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Erlotinib as a Radiosensitizer for Patients with Esophageal Cancer
Proceedings of the 47th Annual ASTRO Meeting
2089
Phase I Dose Escalation Study of CyberKnife Stereotactic Radiosurgery for Liver Malignancies
Y.C. Lieskovsky,1 A. Koong,1 G. Fisher,2 G. Yang,3 A. Ho,1 M. Nguyen,4 I. Gibbs,1 K. Goodman1 Radiation Oncology, Stanford University Medical Center, Stanford, CA, 2Medical Oncology, Stanford University Medical Center, Stanford, CA, 3Surgery, Stanford University Medical Center, Stanford, CA, 4Gastroenterology, Stanford University Medical Center, Stanford, CA 1
Purpose/Objective: Three-dimensional external beam radiation therapy has been used for patients with unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC) with encouraging results. Prospective studies have demonstrated that doses of 48 –72.6 Gy (fraction size 1.5–1.65 Gy bid) can be given, achieving hepatic control rates of 50%. In addition, 3-dimensional treatment planning for liver metastases has allowed the safe irradiation of 2/3 of the normal liver to 48 –52.4 Gy and 1/3 of the liver to 66 –72.6 Gy (fraction size 1.5–1.65 Gy bid). Based on these data, we developed a Phase I study to evaluate the safety and feasibility of single-fraction radiosurgery using CyberKnife for liver tumors. Through a dose escalation schema, we will attempt to determine the maximum tolerated dose (MTD) for such therapy. Radiographic response is a secondary endpoint to assess the efficacy of radiosurgical ablation of liver tumors. Materials/Methods: Patients with HCC, IHCC, or three or fewer liver metastases who had a life expectancy of ⬎6 months were eligible. Tumors did not exceed 5 cm in diameter and were unresectable. Laboratory tests confirmed adequate hepatic function. Three to five gold fiducials for targeting purposes were placed percutaneously directly into the tumor under CT guidance. Within 7 days of fiducial placement, a Vac-LokTM was custom made for each patient, who then underwent a dual-phase contrast CT scan through the entire abdominal cavity, using 1.25 mm thick slices. The lesion representing the gross tumor volume (GTV) was outlined on sequential axial CT slices. The dose was prescribed to the maximum isodose volume which completely covered the GTV. Adjacent normal structures such as the surrounding liver, duodenum, kidneys, inferior vena cava, heart, pancreas, stomach, and small bowel within 5 cm of the GTV were contoured for the purpose of limiting radiation to these structures. Treatments were delivered with motion tracking using X-ray detection of fiducial and surface light emitting diode (LED) positions and development of an algorithm that predicted tumor movement. Follow-up abdominal CT, physician appointment, and laboratory tests were scheduled at 4 – 6 weeks, 3 months, 6 months, and annually until death. Toxicity beyond 3 months was scored according to the RTOG late Radiation Toxicity Scale. Results: To date, 6 patients with 7 tumors have been treated (3 tumors with 18 Gy and 4 tumors with 22 Gy). One patient had IHCC and the remainder had metastatic disease. Mean planning target volume (PTV) was 18.45cc (range 11– 42). Mean maximum dose to the PTV was 26.8 Gy (range 22.5–29.3). In the 18 Gy group, 4% of the liver volume received ⬎20 Gy. In the 22 Gy group, 5–7% of the liver received ⬎20 Gy. Mean follow-up for the 4 living patients was 9.5 months (range 6 –14). There was one incidence of Grade I GI toxicity, which consisted of nausea and vomiting for 1 week after treatment. Four patients had partial response on imaging: 1 progressed locally after 9.5 months, 1 progressed locally as well as distantly after 3.5 months, 1 progressed distantly after 3 months and died 4 months later, and the other continues to have stable response. One patient exhibited no change on imaging. One patient with two tumors treated died of metastatic disease before follow-up imaging could be obtained. Conclusions: Results thus far indicate that single fractions of 18 and 22 Gy are safe to administer to liver tumors with the CyberKnife. We have not yet reached the MTD at 22 Gy. We plan to dose-escalate to 30 Gy.
