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Role of Vascular Endothelial Growth Factor in the Treatment of Locally Advanced Prostate Cancer
I. J. Radiation Oncology d Biology d Physics
S346
Volume 75, Number 3, Supplement, 2009
determined to be 4.5 min. The data seemed to be slightly longer than the data obtained by the water phantom. The half-life of water mainly consisted of 15O (half-life, 2.0 minutes). Therefore, it was speculated that the reason why the half-life of the urine was slightly longer than water was probably because urine contained not only water but also other materials with 13N (half-life, 10.0 minutes) or 11C (half-life, 20.4 minutes). Conclusions: A novel finding that urine was activated after proton beam therapy was proved by the direct measurement and by the PET imaging. These findings may become an important step for the development of a verification method of proton therapy by PET. Author Disclosure: M. Shimizu, None; R. Sasaki, None; D. Miyawaki, None; H. Nishimura, None; Y. Demizu, None; T. Akagi, None; D. Suga, None; M. Murakami, None; K. Sugimura, None; Y. Hishikawa, None.
2366
WITHDRAWN
2367
Daily Vitamin D Supplementation in the Active Surveillance of Low-risk Prostate Cancer
L. Cannick, D. T. Marshall, S. J. Savage, 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 objective of this study is to determine if daily doses of vitamin D3 (VD3) at 4,000 IU by mouth, taken for 12 months will result in decreased PSA levels in patients with low-risk prostate cancer on active surveillance, and to compare percent positive prostate cores pre and post treatment. Materials/Methods: 80 male patients with early stage low risk prostate cancer, serum PSA a serum PSA value of #10.0 ng/ml, and a Gleason score of 6 or less will be enrolled. All subjects will be monitored via active surveillance for at least one year, which will include routine labs every 8 weeks and a prostate biopsy recommended at the end of 12 months. Subjects will be given 4,000 IU of (VD3) each day. Upon completion of the protocol the patients may elect to continue with active surveillance or proceed to definitive treatment. Results: From October 2007 to April 2009, 33 subjects have enrolled onto the study, 12 African America (AA), 20 Caucasian (CC), and 1 Asian. One subject was terminated because he was diagnosed with colorectal cancer shortly after enrollment; a second was removed due to noncompliance with VD3 supplementation. 10 subjects have completed treatment thus far. For subjects with VD3 levels \20ng/ml (severely deficient) the average pre-treatment PSA was 5.183 (n = 9), and for subjects with VD3 levels .20ng/ml their average PSA was 4.02 (n = 20). The average VD3 levels by race were AA 22.48ng/ml (n = 12), and Caucasian 36.18ng/ml (n = 19). All patients’ VD3 levels rose above 20 ng/ml after only 8 weeks of supplementation. There have been no toxicities associated with the trial. For the 21 patients with at least 5 months of VD3 supplementation, 4 were VD3 deficient prior to initiation of supplementation and 17 were not. The average increase in PSA during this time frame for these 21 patients was 0.028 ng/ml for the 4 VD3 deficient patients and 1.075 ng/ml for the 17 patients who were not VD3 deficient at the initiation of VD3 supplementation. Of the 10 subjects that have completed the study the average pre-treatment PSA was 3.88 and post-treatment PSA was 4.03. Four of five patients who have had post-study prostate biopsies have had a decrease in the number of positive cores. Conclusions: These preliminary observations reveal no adverse effects from the use of 4,000 IU of VD3 daily. These data also suggest that vitamin D levels are lower in AA prostate cancer patients than in CC patients. The use of VD3 supplementation may decrease PSA velocity in men with early-stage, low-risk prostate cancer, especially those who are severely vitamin D-deficient (\20 ng 25-OH- D3 per mL of serum). Author Disclosure: L. Cannick, None; D.T. Marshall, None; S.J. Savage, None; L.H. Ambrose, None; S. Gattoni-Celli, None.
