patient outcomes after SRT. Although COX-2 overexpression has been associated with an increased risk of BCF after definitive prostate cancer EBRT plus hormone therapy, our data did not show any significant association between COX-2 expression and the risk of BCF after radiation in the salvage setting. If confirmed, COX-2 is not likely to be useful as a biomarker for predicting which men will benefit most from SRT. Author Disclosure: K.S. Tzou: None. S.J. Buskirk: None. M.G. Heckman: None. A.S. Parker: None. V. Patel: None. L. Pelaez: None. T.W. Hilton: None. J.L. Peterson: None. L.A. Vallow: None. A. Pollack: None.
2418
Prospective Pilot Trial of Daily Vitamin D Supplementation in the Active Surveillance of Low-Risk Prostate Cancer
L. Cannick, D. T. Marshall, S. J. Savage, E. Garrett-Mayer, L. H. Ambrose, S. Gattoni-Celli Medical University of South Carolina, Charleston, SC Purpose/Objective(s): Vitamin D inhibits the stress-activated protein kinase p38, an activator of the pro-inflammatory cytokine interleukin 6, implicated in the initiation and progression of prostate cancer. The specific aims of this study are to: 1) determine if daily doses of vitamin D3 (VD3) at 4,000 IU by mouth, taken for at least 12 months, are safe and will result in decreased PSA levels in patients with low risk prostate cancer on active surveillance, and 2) compare percent positive cores from biopsies done before and after treatment with VD3. Materials/Methods: 52 patients(pts) with early stage low risk prostate cancer, serum PSA value #10.0 ng/ml, and a Gleason score of 6 or less, clinical stage \T2b, have been enrolled in this IRB approved pilot study. All pts are monitored via active surveillance for at least one year, which includes routine labs every 8 weeks and a prostate biopsy recommended 12 months after the initial biopsy. Patients are given 4,000 IU orally of VD3 each day. Upon completion of the protocol pts may elect to continue active surveillance or proceed to definitive treatment. The total planned sample size was 80 pts. The study was closed to accrual in September 2010 due to the start of a competing randomized trial testing VD3 versus placebo in active surveillance for low risk prostate cancer pts. Results: From October 2007 to September 2010, 52 pts were enrolled: 14 African America (AA), 37 white (CC), and 1 Asian. Three pts were withdrawn from the study. For pts with baseline VD3 levels\20ng/ml (severely deficient) the median pre-treatment PSA was 5.65 (n = 11), and for subjects with baseline VD3 levels .20ng/ml their median PSA was 4.07 (n = 41). The average baseline VD3 levels by race were AA 23.89ng/ml (n = 14), and CC 36.56ng/ml (n = 37), (p = 0.002). VD3 levels for all pts rose above 20-ng/ml after only 8 weeks of supplementation. With 11.1 months median follow-up, there have been no toxicities associated with the trial. For the 33 pts that have completed the study, there has been an objective decrease in the overall number of positive cores, with no correlation to changes in PSA. Conclusions: These encouraging preliminary observations reveal no adverse effects from the use of 4,000 IU of VD3 daily with .11 months follow-up. Baseline VD3 levels were lower in AA prostate cancer pts than in CC pts. 8 weeks of oral supplementation is sufficient to achieve levels above 20ng/ml. The use of VD3 supplementation may decrease the volume of prostate cancer as seen on repeat biopsy in these pts with low risk disease on active surveillance. Final results will be analyzed when all enrolled pts have completed the study in August of 2011. Author Disclosure: L. Cannick: None. D.T. Marshall: None. S.J. Savage: None. E. Garrett-Mayer: None. L.H. Ambrose: None. S. Gattoni-Celli: None.
2419
Is Alpha/Beta Value of Linear-Quadratic Model Dependent on Histologic Grade in Prostate Cancer?
1,2
Y. Seo , K. Konishi2, M. Morimoto2, F. Isohashi2, T. Ogata2, Y. Takahashi2, I. Sumida2, M. Koizumi2, Y. Yoshioka2 1
Kaizuka City Hospital, Osaka, Japan, 2Osaka University Graduate School of Medicine, Osaka, Japan
Purpose/Objective(s): Multiple studies have shown that an alpha/beta value of a linear-quadratic (LQ) model is much lower in prostate cancer than that in most rapidly growing tumors. However, it is unknown whether the alpha/beta values differ depending on a histologic grade in prostate cancer.