2090
Erlotinib as a Radiosensitizer for Patients with Esophageal Cancer
M. Dobelbower, S. Russo, K. Raisch, L. Seay, L. Clemons, S. Suter, J. Posey, J. Bonner Radiation Oncology, University of Alabama, Birmingham, AL Purpose/Objective: This Phase I Trial investigates the safety of combining radiation, 5-FU, and cisplatin with the Epidermal Growth Factor Tyrosine Kinase Inhibitor (EGFr TKI), Erlotinib, in patients with esophageal cancer. Studies utilizing preoperative chemoradiation have not consistently demonstrated an advantage over surgery alone for patients with resectable esophageal cancer, but results are promising for complete responders. The pathologic complete response rate to neoadjuvant chemoradiation approaches 30%, resulting in an improved 2-year survival, however the high rate of local and distant failure necessitates more effective therapy. EGFr is overexpressed in 80% squamous cell carcinomas and 60% adenocarcinomas of the esophagus. Preclinical laboratory studies from the University of Alabama at Birmingham have identified Erlotinib as a radiosensitizer in vitro. We propose that the use of Erlotinib as a radiation sensitizer may result in an increased pathological complete response to neoadjuvant therapy, possibly improving survival for patients with localized esophageal cancer. Materials/Methods: EGFr overexpressing and non-overexpressing esophageal cancer cell lines were used in laboratory studies. These studies examined the dose of Erlotinib required to reduce EGFr-specific tyrosine kinase activity and downstream markers, and the combined effect of Erlotinib and radiation on cell proliferation, radiation-induced apoptosis, and clonogenic survival. A phase I study was also performed to determine the maximum tolerated dose (MTD) of Erlotinib delivered concurrently with 5FU, cisplatin and radiation in patients with squamous or adenocarcinomas of the esophagus. Patients received either 50, 100, or 150 mg oral Erlotinib per day beginning on the first day of radiation (3 patients in each dose cohort). Concurrent cisplatin (75 mg/m2 i.v., days 8 and 36) and 5-FU (1000 mg/m2 i.v., days 8 –11, and 36 –39) were also given with 50.4 Gy thoracic radiation, delivered at 180cGy per day, 5 days per week. Toxicity was evaluated using the NCI CTC version 3.0. Results: Laboratory studies showed that Erlotinib inhibits cell proliferation in all cell lines. The inhibition of cell proliferation was greater after the cells were exposed to radiation 2 h post treatment with Erlotinib than after either treatment given alone. Apoptosis studies indicated that the treatment with Erlotinib followed by radiation showed a greater percentage of apoptotic cells than either treatment alone. Clonogenic assays indicated that 0.5M, given 2 h prior to radiation treatment, sensitized the tumor cells to radiation. Erlotinib delivered concurrently with 5FU, cisplatin and thoracic radiation was well-tolerated in the phase I clinical study at 50, 100 and 150 mg daily. The major toxicities encountered were diarrhea (g1 18%, g2 18%), skin rash (g1 54.5%), nausea (g1 18%, g2 54.5%, g3 9%), and dehydration (g3 27%). Conclusions: Preclinical studies demonstrate the potential of Erlotinib as a radiation sensitizer. The Phase I study demonstrates the safety and tolerability of Erlotinib delivered at the identified MTD of 150 mg/day with concurrent 5-FU, cisplatin and
S283
S284
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
thoracic radiation. The major toxicities encountered were diarrhea, skin rash, nausea and dehydration. A Phase II study to determine the pathologic response; time to progression, 2-year disease-free and overall survival for patients undergoing this treatment regimen is planned. This study will also include laboratory correlative studies to explore the potential interaction between Erlotinib and radiation in vivo. TOXICITIES
2091
Genomic Polymorphisms of Angiogenesis Pathway Predict Radiosensitivity in Rectal Cancer