2368
Role of Vascular Endothelial Growth Factor in the Treatment of Locally Advanced Prostate Cancer
H. Bora, E. Yirmibesoglu, M. Demirel, M. Akmansu Gazi Un. Medical Fac, Ankara, Turkey Purpose/Objective(s): Target-based treatment is become a current issue as a result of anti-cancer drugs that are developed in recent years. Vascular endothelial growth factor (VEGF) is a key molecule in angiogenesis that had a major role in cancer growth. High VEGF expression has seen by adaptation to low oxygenation (hypoxia) in the microenvoirement of tumor. Hypoxia is accepted as an actual factor related to/with progression of malignancy, resistance to cancer treatment and poor prognosis. In our research, we aimed to study the possible effect of VEGF expression on results of radiation therapy (RT) in the teratment of locally advanced prostate cancer. Materials/Methods: Fifty diagnosed as locally advanced prostate cancer that are treated with radiation were analysed retrospectively according to VEGF expression and prognosis. Biochemically failure is defined by the American Society for Therapeutic Radiology and Oncology Phoenix Consensus panel statement. For VEGF expression levels, immunreactive score is estimated with percent and intensity score by immunohistochemically. Patients were classified as having low (0-4) and high (5-8) VEGF expression and analysed according to the groups. Results: Median age was 70 (53-82 years). Mean PSA value was 19.5ng/ml (4-66ng/ml) and PSA values of 24 patient were (48%) #10ng/ml at diagnosis. Gleason score reported by transrectal biopsy were #6 in 29 patient (58%), $7 in 21 patient (42%). Nineteen patient (38%) were classified as low risk group according to PSA level and gleason score. Median RT dose was 69Gy (60-74Gy). Median follow up duration was 5 years. RT protocol were planned primer to 41 patient, withal adjuvant after radical prostatectomy to nine patient. VEGF expression were analysed low (0-4) in 27 patient (54%) and high (5-8) in 23 patient (46%). Median progression-free survival was longer in the low VEGF group (10.4 versus 4.6 years). In the univariete analysis, high VEGF expression and high Gleason Score were the statistically significant determinants for biochemical failure after RT but, in the multivariate analysis, VEGF expresyonu is not an independent variable except Gleason Score.
Proceedings of the 51st Annual ASTRO Meeting Conclusions: Standard treatment modalities like surgery, RT and hormonotherapy may be an option as alone or combined in the locally advanced prostate carcinoma. It is a debate to define the patients whom are sensitive to treatment. Cellular and/or moleculer biological markers are needed for assesment of target-based treatment among prostate cancer treatment algorithym. Extended investigations that are designed among large series of locally advanced prostate cancer with long follow up period, aimed to review sensitivity and spesificity of possible related markers are needed. Author Disclosure: H. Bora, None; E. Yirmibesoglu, None; M. Demirel, None; M. Akmansu, None.
2369
Factors Predicting Prostate Gland Shrinkage following Neoadjuvant Cytoreductive Therapy
R. Anderson1, G. S. Merrick1, W. M. Butler1, R. W. Galbreath1,2, K. E. Wallner3, Z. A. Allen1 Schiffler Cancer Center, Wheeling, WV, 2Wheeling Jesuit University, Wheeling, WV, 3Puget Sound Healthcare Corporation, Seattle, WA 1
Purpose/Objective(s): Patients often receive neoadjuvant medical therapy for prostate gland size reduction prior to brachytherapy. Previous studies have demonstrated that a 3 month course of neoadjuvant therapy results in average prostate volume reductions of 21% to 54%. In this study, we evaluated whether multiple parameters including tumor volume and/or tumor grade as determined by transperineal template-guided mapping biopsy (TTMB) correlated with the degree of prostate gland size reduction. Materials/Methods: Seventy-five patients who were diagnosed with prostate cancer by TTMB (median number of biopsies 59) received neoadjuvant cytoreductive therapy. Thirty patients received a 3 month course of a LH/RH agonist and an anti-androgen while 45 patients received a 3 month course of bicalutamide (50mg daily) and Avodart (0.5mg daily) prior to brachytherapy. A transrectal ultrasound volumetric study of the prostate gland and ellipsoid volume determination of the prostate gland and transition zone were obtained immediately prior to TTMB and at 90 days (+/- 5 days) following the initiation of neoadjuvant medical therapy. A multivariate analysis was performed to identify predictors for prostate gland and transition zone volume reduction. Results: At TTMB, the mean prostate volumetric