S411
I. J. Radiation Oncology d Biology d Physics
S412
Volume 81, Number 2, Supplement, 2011
Materials/Methods: We retrospectively analyzed 372 patients with localized prostate adenocarcinoma who received definitive radiotherapy from 1996 to 2009 with three different modalities as follows: conventionally fractionated 2D or 3D-conformal external beam radiotherapy (EBRT) 60 Gy in 30 fractions or 70 Gy in 35 fractions, low-dose-rate (I-125) prostate seed implant (PSI) 145 Gy, and high-dose-rate brachytherapy (HDR-BT) 45.5 Gy in 7 fractions bid, 48 Gy in 8 fractions bid or 54 Gy in 9 fractions bid. Freedom from biochemical failure rate (FFbF) at 5 years was a single clinical endpoint used in this study. Biochemical failure was defined according to the Phoenix definition. FFbF was estimated using a Cox model stratified by the dose fractionation schedule and the histologic grade. FFbF was adjusted by prognostic factors including age, initial PSA at diagnosis (iPSA), and a use of hormonal therapy. The histologic grade was defined as low (Gleason score (GS) = 2-6, or WHO grade 1-2), intermediate (GS = 7), and high (GS = 8-10 or WHO grade 3). Biologically effective dose (BED) and the alpha/beta value were based on the LQ model of radiation survival curve. The clinical outcome was then fitted to a logistic sigmoid model as a function of the BED in conjunction with the LQ model. Results: There were 186 low-grade, 101 intermediate-grade, and 85 high-grade tumors. Median age was 70 years old (range: 4582). Median iPSA was 11 ng/ml (range: 2.7-660). Two hundred fifty-two patients received hormonal therapy in a neoadjuvant, concurrent, and/or adjuvant setting. Median follow-up was 34 months. Adjusted FFbF was 90.4 %, 78.4 %, 90.0 %, 23.7 %, 69.9 %, and 77.1 % in patients treated with HDR-BT 45.5 Gy, HDR-BT 48 Gy, HDR-BT 54 Gy, EBRT 60 Gy, EBRT 70 Gy, and PSI 145 Gy, respectively. Adjusted FFbF was 86.7 %, 84.0 %, and 80.3 % in patients with a low-, intermediate-, and high-grade tumor, respectively. The alpha/beta value was estimated to be 1.7 Gy (95% CI: 1.0-2.4), 2.4 Gy (1.1-3.7), and 2.2 Gy (1.6-2.8) for low-, intermediate-, and high-grade tumors, respectively. Conclusions: No significant difference was found in the alpha/beta value among the histologic grades of tumors. The alpha/beta value was less than 3 Gy even in high-grade tumors. In prostate cancer our data does not support a hypothesis in basic radiobiology that fractionation sensitivity is lower in higher-grade tumors. Author Disclosure: Y. Seo: None. K. Konishi: None. M. Morimoto: None. F. Isohashi: None. T. Ogata: None. Y. Takahashi: None. I. Sumida: None. M. Koizumi: None. Y. Yoshioka: None.
2420
A Multi-institutional Trial Of Rectal Dose Reduction During Prostate Radiotherapy Via Polyethyleneglycol Hydrogel Injection: Initial Results
D. Song1, K. Herfarth2, M. Uhl2, B. van Triest3, R. Kalisvaart3, M. Eble4, M. Pinkawa4, D. Weber5, R. Miralbell5, T. DeWeese1 1 Johns Hopkins University, Baltimore, MD, 2University of Heidelberg, Heidelberg, Germany, 3Netherlands Cancer Institute, Amsterdam, Netherlands, 4Aachen University, Aachen, Germany, 5Geneva University, Geneva, Switzerland
Purpose/Objective(s): Rectal toxicity is a major concern following radiotherapy for prostate cancer, and correlated with rectal dose. The purpose of this study was to determine effect on rectal dose of injecting bioabsorbable hydrogel into the prostatic-rectal interface in patients undergoing radiotherapy for prostate cancer. Materials/Methods: Using a transperineal approach under ultrasound guidance, a polyethylene glycol-based hydrogel was injected into the potential space posterior to Denonvilliers’ fascia. Patients underwent imaging prior to and after injection, and IMRT treatment plans were generated on both image sets for comparison. Results: A total of 25 evaluable patients were enrolled at 4 centers under an institutional ethics panel approved protocol. The mean change in prostate to rectal wall distance (measured at base, midgland, and apex) was 8.1mm. Volume of rectum receiving 70 Gy (V70) was reduced from a median of 14.1% pre-injection (range 5.8-26.7%) to a median of 3.0% (0-20.1%) post-injection (p\0.001), with median absolute reduction in rectal V70 of 8.0% (2.9 - 24.5%). Rectal V50 was reduced from a median of 32.1% pre-injection to 13.6% post-injection (median reduction of 16.7%). No significant differences were found between pre- and postinjection rectal volumes. Images obtained at end of radiotherapy course showed persistence of hydrogel. Among 5 patients with images at .12 months following radiotherapy completion, none had visible hydrogel. Conclusions: Injection of polyethylene-glycol based hydrogel results in significant reductions in dose to rectum for prostate radiotherapy. Hydrogel persists through a standard course of radiotherapy, and is absorbed following completion of treatment. Effects of rectal dose reduction on toxicity will be assessed upon further follow-up. Author Disclosure: D. Song: C. Other Research Support; Augmenix research funding. K. Herfarth: C. Other Research Support; Augmenix research funding. M. Uhl: C. Other Research Support; Augmenix research funding. B. van Triest: C. Other Research Support; Augmenix research funding. R. Kalisvaart: C. Other Research Support; Augmenix research funding. M. Eble: C. Other Research Support; Augmenix research funding. M. Pinkawa: C. Other Research Support; Augmenix research funding. D. Weber: C. Other Research Support; Augmenix research funding. R. Miralbell: C. Other Research Support; Augmenix research funding. T. DeWeese: C. Other Research Support; Augmenix research funding.