W. Zhang, M. Gordon, D. Yang, J. Yun, O. Press, K. Rhodes, S. Groshen, H. Lenz University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA Purpose/Objective: A link between angiogenesis signaling pathway and tumor response to radiation therapy has been found. Inhibitors of tumor angiogenesis are being used in combination with radiotherapy to improve the therapeutic index. We investigate whether cyclooxygenase 2 (Cox-2) G-765C, Interleukin 8 (IL-8) T-251A, vascular endothelial growth factor (VEGF) C936T, transforming growth factor beta(TGF-) T29C and intercellular adhesion molecular-1(ICAM-1) K469E gene polymorphisms, all members of the angiogenesis signaling pathway, are associated with radiosensitivity in locally advanced rectal cancer patients treated with neo-adjuvant or adjuvant chemoradiation. Materials/Methods: Ninety patients with locally advanced rectal cancer (UICC stage II and III) who were treated with neo-adjuvant or adjuvant chemoradiation therapy at the University of Southern California/Norris Comprehensive Cancer Center, Los Angeles between 1991 and 2000 were eligible for the present study. This study was investigated at USC/Norris Comprehensive Cancer Center and approved by the Institutional Review Board of the University of Southern California for Medical Sciences. Out of 90 patients, 67 patients were treated with adjuvant 5-Fu infusion plus pelvic radiation; 23 patients were treated with neo-adjuvant chemoradiation therapy. For patients with adjuvant chemoradiation, Patients underwent lower anterior resectomy (LAR; n⫽55), abdominal perineal resectomy (APR; n⫽26), or transanal resectomy (TR; n⫽9), followed by 5-FU infusion plus pelvic radiation. Pelvic irradiation was given as a dose of 45 Gy to the whole pelvis and an additional boost up to 54 Gy. Gene polymorphisms of COX-2, IL-8, VEGF, TGF- and ICAM-1 were assessed from genomic DNA extracted from blood samples using the PCR-RFLP method. Results: A significant associations between IL-8(T-251A) polymorphism and possibility of local recurrence was found. Patients with AA genotype have 88% recurred compare with those patients with TT genotype have only 38% recurred, while patients with heterozygous AT genotype in the middle, have 57% recurred.(p⫽0.029, fisher exact test). Also, there are trend association among cox-2 polymorphism(p⫽0.08), TGF- polymorphism(p⫽0.12), VEGF polymorphism(p⫽0.15), ICAM-1 polymorphism(p⫽0.16) and possibility of local recurrence, respectively. Combination analysis is on the way and will be update at the annual meeting. Conclusions: Our data suggest gene polymorphisms of angiogenesis pathway may be potential molecular markers to predict local regional recurrence in stage II/III rectal cancer patients treated with chemoradiation.
2092
Predictive Factors for Response of Rectal Cancer to Preoperative Chemoradiotherapy
W.T. Lamoreaux,1 R.J. Myerson,1 R.S. Malyapa,1 R. Higashikubo,1 E. Kim,1 M.D. LaZar,1 J.H. Ritter,2 J. Schwarz1 Radiation Oncology, Washington University, St Louis, MO, 2Pathology, Washington University, St Louis, MO
1
Purpose/Objective: In rectal carcinoma, non-responders to preoperative chemoradiotherapy have significantly worse outcome than do responders. We sought to identify the value of p53, p21, BAX, Thymidylate synthase (TS), Ki-67, and Proliferating cell nuclear antigen (PCNA) expression as predictive markers of response. We reviewed a clinically uniform group of cases. We have previously shown that outcome for a given clinical T stage is strongly dependent on a Clinical Score (CS) based on number of adverse physical findings. We have also found that trans rectal ultrasound (TRUS) is less likely to have false positives for larger tumors with CS ⬎ 0. Materials/Methods: We reviewed biopsy specimens for 38 cases with CS 1, size 4cm, TRUS stage T3 or T4. All patients were treated with preoperative, conventionally fractionated radiotherapy (mean 45 Gy) concurrent 5FU chemotherapy (CRT) followed by surgery an average of 7.5 weeks later. We immunohistochemically stained paraffin-embedded pretreatment tumor specimens for all six markers. Expression of p53, p21, BAX, and TS was scored blindly by two observers for percentage of positive cells (⬍5%⫽0, 6 –33%⫽1, 34 – 66%⫽2,⬎67%⫽3) and staining intensity (no staining⫽0, light⫽1, moderate⫽2, dark⫽3), resulting in a summed total score ranging from 0 – 6. PCNA and Ki-67 were scored only for percentage of positive cells (0 –33%⫽1, 34 – 66%⫽2,⬎67%⫽3). Total scores were correlated to treatment response (downstaging), defined in this study as pathologic T stage (pT) less than pretreatment TRUS stage. Results: There was approximately 80% concordance between the observers, and any discrepancies were resolved by consensus. Overall, there were 16 responders and 22 non-responders. There was a poor response rate in tumors which showed a combined TS score ⬎ 4 (6/18). All but two of the non-responders had either a TS or BAX score ⬎ 4.