and ellipsoid volumes were 57.1cm3 and 50.6cm3, respectively with a mean ellipsoid transition zone volume of 20.5cm3. Following neoadjuvant medical therapy, the mean volumetric and ellipsoid prostate volumes were 31.7cm3 and 29.2cm3 with a mean ellipsoid transition zone volume of 10.3cm3. On average, the prostate volume decreased by 43.6% and 41.4% by volumetric and ellipsoid determinations, while the transition zone volume decreased by 48.0%. Volumetric and ellipsoid prostate volumes were associated with percent positive biopsies (p = 0.006 volumetric; p = 0.026 ellipsoid). In addition, a correlation existed between percent positive transition zone cores and the percent transition zone cytoreduction (p = 0.019). Higher Gleason scores correlated with greater prostate volumetric, ellipsoid and transition zone cytoreduction (p = 0.001, p = 0.04 and p = 0.006, respectively). In multivariate analysis, prostate volume cytoreduction was best predicted by perineural invasion and tobacco consumption while transition zone cytoreduction was most closely related to pre-biopsy PSA and tobacco. In multivariate analysis, neither tumor volume or Gleason score maintained statistical significance. Conclusions: Prostate volume cytoreduction was closely related to tobacco consumption. In patients with current tobacco consumption, maximal cytoreduction may require an extended course of neoadjuvant medical therapy. Author Disclosure: R. Anderson, None; G.S. Merrick, None; W.M. Butler, None; R.W. Galbreath, None; K.E. Wallner, None; Z.A. Allen, None.
2370
A Method to Overcome the Limitations of KVCT and MVCT in Treatment Planning for Patients with Bilateral Hip Prostheses
J. Duan, C. D. Willey, S. Shen, I. A. Brezovich University of Alabama Medical Center, Birmingham, AL Purpose/Objective(s): Treatment planning for patients with bilateral hip replacements is challenging, especially if beams must penetrate the prosthesis to treat the surrounding tissues. The high density prosthesis causes severe artifacts in conventional KVCT, which makes it extremely difficult to identify the target and normal structures and also introduces significant errors in heterogeneity-corrected dose calculation. Though tomotherapy MVCT does not suffer strong artifacts from the prosthesis, it is limited by the 40 cm field of view, which is too small to image the whole pelvis for most patients, and poorer image contrast. The purpose of this study is to demonstrate a treatment planning technique that overcomes these limitations by combining the advantages of KV and MV CTs. Materials/Methods: For patients with bilateral hip prostheses, treatment planning CTs were acquired with conventional KVCT and tomotherapy MVCT with identical patient positioning. The two CTs were registered with a priority on the prostheses. Targets and critical normal organs were identified on the KVCT with the assistance of the MVCT and other imaging modalities such as MRI. The prostheses were precisely identified on the MVCT and the contours were copied to KVCT. The CT number-electron density calibration curve for the KVCT was artificially extended beyond the density of the prosthesis. For CT slices containing artifacts, tissues were assigned a CT number of 0. The prosthesis was assigned the CT number corresponding to its electron density. Two identical treatment plans were generated based on the KVCT and MVCT, respectively, and doses were calculated with tissue heterogeneity correction. For the purpose of analysis, the plans were designed such that no beams enter through the image cutoff regions. The KVCT-based plan was compared with the MVCT-based one (as ‘‘gold standard’’). Results: When the KVCT was used without any correction, the dose discrepancy between the KVCT plan and MVCT plan was as high as 11%. Dose errors for beams exiting the prosthesis could be greater than 30%. If the prostheses were assigned the CT number corresponding to its electron density, the dose discrepancy was reduced to within 6.6%. If the pelvic tissues were assigned a CT number of 0 to minimize the effect of artifacts caused by the prostheses, the dose discrepancy was further reduced to within 3.5%. Conclusions: For patients with bilateral hip prostheses, dose calculation errors in KVCT-based treatment plans can be substantially reduced by using the MVCT to precisely identify the prostheses and using manually assigned CT numbers for the prostheses and artifact-affected pelvic tissues. This technique overcomes the limitations of KVCT or MVCT used alone in treatment planning and can be routinely applied in the clinic. Author Disclosure: J. Duan, None; C.D. Willey, None; S. Shen, None; I.A. Brezovich, None.
