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Sustained Long-term Immune Responses Following In Situ Gene Therapy Combined with Radiotherapy and Hormonal Therapy in Prostate Cancer Patients
Proceedings of the 47th Annual ASTRO Meeting
2117
Efficacy of Neoadjuvant Dutasteride and Bicalutamide as a Cytoreductive Regimen Prior to Permanent Interstitial Brachytherapy
R.L. Anderson,1 G. Merrick,1,2 W. Butler,1,2 K. Wallner,3 R. Galbreath,1,4 R. Coram5 Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, 2Wheeling Jesuit University, Wheeling, WV, 3Group Health Cooperative, Puget Sound Veterans Administration, and University of Washington, Seattle, WA, 4Ohio University Eastern, St. Clairsville, OH, 5Department of Pharmacy, Wheeling Hospital, Wheeling, WV 1
Purpose/Objective: In patients with a large prostate gland and/or urinary obstructive symptoms, neoadjuvant treatment with an LHRH agonist and an anti-androgen is often used for cytoreduction prior to brachytherapy. Because of the morbidity of this approach, we evaluated the cytoreductive effectiveness of neoadjuvant dutasteride and bicalutamide. Materials/Methods: Between April 2003 and February 2005, 26 patients opted for cytoreduction with dutasteride (0.5 mg daily) and bicalutamide (50 mg daily). Following initiation of bicalutamide, liver function studies were obtained at 4 and 8 weeks to rule out hepatotoxicity. Prior to the initiation of medical therapy and at 3 months, all patients underwent a transrectal ultrasound volumetric study of the prostate gland, an ellipsoid volume determination of the prostate gland, and an ellipsoid volume determination of the transition zone. All ultrasounds were obtained by the same ultrasonographer. Variables analyzed include pre- and post-treatment prostate and transition zone volumes and changes in width, height, and length of the prostate gland and transition zone. Results: Prior to the initiation of dutasteride and bicalutamide, the mean prostate volume was 56.3 cm3 by volumetric evaluation and 51.5 cm3 by ellipsoid volume determination. Following a 3-month course of dutasteride and bicalutamide, the average prostate volume was 38.1 cm3 (a 33% reduction) and 34.8 cm3 (a 32% reduction) by volumetric and ellipsoid volume determinations respectively. Dutasteride and bicalutamide resulted in a 37.0% reduction in transition zone volume (22.6 cm3 versus 14.0 cm3 before and after treatment). In terms of width, height and length, the prostate gland and transition zone dimensions decreased on average from 11.0% to 17.4%. Conclusions: Prostate gland and transition zone volume reductions with dutasteride and bicalutamide are comparable to previous reports of volume reduction using an LHRH agonist with or without an anti-androgen. Because of a presumed lesser incidence of treatment-related morbidity, the cytoreductive regimen of dutasteride and bicalutamide deserves additional investigation.
2118
Prostate Brachytherapy-Induced Urethral Strictures
W.M. Butler,1,2 G. Merrick,1,2 K. Wallner,3 R. Galbreath,1,4 R. Anderson,1 Z. Allen1,2 Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, 2Wheeling Jesuit University, Wheeling, WV, 3Group Health Cooperative, Puget Sound Veterans Administration, and University of Washington, Seattle, WA, 4Ohio University Eastern, St. Clairsville, OH 1
Purpose/Objective: To determine the incidence and to identify clinical, treatment and dosimetric parameters associated with the development of urethral strictures following permanent prostate brachytherapy. Materials/Methods: From April 1995 through May 2003, 1,186 consecutive patients underwent prostate brachytherapy for clinical stage T1b-T3a NxM0 (2002 AJCC) prostate cancer. Nine hundred and twelve patients (76.9%) were implanted with Pd-103 and 204 (23.1%) with I-125. The median follow-up was 4.3 years. Follow-up was calculated from the date of implantation. Clinical, treatment and dosimetric parameters evaluated for bulbomembranous urethral strictures included patient age, prostate volume, the use of supplemental XRT, isotope, androgen deprivation therapy (ADT), duration of ADT, prostate V100/150/200, D90, prostatic urethral dose (mean, median and maximum), bulbomembranous urethral dose (mean, median and maximum), tobacco use, hypertension, diabetes and BMI. Results: Twenty-nine patients developed brachytherapy-induced strictures with all strictures involving the bulbomembranous urethra. The 9-year actuarial risk for the development of a bulbomembranous urethral stricture was 3.6% with a median time to development of 34 months. The mean radiation dose to the bulbomembranous urethra was significantly greater in patients with strictures than those without (p ⫽ 0.002). In particular, the urethral dose 10 and 15 mm distal to the prostate apex was significantly greater in patients with strictures (p ⬍ 0.001). In multivariate analysis, the bulbomembranous urethral dose and the use of supplemental XRT predicted for the development of a urethral stricture. All but one patient was successfully managed by either urethral dilatation or internal optical urethrotomy. Conclusions: Brachytherapy-related urethral strictures are related to overaggressive implantation of the periapical region and the use of supplemental XRT. Careful attention to preplanning and intraoperative execution, along with the judicious use of supplemental XRT, is essential to minimize the incidence of brachytherapy-related strictures.