2421
Differential Dose (a.k.a. Dose Painted) Prostate Brachytherapy Guided by Cancer-Specific Ultrasound Spectrum Analysis (USA) Prostate Imaging: A Prospective Phase I Trial
R. D. Ennis St. Luke’s-Roosevelt Hospital Center/Continuum Cancer Centers of NY, New York, NY Purpose/Objective(s): Standard prostate cancer treatments treat the entire gland because of the known multifocal nature of prostate cancer and the inability to image the discrete tumors with standard imaging. Some have recently proposed focal treatment in which only the dominant tumor is treated. We propose an alternative approach in which the tumor areas are treated with a higher than standard dose of radiotherapy and the remainder of the prostate with a lesser, microscopically adequate, dose. Ultrasound spectrum analysis (USA) is an imaging method which analyzes the spectrum of the radiofrequency signal of an ultrasound to identify the tumor area. This method has been tested in a large biopsy cohort and found to have a ROC of 0.84 (Feleppa Cancer Biomarkers 4:201-212; 2008). We conducted a phase I prospective trial to evaluate the safety and technical capability of using this imaging to guide differential dose prostate brachytherapy. Materials/Methods: 9 low risk patients were enrolled. Both standard B-mode US and USA were performed in OR and images fused. Tumor volumes, prostate and normal tissues contoured. A conservative change from our standard plans was used. Plans
2418
Prospective Pilot Trial of Daily Vitamin D Supplementation in the Active Surveillance of Low-Risk Prostate Cancer
L. Cannick, D. T. Marshall, S. J. Savage, E. Garrett-Mayer, L. H. Ambrose, S. Gattoni-Celli Medical University of South Carolina, Charleston, SC Purpose/Objective(s): Vitamin D inhibits the stress-activated protein kinase p38, an activator of the pro-inflammatory cytokine interleukin 6, implicated in the initiation and progression of prostate cancer. The specific aims of this study are to: 1) determine if daily doses of vitamin D3 (VD3) at 4,000 IU by mouth, taken for at least 12 months, are safe and will result in decreased PSA levels in patients with low risk prostate cancer on active surveillance, and 2) compare percent positive cores from biopsies done before and after treatment with VD3. Materials/Methods: 52 patients(pts) with early stage low risk prostate cancer, serum PSA value #10.0 ng/ml, and a Gleason score of 6 or less, clinical stage \T2b, have been enrolled in this IRB approved pilot study. All pts are monitored via active surveillance for at least one year, which includes routine labs every 8 weeks and a prostate biopsy recommended 12 months after the initial biopsy. Patients are given 4,000 IU orally of VD3 each day. Upon completion of the protocol pts may elect to continue active surveillance or proceed to definitive treatment. The total planned sample size was 80 pts. The study was closed to accrual in September 2010 due to the start of a competing randomized trial testing VD3 versus placebo in active surveillance for low risk prostate cancer pts. Results: From October 2007 to September 2010, 52 pts were enrolled: 14 African America (AA), 37 white (CC), and 1 Asian. Three pts were withdrawn from the study. For pts with baseline VD3 levels\20ng/ml (severely deficient) the median pre-treatment PSA was 5.65 (n = 11), and for subjects with baseline VD3 levels .20ng/ml their median PSA was 4.07 (n = 41). The average baseline VD3 levels by race were AA 23.89ng/ml (n = 14), and CC 36.56ng/ml (n = 37), (p = 0.002). VD3 levels for all pts rose above 20-ng/ml after only 8 weeks of supplementation. With 11.1 months median follow-up, there have been no toxicities associated with the trial. For the 33 pts that have completed the study, there has been an objective decrease in the overall number of positive cores, with no correlation to changes in PSA. Conclusions: These encouraging preliminary observations reveal no adverse effects from the use of 4,000 IU of VD3 daily with .11 months follow-up. Baseline VD3 levels were lower in AA prostate cancer pts than in CC pts. 8 weeks of oral supplementation is sufficient to achieve levels above 20ng/ml. The use of VD3 supplementation may decrease the volume of prostate cancer as seen on repeat biopsy in these pts with low risk disease on active surveillance. Final results will be analyzed when all enrolled pts have completed the study in August of 2011. Author Disclosure: L. Cannick: None. D.T. Marshall: None. S.J. Savage: None. E. Garrett-Mayer: None. L.H. Ambrose: None. S. Gattoni-Celli: None.