S347
S346
Volume 75, Number 3, Supplement, 2009
determined to be 4.5 min. The data seemed to be slightly longer than the data obtained by the water phantom. The half-life of water mainly consisted of 15O (half-life, 2.0 minutes). Therefore, it was speculated that the reason why the half-life of the urine was slightly longer than water was probably because urine contained not only water but also other materials with 13N (half-life, 10.0 minutes) or 11C (half-life, 20.4 minutes). Conclusions: A novel finding that urine was activated after proton beam therapy was proved by the direct measurement and by the PET imaging. These findings may become an important step for the development of a verification method of proton therapy by PET. Author Disclosure: M. Shimizu, None; R. Sasaki, None; D. Miyawaki, None; H. Nishimura, None; Y. Demizu, None; T. Akagi, None; D. Suga, None; M. Murakami, None; K. Sugimura, None; Y. Hishikawa, None.
2366
WITHDRAWN
2367
Daily Vitamin D Supplementation in the Active Surveillance of Low-risk Prostate Cancer
L. Cannick, D. T. Marshall, S. J. Savage, 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 objective of this study is to determine if daily doses of vitamin D3 (VD3) at 4,000 IU by mouth, taken for 12 months will result in decreased PSA levels in patients with low-risk prostate cancer on active surveillance, and to compare percent positive prostate cores pre and post treatment. Materials/Methods: 80 male patients with early stage low risk prostate cancer, serum PSA a serum PSA value of #10.0 ng/ml, and a Gleason score of 6 or less will be enrolled. All subjects will be monitored via active surveillance for at least one year, which will include routine labs every 8 weeks and a prostate biopsy recommended at the end of 12 months. Subjects will be given 4,000 IU of (VD3) each day. Upon completion of the protocol the patients may elect to continue with active surveillance or proceed to definitive treatment. Results: From October 2007 to April 2009, 33 subjects have enrolled onto the study, 12 African America (AA), 20 Caucasian (CC), and 1 Asian. One subject was terminated because he was diagnosed with colorectal cancer shortly after enrollment; a second was removed due to noncompliance with VD3 supplementation. 10 subjects have completed treatment thus far. For subjects with VD3 levels \20ng/ml (severely deficient) the average pre-treatment PSA was 5.183 (n = 9), and for subjects with VD3 levels .20ng/ml their average PSA was 4.02 (n = 20). The average VD3 levels by race were AA 22.48ng/ml (n = 12), and Caucasian 36.18ng/ml (n = 19). All patients’ VD3 levels rose above 20 ng/ml after only 8 weeks of supplementation. There have been no toxicities associated with the trial. For the 21 patients with at least 5 months of VD3 supplementation, 4 were VD3 deficient prior to initiation of supplementation and 17 were not. The average increase in PSA during this time frame for these 21 patients was 0.028 ng/ml for the 4 VD3 deficient patients and 1.075 ng/ml for the 17 patients who were not VD3 deficient at the initiation of VD3 supplementation. Of the 10 subjects that have completed the study the average pre-treatment PSA was 3.88 and post-treatment PSA was 4.03. Four of five patients who have had post-study prostate biopsies have had a decrease in the number of positive cores. Conclusions: These preliminary observations reveal no adverse effects from the use of 4,000 IU of VD3 daily. These data also suggest that vitamin D levels are lower in AA prostate cancer patients than in CC patients. The use of VD3 supplementation may decrease PSA velocity in men with early-stage, low-risk prostate cancer, especially those who are severely vitamin D-deficient (\20 ng 25-OH- D3 per mL of serum). Author Disclosure: L. Cannick, None; D.T. Marshall, None; S.J. Savage, None; L.H. Ambrose, None; S. Gattoni-Celli, None.