2089
Phase I Dose Escalation Study of CyberKnife Stereotactic Radiosurgery for Liver Malignancies
Y.C. Lieskovsky,1 A. Koong,1 G. Fisher,2 G. Yang,3 A. Ho,1 M. Nguyen,4 I. Gibbs,1 K. Goodman1 Radiation Oncology, Stanford University Medical Center, Stanford, CA, 2Medical Oncology, Stanford University Medical Center, Stanford, CA, 3Surgery, Stanford University Medical Center, Stanford, CA, 4Gastroenterology, Stanford University Medical Center, Stanford, CA 1
Purpose/Objective: Three-dimensional external beam radiation therapy has been used for patients with unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC) with encouraging results. Prospective studies have demonstrated that doses of 48 –72.6 Gy (fraction size 1.5–1.65 Gy bid) can be given, achieving hepatic control rates of 50%. In addition, 3-dimensional treatment planning for liver metastases has allowed the safe irradiation of 2/3 of the normal liver to 48 –52.4 Gy and 1/3 of the liver to 66 –72.6 Gy (fraction size 1.5–1.65 Gy bid). Based on these data, we developed a Phase I study to evaluate the safety and feasibility of single-fraction radiosurgery using CyberKnife for liver tumors. Through a dose escalation schema, we will attempt to determine the maximum tolerated dose (MTD) for such therapy. Radiographic response is a secondary endpoint to assess the efficacy of radiosurgical ablation of liver tumors. Materials/Methods: Patients with HCC, IHCC, or three or fewer liver metastases who had a life expectancy of ⬎6 months were eligible. Tumors did not exceed 5 cm in diameter and were unresectable. Laboratory tests confirmed adequate hepatic function. Three to five gold fiducials for targeting purposes were placed percutaneously directly into the tumor under CT guidance. Within 7 days of fiducial placement, a Vac-LokTM was custom made for each patient, who then underwent a dual-phase contrast CT scan through the entire abdominal cavity, using 1.25 mm thick slices. The lesion representing the gross tumor volume (GTV) was outlined on sequential axial CT slices. The dose was prescribed to the maximum isodose volume which completely covered the GTV. Adjacent normal structures such as the surrounding liver, duodenum, kidneys, inferior vena cava, heart, pancreas, stomach, and small bowel within 5 cm of the GTV were contoured for the purpose of limiting radiation to these structures. Treatments were delivered with motion tracking using X-ray detection of fiducial and surface light emitting diode (LED) positions and development of an algorithm that predicted tumor movement. Follow-up abdominal CT, physician appointment, and laboratory tests were scheduled at 4 – 6 weeks, 3 months, 6 months, and annually until death. Toxicity beyond 3 months was scored according to the RTOG late Radiation Toxicity Scale. Results: To date, 6 patients with 7 tumors have been treated (3 tumors with 18 Gy and 4 tumors with 22 Gy). One patient had IHCC and the remainder had metastatic disease. Mean planning target volume (PTV) was 18.45cc (range 11– 42). Mean maximum dose to the PTV was 26.8 Gy (range 22.5–29.3). In the 18 Gy group, 4% of the liver volume received ⬎20 Gy. In the 22 Gy group, 5–7% of the liver received ⬎20 Gy. Mean follow-up for the 4 living patients was 9.5 months (range 6 –14). There was one incidence of Grade I GI toxicity, which consisted of nausea and vomiting for 1 week after treatment. Four patients had partial response on imaging: 1 progressed locally after 9.5 months, 1 progressed locally as well as distantly after 3.5 months, 1 progressed distantly after 3 months and died 4 months later, and the other continues to have stable response. One patient exhibited no change on imaging. One patient with two tumors treated died of metastatic disease before follow-up imaging could be obtained. Conclusions: Results thus far indicate that single fractions of 18 and 22 Gy are safe to administer to liver tumors with the CyberKnife. We have not yet reached the MTD at 22 Gy. We plan to dose-escalate to 30 Gy.