2419
Is Alpha/Beta Value of Linear-Quadratic Model Dependent on Histologic Grade in Prostate Cancer?
1,2
Y. Seo , K. Konishi2, M. Morimoto2, F. Isohashi2, T. Ogata2, Y. Takahashi2, I. Sumida2, M. Koizumi2, Y. Yoshioka2 1
Kaizuka City Hospital, Osaka, Japan, 2Osaka University Graduate School of Medicine, Osaka, Japan
Purpose/Objective(s): Multiple studies have shown that an alpha/beta value of a linear-quadratic (LQ) model is much lower in prostate cancer than that in most rapidly growing tumors. However, it is unknown whether the alpha/beta values differ depending on a histologic grade in prostate cancer.
S411
I. J. Radiation Oncology d Biology d Physics
S412
Volume 81, Number 2, Supplement, 2011
Materials/Methods: We retrospectively analyzed 372 patients with localized prostate adenocarcinoma who received definitive radiotherapy from 1996 to 2009 with three different modalities as follows: conventionally fractionated 2D or 3D-conformal external beam radiotherapy (EBRT) 60 Gy in 30 fractions or 70 Gy in 35 fractions, low-dose-rate (I-125) prostate seed implant (PSI) 145 Gy, and high-dose-rate brachytherapy (HDR-BT) 45.5 Gy in 7 fractions bid, 48 Gy in 8 fractions bid or 54 Gy in 9 fractions bid. Freedom from biochemical failure rate (FFbF) at 5 years was a single clinical endpoint used in this study. Biochemical failure was defined according to the Phoenix definition. FFbF was estimated using a Cox model stratified by the dose fractionation schedule and the histologic grade. FFbF was adjusted by prognostic factors including age, initial PSA at diagnosis (iPSA), and a use of hormonal therapy. The histologic grade was defined as low (Gleason score (GS) = 2-6, or WHO grade 1-2), intermediate (GS = 7), and high (GS = 8-10 or WHO grade 3). Biologically effective dose (BED) and the alpha/beta value were based on the LQ model of radiation survival curve. The clinical outcome was then fitted to a logistic sigmoid model as a function of the BED in conjunction with the LQ model. Results: There were 186 low-grade, 101 intermediate-grade, and 85 high-grade tumors. Median age was 70 years old (range: 4582). Median iPSA was 11 ng/ml (range: 2.7-660). Two hundred fifty-two patients received hormonal therapy in a neoadjuvant, concurrent, and/or adjuvant setting. Median follow-up was 34 months. Adjusted FFbF was 90.4 %, 78.4 %, 90.0 %, 23.7 %, 69.9 %, and 77.1 % in patients treated with HDR-BT 45.5 Gy, HDR-BT 48 Gy, HDR-BT 54 Gy, EBRT 60 Gy, EBRT 70 Gy, and PSI 145 Gy, respectively. Adjusted FFbF was 86.7 %, 84.0 %, and 80.3 % in patients with a low-, intermediate-, and high-grade tumor, respectively. The alpha/beta value was estimated to be 1.7 Gy (95% CI: 1.0-2.4), 2.4 Gy (1.1-3.7), and 2.2 Gy (1.6-2.8) for low-, intermediate-, and high-grade tumors, respectively. Conclusions: No significant difference was found in the alpha/beta value among the histologic grades of tumors. The alpha/beta value was less than 3 Gy even in high-grade tumors. In prostate cancer our data does not support a hypothesis in basic radiobiology that fractionation sensitivity is lower in higher-grade tumors. Author Disclosure: Y. Seo: None. K. Konishi: None. M. Morimoto: None. F. Isohashi: None. T. Ogata: None. Y. Takahashi: None. I. Sumida: None. M. Koizumi: None. Y. Yoshioka: None.