2368
Role of Vascular Endothelial Growth Factor in the Treatment of Locally Advanced Prostate Cancer
H. Bora, E. Yirmibesoglu, M. Demirel, M. Akmansu Gazi Un. Medical Fac, Ankara, Turkey Purpose/Objective(s): Target-based treatment is become a current issue as a result of anti-cancer drugs that are developed in recent years. Vascular endothelial growth factor (VEGF) is a key molecule in angiogenesis that had a major role in cancer growth. High VEGF expression has seen by adaptation to low oxygenation (hypoxia) in the microenvoirement of tumor. Hypoxia is accepted as an actual factor related to/with progression of malignancy, resistance to cancer treatment and poor prognosis. In our research, we aimed to study the possible effect of VEGF expression on results of radiation therapy (RT) in the teratment of locally advanced prostate cancer. Materials/Methods: Fifty diagnosed as locally advanced prostate cancer that are treated with radiation were analysed retrospectively according to VEGF expression and prognosis. Biochemically failure is defined by the American Society for Therapeutic Radiology and Oncology Phoenix Consensus panel statement. For VEGF expression levels, immunreactive score is estimated with percent and intensity score by immunohistochemically. Patients were classified as having low (0-4) and high (5-8) VEGF expression and analysed according to the groups. Results: Median age was 70 (53-82 years). Mean PSA value was 19.5ng/ml (4-66ng/ml) and PSA values of 24 patient were (48%) #10ng/ml at diagnosis. Gleason score reported by transrectal biopsy were #6 in 29 patient (58%), $7 in 21 patient (42%). Nineteen patient (38%) were classified as low risk group according to PSA level and gleason score. Median RT dose was 69Gy (60-74Gy). Median follow up duration was 5 years. RT protocol were planned primer to 41 patient, withal adjuvant after radical prostatectomy to nine patient. VEGF expression were analysed low (0-4) in 27 patient (54%) and high (5-8) in 23 patient (46%). Median progression-free survival was longer in the low VEGF group (10.4 versus 4.6 years). In the univariete analysis, high VEGF expression and high Gleason Score were the statistically significant determinants for biochemical failure after RT but, in the multivariate analysis, VEGF expresyonu is not an independent variable except Gleason Score.
Proceedings of the 51st Annual ASTRO Meeting Conclusions: Standard treatment modalities like surgery, RT and hormonotherapy may be an option as alone or combined in the locally advanced prostate carcinoma. It is a debate to define the patients whom are sensitive to treatment. Cellular and/or moleculer biological markers are needed for assesment of target-based treatment among prostate cancer treatment algorithym. Extended investigations that are designed among large series of locally advanced prostate cancer with long follow up period, aimed to review sensitivity and spesificity of possible related markers are needed. Author Disclosure: H. Bora, None; E. Yirmibesoglu, None; M. Demirel, None; M. Akmansu, None.
2369
Factors Predicting Prostate Gland Shrinkage following Neoadjuvant Cytoreductive Therapy
R. Anderson1, G. S. Merrick1, W. M. Butler1, R. W. Galbreath1,2, K. E. Wallner3, Z. A. Allen1 Schiffler Cancer Center, Wheeling, WV, 2Wheeling Jesuit University, Wheeling, WV, 3Puget Sound Healthcare Corporation, Seattle, WA 1
Purpose/Objective(s): Patients often receive neoadjuvant medical therapy for prostate gland size reduction prior to brachytherapy. Previous studies have demonstrated that a 3 month course of neoadjuvant therapy results in average prostate volume reductions of 21% to 54%. In this study, we evaluated whether multiple parameters including tumor volume and/or tumor grade as determined by transperineal template-guided mapping biopsy (TTMB) correlated with the degree of prostate gland size reduction. Materials/Methods: Seventy-five patients who were diagnosed with prostate cancer by TTMB (median number of biopsies 59) received neoadjuvant cytoreductive therapy. Thirty patients received a 3 month course of a LH/RH agonist and an anti-androgen while 45 patients received a 3 month course of bicalutamide (50mg daily) and Avodart (0.5mg daily) prior to brachytherapy. A transrectal ultrasound volumetric study of the prostate gland and ellipsoid volume determination of the prostate gland and transition zone were obtained immediately prior to TTMB and at 90 days (+/- 5 days) following the initiation of neoadjuvant medical therapy. A multivariate analysis was performed to identify predictors for prostate gland and transition zone volume reduction. Results: At TTMB, the mean prostate volumetric