2090
Erlotinib as a Radiosensitizer for Patients with Esophageal Cancer
M. Dobelbower, S. Russo, K. Raisch, L. Seay, L. Clemons, S. Suter, J. Posey, J. Bonner Radiation Oncology, University of Alabama, Birmingham, AL Purpose/Objective: This Phase I Trial investigates the safety of combining radiation, 5-FU, and cisplatin with the Epidermal Growth Factor Tyrosine Kinase Inhibitor (EGFr TKI), Erlotinib, in patients with esophageal cancer. Studies utilizing preoperative chemoradiation have not consistently demonstrated an advantage over surgery alone for patients with resectable esophageal cancer, but results are promising for complete responders. The pathologic complete response rate to neoadjuvant chemoradiation approaches 30%, resulting in an improved 2-year survival, however the high rate of local and distant failure necessitates more effective therapy. EGFr is overexpressed in 80% squamous cell carcinomas and 60% adenocarcinomas of the esophagus. Preclinical laboratory studies from the University of Alabama at Birmingham have identified Erlotinib as a radiosensitizer in vitro. We propose that the use of Erlotinib as a radiation sensitizer may result in an increased pathological complete response to neoadjuvant therapy, possibly improving survival for patients with localized esophageal cancer. Materials/Methods: EGFr overexpressing and non-overexpressing esophageal cancer cell lines were used in laboratory studies. These studies examined the dose of Erlotinib required to reduce EGFr-specific tyrosine kinase activity and downstream markers, and the combined effect of Erlotinib and radiation on cell proliferation, radiation-induced apoptosis, and clonogenic survival. A phase I study was also performed to determine the maximum tolerated dose (MTD) of Erlotinib delivered concurrently with 5FU, cisplatin and radiation in patients with squamous or adenocarcinomas of the esophagus. Patients received either 50, 100, or 150 mg oral Erlotinib per day beginning on the first day of radiation (3 patients in each dose cohort). Concurrent cisplatin (75 mg/m2 i.v., days 8 and 36) and 5-FU (1000 mg/m2 i.v., days 8 –11, and 36 –39) were also given with 50.4 Gy thoracic radiation, delivered at 180cGy per day, 5 days per week. Toxicity was evaluated using the NCI CTC version 3.0. Results: Laboratory studies showed that Erlotinib inhibits cell proliferation in all cell lines. The inhibition of cell proliferation was greater after the cells were exposed to radiation 2 h post treatment with Erlotinib than after either treatment given alone. Apoptosis studies indicated that the treatment with Erlotinib followed by radiation showed a greater percentage of apoptotic cells than either treatment alone. Clonogenic assays indicated that 0.5M, given 2 h prior to radiation treatment, sensitized the tumor cells to radiation. Erlotinib delivered concurrently with 5FU, cisplatin and thoracic radiation was well-tolerated in the phase I clinical study at 50, 100 and 150 mg daily. The major toxicities encountered were diarrhea (g1 18%, g2 18%), skin rash (g1 54.5%), nausea (g1 18%, g2 54.5%, g3 9%), and dehydration (g3 27%). Conclusions: Preclinical studies demonstrate the potential of Erlotinib as a radiation sensitizer. The Phase I study demonstrates the safety and tolerability of Erlotinib delivered at the identified MTD of 150 mg/day with concurrent 5-FU, cisplatin and
S283
S284
I. J. Radiation Oncology
● Biology ● Physics
Volume 63, Number 2, Supplement, 2005
thoracic radiation. The major toxicities encountered were diarrhea, skin rash, nausea and dehydration. A Phase II study to determine the pathologic response; time to progression, 2-year disease-free and overall survival for patients undergoing this treatment regimen is planned. This study will also include laboratory correlative studies to explore the potential interaction between Erlotinib and radiation in vivo. TOXICITIES
2091
Genomic Polymorphisms of Angiogenesis Pathway Predict Radiosensitivity in Rectal Cancer