2119
Sustained Long-term Immune Responses Following In Situ Gene Therapy Combined with Radiotherapy and Hormonal Therapy in Prostate Cancer Patients
T. Fujita,1 B.S. Teh,2,3 T.L. Timme,1 W. Mai,2 T. Satoh,1 N. Kusaka,1 K. Naruishi,1 E.A. Fattah,1 E. Aguilar-Cordova,4 E. Butler,2,3 T.C. Thompson1,5 1 Scott Department of Urology, Baylor College of Medicine, Houston, TX, 2Radiology / Section of Radiation Oncology, Baylor College of Medicine, Houston, TX, 3Radiation Oncology, The Methodist Hospital, Houston, TX, 4Gene Vector Laboratory, Baylor College of Medicine, Houston, TX, 5Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX Purpose/Objective: Adenoviral vector mediated Herpes Simplex Virus-thymidine kinase (AdHSVtk) ⫹ valacyclovir (VCV) in situ gene therapy combined with intensity-modulated radiation therapy (IMRT) and hormonal therapy may have an enhanced efficacy because of complementary mechanisms of cytotoxicity. We are currently conducting clinical trials using this approach. This study explores sustained long-term immune responses following combined radio-gene and hormonal therapy.
S299
S300
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Materials/Methods: Thirty-three patients with PSA ⬎/⫽ 10 or Gleason score ⬎/⫽ 7 or clinical stage T2b-T3 were treated as follows: Gene therapy: 3 separate intraprostatic injections of AdHSV-tk were performed on days 0, 56, and 70. Each injection was followed by 2 weeks of VCV. IMRT was delivered 2 days after the second AdHSV-tk injection for 7 weeks. Hormonal therapy: lupron and flutamide were initiated on day 0 and continued for 4 months or 2.3 years. Heparin-treated bloods were taken at selected intervals before, during, and after the treatment. Peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting (FACS) after labeling with dual color labeled antibody pairs. FACS results following initiation of treatment were compared with pre-treatment values. Results: Median follow-up for the entire group was 26 months (4 – 48 months). The pre-treatment mean percentages of total CD8⫹ T cells, activated CD8⫹ (DR⫹CD8⫹) T cells, and activated CD4⫹ (DR⫹CD4⫹) T cells were 19.2%, 14.7%, and 7.8% respectively. Specific T-cell populations were increased at specific time points following treatment and compared with pretreatment levels as follows: Two weeks after the first gene therapy injection, the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 26.6%, 37.5% (P ⫽ 0.0003), and 9.7% respectively. On day 56, the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 24.1% (P ⫽ 0.0074), 25.1% (P ⬍ 0.0001), and 9.4% respectively. On day 70 (2 weeks after the second gene therapy injection), the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 21.8% (P ⫽ 0.0116), 20.7% (P ⫽ 0.0010), and 9.8% respectively. On day 84 (2 weeks after the third gene therapy injection), the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 20.7%, 23.5% (P ⫽ 0.0001), and 10.8% (P ⫽ 0.0006) respectively. The mean percentage of DR⫹CD8⫹ T cells at 8 months was 20.8% (P ⫽ 0.0031) and of DR⫹CD4⫹ T cells at 12 months was 11.2% (P ⫽ 0.0015). Long term (2.3 yr) use of hormonal therapy did not affect the percentage of any of the lymphocyte populations compared to short term use (4 mo). Conclusions: We present evidence showing sustained long-term (up to 8 –12 months) systemic T-cell responses to three consecutive AdHSV-tk injections during combination in situ gene therapy, IMRT and hormonal therapy for prostate cancer. Prolonged use of hormonal therapy does not suppress this response. These results suggest the potential for sustained activation of cell-mediated immune responses against cancer with continued treatment.