and ellipsoid volumes were 57.1cm3 and 50.6cm3, respectively with a mean ellipsoid transition zone volume of 20.5cm3. Following neoadjuvant medical therapy, the mean volumetric and ellipsoid prostate volumes were 31.7cm3 and 29.2cm3 with a mean ellipsoid transition zone volume of 10.3cm3. On average, the prostate volume decreased by 43.6% and 41.4% by volumetric and ellipsoid determinations, while the transition zone volume decreased by 48.0%. Volumetric and ellipsoid prostate volumes were associated with percent positive biopsies (p = 0.006 volumetric; p = 0.026 ellipsoid). In addition, a correlation existed between percent positive transition zone cores and the percent transition zone cytoreduction (p = 0.019). Higher Gleason scores correlated with greater prostate volumetric, ellipsoid and transition zone cytoreduction (p = 0.001, p = 0.04 and p = 0.006, respectively). In multivariate analysis, prostate volume cytoreduction was best predicted by perineural invasion and tobacco consumption while transition zone cytoreduction was most closely related to pre-biopsy PSA and tobacco. In multivariate analysis, neither tumor volume or Gleason score maintained statistical significance. Conclusions: Prostate volume cytoreduction was closely related to tobacco consumption. In patients with current tobacco consumption, maximal cytoreduction may require an extended course of neoadjuvant medical therapy. Author Disclosure: R. Anderson, None; G.S. Merrick, None; W.M. Butler, None; R.W. Galbreath, None; K.E. Wallner, None; Z.A. Allen, None.
2370
A Method to Overcome the Limitations of KVCT and MVCT in Treatment Planning for Patients with Bilateral Hip Prostheses
J. Duan, C. D. Willey, S. Shen, I. A. Brezovich University of Alabama Medical Center, Birmingham, AL Purpose/Objective(s): Treatment planning for patients with bilateral hip replacements is challenging, especially if beams must penetrate the prosthesis to treat the surrounding tissues. The high density prosthesis causes severe artifacts in conventional KVCT, which makes it extremely difficult to identify the target and normal structures and also introduces significant errors in heterogeneity-corrected dose calculation. Though tomotherapy MVCT does not suffer strong artifacts from the prosthesis, it is limited by the 40 cm field of view, which is too small to image the whole pelvis for most patients, and poorer image contrast. The purpose of this study is to demonstrate a treatment planning technique that overcomes these limitations by combining the advantages of KV and MV CTs. Materials/Methods: For patients with bilateral hip prostheses, treatment planning CTs were acquired with conventional KVCT and tomotherapy MVCT with identical patient positioning. The two CTs were registered with a priority on the prostheses. Targets and critical normal organs were identified on the KVCT with the assistance of the MVCT and other imaging modalities such as MRI. The prostheses were precisely identified on the MVCT and the contours were copied to KVCT. The CT number-electron density calibration curve for the KVCT was artificially extended beyond the density of the prosthesis. For CT slices containing artifacts, tissues were assigned a CT number of 0. The prosthesis was assigned the CT number corresponding to its electron density. Two identical treatment plans were generated based on the KVCT and MVCT, respectively, and doses were calculated with tissue heterogeneity correction. For the purpose of analysis, the plans were designed such that no beams enter through the image cutoff regions. The KVCT-based plan was compared with the MVCT-based one (as ‘‘gold standard’’). Results: When the KVCT was used without any correction, the dose discrepancy between the KVCT plan and MVCT plan was as high as 11%. Dose errors for beams exiting the prosthesis could be greater than 30%. If the prostheses were assigned the CT number corresponding to its electron density, the dose discrepancy was reduced to within 6.6%. If the pelvic tissues were assigned a CT number of 0 to minimize the effect of artifacts caused by the prostheses, the dose discrepancy was further reduced to within 3.5%. Conclusions: For patients with bilateral hip prostheses, dose calculation errors in KVCT-based treatment plans can be substantially reduced by using the MVCT to precisely identify the prostheses and using manually assigned CT numbers for the prostheses and artifact-affected pelvic tissues. This technique overcomes the limitations of KVCT or MVCT used alone in treatment planning and can be routinely applied in the clinic. Author Disclosure: J. Duan, None; C.D. Willey, None; S. Shen, None; I.A. Brezovich, None.
S347