W. Zhang, M. Gordon, D. Yang, J. Yun, O. Press, K. Rhodes, S. Groshen, H. Lenz University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA Purpose/Objective: A link between angiogenesis signaling pathway and tumor response to radiation therapy has been found. Inhibitors of tumor angiogenesis are being used in combination with radiotherapy to improve the therapeutic index. We investigate whether cyclooxygenase 2 (Cox-2) G-765C, Interleukin 8 (IL-8) T-251A, vascular endothelial growth factor (VEGF) C936T, transforming growth factor beta(TGF-) T29C and intercellular adhesion molecular-1(ICAM-1) K469E gene polymorphisms, all members of the angiogenesis signaling pathway, are associated with radiosensitivity in locally advanced rectal cancer patients treated with neo-adjuvant or adjuvant chemoradiation. Materials/Methods: Ninety patients with locally advanced rectal cancer (UICC stage II and III) who were treated with neo-adjuvant or adjuvant chemoradiation therapy at the University of Southern California/Norris Comprehensive Cancer Center, Los Angeles between 1991 and 2000 were eligible for the present study. This study was investigated at USC/Norris Comprehensive Cancer Center and approved by the Institutional Review Board of the University of Southern California for Medical Sciences. Out of 90 patients, 67 patients were treated with adjuvant 5-Fu infusion plus pelvic radiation; 23 patients were treated with neo-adjuvant chemoradiation therapy. For patients with adjuvant chemoradiation, Patients underwent lower anterior resectomy (LAR; n⫽55), abdominal perineal resectomy (APR; n⫽26), or transanal resectomy (TR; n⫽9), followed by 5-FU infusion plus pelvic radiation. Pelvic irradiation was given as a dose of 45 Gy to the whole pelvis and an additional boost up to 54 Gy. Gene polymorphisms of COX-2, IL-8, VEGF, TGF- and ICAM-1 were assessed from genomic DNA extracted from blood samples using the PCR-RFLP method. Results: A significant associations between IL-8(T-251A) polymorphism and possibility of local recurrence was found. Patients with AA genotype have 88% recurred compare with those patients with TT genotype have only 38% recurred, while patients with heterozygous AT genotype in the middle, have 57% recurred.(p⫽0.029, fisher exact test). Also, there are trend association among cox-2 polymorphism(p⫽0.08), TGF- polymorphism(p⫽0.12), VEGF polymorphism(p⫽0.15), ICAM-1 polymorphism(p⫽0.16) and possibility of local recurrence, respectively. Combination analysis is on the way and will be update at the annual meeting. Conclusions: Our data suggest gene polymorphisms of angiogenesis pathway may be potential molecular markers to predict local regional recurrence in stage II/III rectal cancer patients treated with chemoradiation.
2092
Predictive Factors for Response of Rectal Cancer to Preoperative Chemoradiotherapy
W.T. Lamoreaux,1 R.J. Myerson,1 R.S. Malyapa,1 R. Higashikubo,1 E. Kim,1 M.D. LaZar,1 J.H. Ritter,2 J. Schwarz1 Radiation Oncology, Washington University, St Louis, MO, 2Pathology, Washington University, St Louis, MO
1
Purpose/Objective: In rectal carcinoma, non-responders to preoperative chemoradiotherapy have significantly worse outcome than do responders. We sought to identify the value of p53, p21, BAX, Thymidylate synthase (TS), Ki-67, and Proliferating cell nuclear antigen (PCNA) expression as predictive markers of response. We reviewed a clinically uniform group of cases. We have previously shown that outcome for a given clinical T stage is strongly dependent on a Clinical Score (CS) based on number of adverse physical findings. We have also found that trans rectal ultrasound (TRUS) is less likely to have false positives for larger tumors with CS ⬎ 0. Materials/Methods: We reviewed biopsy specimens for 38 cases with CS 1, size 4cm, TRUS stage T3 or T4. All patients were treated with preoperative, conventionally fractionated radiotherapy (mean 45 Gy) concurrent 5FU chemotherapy (CRT) followed by surgery an average of 7.5 weeks later. We immunohistochemically stained paraffin-embedded pretreatment tumor specimens for all six markers. Expression of p53, p21, BAX, and TS was scored blindly by two observers for percentage of positive cells (⬍5%⫽0, 6 –33%⫽1, 34 – 66%⫽2,⬎67%⫽3) and staining intensity (no staining⫽0, light⫽1, moderate⫽2, dark⫽3), resulting in a summed total score ranging from 0 – 6. PCNA and Ki-67 were scored only for percentage of positive cells (0 –33%⫽1, 34 – 66%⫽2,⬎67%⫽3). Total scores were correlated to treatment response (downstaging), defined in this study as pathologic T stage (pT) less than pretreatment TRUS stage. Results: There was approximately 80% concordance between the observers, and any discrepancies were resolved by consensus. Overall, there were 16 responders and 22 non-responders. There was a poor response rate in tumors which showed a combined TS score ⬎ 4 (6/18). All but two of the non-responders had either a TS or BAX score ⬎ 4.