2120
Defining the Rectal Dose Constraint for Permanent Radioactive Seed Implantation of the Prostate 1,2
M. Albert, J.S. Song,1 D. Schultz,4 R. Cormack,1,2 C. Tempany-Afdhal,3,2 S. Haker,3 A. Szot-Barnes,3 C. Beard,1,2 M. Hurwitz,1,2 W. Suh,1,2 F. Jolesz,3,2 A.V. D’Amico1,2 1 Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, 2Dana Farber Cancer Institute, Boston, MA, 3 Radiology, Brigham and Women’s Hospital, Boston, MA, 4Mathematics, Millersville University, Millersville, PA Purpose/Objective: This study was performed to define the rectal dose constraint that would predict late rectal bleeding requiring argon plasma coagulation (APC) following prostate brachy mono-therapy Materials/Methods: Between February 1999 and April 2002, 91 patients with low risk prostate cancer underwent permanent I125 radioactive seed implantation without the use of supplemental external beam radiation or androgen suppression therapy. Patients received both CT and MRI scans 6 weeks post implant for evaluation of dosimetry. The CT and MRI scans were fused using the implanted sources as fiducials. Rectal volume was contoured on the T2 weighted MR images from the base of the seminal vesicles to the penile bulb. For those patients requiring APC, the date on which a patient reported rectal bleeding was recorded. A Cox regression analysis was performed to assess whether there was a significant association between the rectal volume (continuous) exceeding 100 Gy and time to patient reported rectal bleeding requiring APC. Comparisons of estimates of rectal bleeding requiring APC were made using a 2-sided log rank test Results: There was a significant association (Hazard Ratio ⫽ 5.6 [95% Confidence Interval: 1.3, 23.8]; p ⫽ 0.02) between the rectal volume exceeding 100 Gy and rectal bleeding requiring APC. As shown in the figure after a median follow up of 4.25(1– 6) years, no patients with less the median value of 8 cc of rectum exceeding 100 Gy required APC whereas, 20%(p⫽0.004) were estimated to require APC within 3 years following treatment. Conclusions: Keeping the rectal volume receiving more than 100 Gy below 8 cc will minimize the risk of rectal bleeding requiring APC following I125 permanent prostate brachy mono-therapy.
2117
Efficacy of Neoadjuvant Dutasteride and Bicalutamide as a Cytoreductive Regimen Prior to Permanent Interstitial Brachytherapy
R.L. Anderson,1 G. Merrick,1,2 W. Butler,1,2 K. Wallner,3 R. Galbreath,1,4 R. Coram5 Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, 2Wheeling Jesuit University, Wheeling, WV, 3Group Health Cooperative, Puget Sound Veterans Administration, and University of Washington, Seattle, WA, 4Ohio University Eastern, St. Clairsville, OH, 5Department of Pharmacy, Wheeling Hospital, Wheeling, WV 1
Purpose/Objective: In patients with a large prostate gland and/or urinary obstructive symptoms, neoadjuvant treatment with an LHRH agonist and an anti-androgen is often used for cytoreduction prior to brachytherapy. Because of the morbidity of this approach, we evaluated the cytoreductive effectiveness of neoadjuvant dutasteride and bicalutamide. Materials/Methods: Between April 2003 and February 2005, 26 patients opted for cytoreduction with dutasteride (0.5 mg daily) and bicalutamide (50 mg daily). Following initiation of bicalutamide, liver function studies were obtained at 4 and 8 weeks to rule out hepatotoxicity. Prior to the initiation of medical therapy and at 3 months, all patients underwent a transrectal ultrasound volumetric study of the prostate gland, an ellipsoid volume determination of the prostate gland, and an ellipsoid volume determination of the transition zone. All ultrasounds were obtained by the same ultrasonographer. Variables analyzed include pre- and post-treatment prostate and transition zone volumes and changes in width, height, and length of the prostate gland and transition zone. Results: Prior to the initiation of dutasteride and bicalutamide, the mean prostate volume was 56.3 cm3 by volumetric evaluation and 51.5 cm3 by ellipsoid volume determination. Following a 3-month course of dutasteride and bicalutamide, the average prostate volume was 38.1 cm3 (a 33% reduction) and 34.8 cm3 (a 32% reduction) by volumetric and ellipsoid volume determinations respectively. Dutasteride and bicalutamide resulted in a 37.0% reduction in transition zone volume (22.6 cm3 versus 14.0 cm3 before and after treatment). In terms of width, height and length, the prostate gland and transition zone dimensions decreased on average from 11.0% to 17.4%. Conclusions: Prostate gland and transition zone volume reductions with dutasteride and bicalutamide are comparable to previous reports of volume reduction using an LHRH agonist with or without an anti-androgen. Because of a presumed lesser incidence of treatment-related morbidity, the cytoreductive regimen of dutasteride and bicalutamide deserves additional investigation.