2420
A Multi-institutional Trial Of Rectal Dose Reduction During Prostate Radiotherapy Via Polyethyleneglycol Hydrogel Injection: Initial Results
D. Song1, K. Herfarth2, M. Uhl2, B. van Triest3, R. Kalisvaart3, M. Eble4, M. Pinkawa4, D. Weber5, R. Miralbell5, T. DeWeese1 1 Johns Hopkins University, Baltimore, MD, 2University of Heidelberg, Heidelberg, Germany, 3Netherlands Cancer Institute, Amsterdam, Netherlands, 4Aachen University, Aachen, Germany, 5Geneva University, Geneva, Switzerland
Purpose/Objective(s): Rectal toxicity is a major concern following radiotherapy for prostate cancer, and correlated with rectal dose. The purpose of this study was to determine effect on rectal dose of injecting bioabsorbable hydrogel into the prostatic-rectal interface in patients undergoing radiotherapy for prostate cancer. Materials/Methods: Using a transperineal approach under ultrasound guidance, a polyethylene glycol-based hydrogel was injected into the potential space posterior to Denonvilliers’ fascia. Patients underwent imaging prior to and after injection, and IMRT treatment plans were generated on both image sets for comparison. Results: A total of 25 evaluable patients were enrolled at 4 centers under an institutional ethics panel approved protocol. The mean change in prostate to rectal wall distance (measured at base, midgland, and apex) was 8.1mm. Volume of rectum receiving 70 Gy (V70) was reduced from a median of 14.1% pre-injection (range 5.8-26.7%) to a median of 3.0% (0-20.1%) post-injection (p\0.001), with median absolute reduction in rectal V70 of 8.0% (2.9 - 24.5%). Rectal V50 was reduced from a median of 32.1% pre-injection to 13.6% post-injection (median reduction of 16.7%). No significant differences were found between pre- and postinjection rectal volumes. Images obtained at end of radiotherapy course showed persistence of hydrogel. Among 5 patients with images at .12 months following radiotherapy completion, none had visible hydrogel. Conclusions: Injection of polyethylene-glycol based hydrogel results in significant reductions in dose to rectum for prostate radiotherapy. Hydrogel persists through a standard course of radiotherapy, and is absorbed following completion of treatment. Effects of rectal dose reduction on toxicity will be assessed upon further follow-up. Author Disclosure: D. Song: C. Other Research Support; Augmenix research funding. K. Herfarth: C. Other Research Support; Augmenix research funding. M. Uhl: C. Other Research Support; Augmenix research funding. B. van Triest: C. Other Research Support; Augmenix research funding. R. Kalisvaart: C. Other Research Support; Augmenix research funding. M. Eble: C. Other Research Support; Augmenix research funding. M. Pinkawa: C. Other Research Support; Augmenix research funding. D. Weber: C. Other Research Support; Augmenix research funding. R. Miralbell: C. Other Research Support; Augmenix research funding. T. DeWeese: C. Other Research Support; Augmenix research funding.
2421
Differential Dose (a.k.a. Dose Painted) Prostate Brachytherapy Guided by Cancer-Specific Ultrasound Spectrum Analysis (USA) Prostate Imaging: A Prospective Phase I Trial
R. D. Ennis St. Luke’s-Roosevelt Hospital Center/Continuum Cancer Centers of NY, New York, NY Purpose/Objective(s): Standard prostate cancer treatments treat the entire gland because of the known multifocal nature of prostate cancer and the inability to image the discrete tumors with standard imaging. Some have recently proposed focal treatment in which only the dominant tumor is treated. We propose an alternative approach in which the tumor areas are treated with a higher than standard dose of radiotherapy and the remainder of the prostate with a lesser, microscopically adequate, dose. Ultrasound spectrum analysis (USA) is an imaging method which analyzes the spectrum of the radiofrequency signal of an ultrasound to identify the tumor area. This method has been tested in a large biopsy cohort and found to have a ROC of 0.84 (Feleppa Cancer Biomarkers 4:201-212; 2008). We conducted a phase I prospective trial to evaluate the safety and technical capability of using this imaging to guide differential dose prostate brachytherapy. Materials/Methods: 9 low risk patients were enrolled. Both standard B-mode US and USA were performed in OR and images fused. Tumor volumes, prostate and normal tissues contoured. A conservative change from our standard plans was used. Plans