2118
Prostate Brachytherapy-Induced Urethral Strictures
W.M. Butler,1,2 G. Merrick,1,2 K. Wallner,3 R. Galbreath,1,4 R. Anderson,1 Z. Allen1,2 Schiffler Cancer Center, Wheeling Hospital, Wheeling, WV, 2Wheeling Jesuit University, Wheeling, WV, 3Group Health Cooperative, Puget Sound Veterans Administration, and University of Washington, Seattle, WA, 4Ohio University Eastern, St. Clairsville, OH 1
Purpose/Objective: To determine the incidence and to identify clinical, treatment and dosimetric parameters associated with the development of urethral strictures following permanent prostate brachytherapy. Materials/Methods: From April 1995 through May 2003, 1,186 consecutive patients underwent prostate brachytherapy for clinical stage T1b-T3a NxM0 (2002 AJCC) prostate cancer. Nine hundred and twelve patients (76.9%) were implanted with Pd-103 and 204 (23.1%) with I-125. The median follow-up was 4.3 years. Follow-up was calculated from the date of implantation. Clinical, treatment and dosimetric parameters evaluated for bulbomembranous urethral strictures included patient age, prostate volume, the use of supplemental XRT, isotope, androgen deprivation therapy (ADT), duration of ADT, prostate V100/150/200, D90, prostatic urethral dose (mean, median and maximum), bulbomembranous urethral dose (mean, median and maximum), tobacco use, hypertension, diabetes and BMI. Results: Twenty-nine patients developed brachytherapy-induced strictures with all strictures involving the bulbomembranous urethra. The 9-year actuarial risk for the development of a bulbomembranous urethral stricture was 3.6% with a median time to development of 34 months. The mean radiation dose to the bulbomembranous urethra was significantly greater in patients with strictures than those without (p ⫽ 0.002). In particular, the urethral dose 10 and 15 mm distal to the prostate apex was significantly greater in patients with strictures (p ⬍ 0.001). In multivariate analysis, the bulbomembranous urethral dose and the use of supplemental XRT predicted for the development of a urethral stricture. All but one patient was successfully managed by either urethral dilatation or internal optical urethrotomy. Conclusions: Brachytherapy-related urethral strictures are related to overaggressive implantation of the periapical region and the use of supplemental XRT. Careful attention to preplanning and intraoperative execution, along with the judicious use of supplemental XRT, is essential to minimize the incidence of brachytherapy-related strictures.
2119
Sustained Long-term Immune Responses Following In Situ Gene Therapy Combined with Radiotherapy and Hormonal Therapy in Prostate Cancer Patients
T. Fujita,1 B.S. Teh,2,3 T.L. Timme,1 W. Mai,2 T. Satoh,1 N. Kusaka,1 K. Naruishi,1 E.A. Fattah,1 E. Aguilar-Cordova,4 E. Butler,2,3 T.C. Thompson1,5 1 Scott Department of Urology, Baylor College of Medicine, Houston, TX, 2Radiology / Section of Radiation Oncology, Baylor College of Medicine, Houston, TX, 3Radiation Oncology, The Methodist Hospital, Houston, TX, 4Gene Vector Laboratory, Baylor College of Medicine, Houston, TX, 5Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX Purpose/Objective: Adenoviral vector mediated Herpes Simplex Virus-thymidine kinase (AdHSVtk) ⫹ valacyclovir (VCV) in situ gene therapy combined with intensity-modulated radiation therapy (IMRT) and hormonal therapy may have an enhanced efficacy because of complementary mechanisms of cytotoxicity. We are currently conducting clinical trials using this approach. This study explores sustained long-term immune responses following combined radio-gene and hormonal therapy.
S299
S300
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
Materials/Methods: Thirty-three patients with PSA ⬎/⫽ 10 or Gleason score ⬎/⫽ 7 or clinical stage T2b-T3 were treated as follows: Gene therapy: 3 separate intraprostatic injections of AdHSV-tk were performed on days 0, 56, and 70. Each injection was followed by 2 weeks of VCV. IMRT was delivered 2 days after the second AdHSV-tk injection for 7 weeks. Hormonal therapy: lupron and flutamide were initiated on day 0 and continued for 4 months or 2.3 years. Heparin-treated bloods were taken at selected intervals before, during, and after the treatment. Peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting (FACS) after labeling with dual color labeled antibody pairs. FACS results following initiation of treatment were compared with pre-treatment values. Results: Median follow-up for the entire group was 26 months (4 – 48 months). The pre-treatment mean percentages of total CD8⫹ T cells, activated CD8⫹ (DR⫹CD8⫹) T cells, and activated CD4⫹ (DR⫹CD4⫹) T cells were 19.2%, 14.7%, and 7.8% respectively. Specific T-cell populations were increased at specific time points following treatment and compared with pretreatment levels as follows: Two weeks after the first gene therapy injection, the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 26.6%, 37.5% (P ⫽ 0.0003), and 9.7% respectively. On day 56, the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 24.1% (P ⫽ 0.0074), 25.1% (P ⬍ 0.0001), and 9.4% respectively. On day 70 (2 weeks after the second gene therapy injection), the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 21.8% (P ⫽ 0.0116), 20.7% (P ⫽ 0.0010), and 9.8% respectively. On day 84 (2 weeks after the third gene therapy injection), the mean percentages of total CD8⫹ T cells, DR⫹CD8⫹ T cells, and DR⫹CD4⫹ T cells were 20.7%, 23.5% (P ⫽ 0.0001), and 10.8% (P ⫽ 0.0006) respectively. The mean percentage of DR⫹CD8⫹ T cells at 8 months was 20.8% (P ⫽ 0.0031) and of DR⫹CD4⫹ T cells at 12 months was 11.2% (P ⫽ 0.0015). Long term (2.3 yr) use of hormonal therapy did not affect the percentage of any of the lymphocyte populations compared to short term use (4 mo). Conclusions: We present evidence showing sustained long-term (up to 8 –12 months) systemic T-cell responses to three consecutive AdHSV-tk injections during combination in situ gene therapy, IMRT and hormonal therapy for prostate cancer. Prolonged use of hormonal therapy does not suppress this response. These results suggest the potential for sustained activation of cell-mediated immune responses against cancer with continued treatment.
2120
Defining the Rectal Dose Constraint for Permanent Radioactive Seed Implantation of the Prostate 1,2
M. Albert, J.S. Song,1 D. Schultz,4 R. Cormack,1,2 C. Tempany-Afdhal,3,2 S. Haker,3 A. Szot-Barnes,3 C. Beard,1,2 M. Hurwitz,1,2 W. Suh,1,2 F. Jolesz,3,2 A.V. D’Amico1,2 1 Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, 2Dana Farber Cancer Institute, Boston, MA, 3 Radiology, Brigham and Women’s Hospital, Boston, MA, 4Mathematics, Millersville University, Millersville, PA Purpose/Objective: This study was performed to define the rectal dose constraint that would predict late rectal bleeding requiring argon plasma coagulation (APC) following prostate brachy mono-therapy Materials/Methods: Between February 1999 and April 2002, 91 patients with low risk prostate cancer underwent permanent I125 radioactive seed implantation without the use of supplemental external beam radiation or androgen suppression therapy. Patients received both CT and MRI scans 6 weeks post implant for evaluation of dosimetry. The CT and MRI scans were fused using the implanted sources as fiducials. Rectal volume was contoured on the T2 weighted MR images from the base of the seminal vesicles to the penile bulb. For those patients requiring APC, the date on which a patient reported rectal bleeding was recorded. A Cox regression analysis was performed to assess whether there was a significant association between the rectal volume (continuous) exceeding 100 Gy and time to patient reported rectal bleeding requiring APC. Comparisons of estimates of rectal bleeding requiring APC were made using a 2-sided log rank test Results: There was a significant association (Hazard Ratio ⫽ 5.6 [95% Confidence Interval: 1.3, 23.8]; p ⫽ 0.02) between the rectal volume exceeding 100 Gy and rectal bleeding requiring APC. As shown in the figure after a median follow up of 4.25(1– 6) years, no patients with less the median value of 8 cc of rectum exceeding 100 Gy required APC whereas, 20%(p⫽0.004) were estimated to require APC within 3 years following treatment. Conclusions: Keeping the rectal volume receiving more than 100 Gy below 8 cc will minimize the risk of rectal bleeding requiring APC following I125 permanent prostate brachy mono-therapy.