- Email: [email protected]
96 Molecular target radiosensitization: From laboratory to phase III clinical trial
CARO 2004
September 9-12 $29
93 Radiation-Induced Apoptosis of Lymphocytes to Predict Late Toxicity from Radiotherapy.
95 Toxicity From Radiation Therapy Associated with Abnormal Transcriptional Responses to DNA Damage.
K. Schnarr ~, L. Ryan ~, N. McFar/ane ~, N.E.A. Crompton2, J. Sathya 3, I. Dayes~, D. Boreham ~. ~Department of Medical Physics, McMaster University, Hamilton, Ontario; 2Sir John Eccles Professor of Philosophy of Science, Cornerstone University, Grand Rapids, Michigan; ~Department of Radiation Oncology, Juravinski Cancer Centre, Department of Medicine, McMaster University, Hamilton, Ontario; 4Department of Medical Physics, McMaster University, Hamilton, Ontario
K. E. Rieger I, W.J. Hong 1, V. G. Tusher ~, J. Tang~, R. Tibshiranf, and G. Chu ~ 1Departments of Medicine and Biochemistry, Stanford University School of Medicine, Stanford, Califomia; 2Health Research & Policy and Statistics, Stanford University School of Medicine, Stanford, Cafifomia
An important challenge arises in radiotherapy when certain individuals present with abnormal radiosensitivities. Radiosensitive individuals may not tolerate normal therapy and encounter complications whereas radioresistant patients may not respond adequately to standard treatments regimes because of intrinsic cellular resistance. Crompton et al. (IJROBP 1999; 45:707-714 and IJROBP 2001; 49:547-554) have performed retrospective studies that suggest 1-lymphocytes (CD4/CD8) can be used to predict normal tissue adverse response based on lymphocyte radiosensitivity among a patient group. These studies showed late normal tissue toxicity was correlated to low level apoptosis in CD4 and CD8 lymphocytes. The assay developed by this group used a simple flow cytometry based assay. Our group has researched the sensitivity of alternative apoptosis assays (DiOC6, Caspase-3, Annexin-V, PI, 7AAD and Comet), and have shown that FITC conjugated caspase-3 and Annexin V-FITC assays had the greatest sensitivity. However, the caspase-3 assay is more labour intensive, and therefore we are using Annexin V-FITC for speed, simplicity and sensitivity and comparing this assay (Annexin-V) with Crompton et al. for suitability in clinical use. In the present study, 80 prostate cancer patients will be tested for radiosensitivity using lymphocyte apoptosis assays. These patients were formerly enrolled in a randomized doseescalation study by Sathya et al. (unpublished data). Toxicity was recorded prospectively. The aim of this study is to determine a correlation between the proportion of Tlymphocytes undergoing apoptosis when irradiated (2 and 9 Gy) and the occurrence of late toxicity (Grade II and above). We will report our preliminary data that shows individual radioresponses have small intra-individual and large interindividual variation and attempt to correlate this to clinical outcome. 94 Practical Lessons From the Molecular Biology of Head and Neck Cancer Development
J. Ca~llano. Department Of Otolaryngology-Head And Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Recent investigations have provided a more precise understanding of early molecular events and their impact on biologic behavior in the development of head and neck squamous cell carcinoma. This understanding has significant implications for directing future advances in surgical and radiation therapy, chemoprevention, and molecular targeted therapy. These findings also provide a more complete understanding of the biology underlying the concept of "field cancerization" and risk of second primary tumor after treatment of primary head and neck cancer.
Toxicity from radiation therapy is a grave problem for cancer patients. We hypothesized that some cases of toxicity are associated with abnormal transcriptional responses to radiation. We used microarrays to measure responses to ionizing and ultraviolet radiation in lymphoblastoid cells derived from 14 patients with acute radiation toxicity. The analysis utilized a new method, heterogeneity-associated transformation of the data, to account for a clinical outcome arising from more than one underlying cause. To compute the risk of toxicity for each patient, we applied nearest shrunken centroids, a method that identifies and cross-validates predictive genes. Transcriptional responses in 24 genes predicted radiation toxicity in 9 of 14 patients with no false positives among 43 controls (p = 2.2¥107). The responses of these 9 patients displayed significant heterogeneity. Of the 5 patients with toxicity and normal responses, 2 were treated with protocols that proved to be highly toxic. These results may enable physicians to predict toxicity and tailor treatment for individual patients. 96 Molecular Target Radiosensitization: From Laboratory to Phase III Clinical Trial.
P. M. Harari. University of Wisconsin Comprehensive Madison, Wisconsin
Cancer Center,
For many epithelial cancers (ie, lung, H&N, esophagus, cervix), dominant clinical research strategies in recent decades have involved intensification of radiation and chemotherapy. This effort has commonly taken the form of either altered radiation fractionation or chemoradiation. During recent years in particular, concurrent chemoradiation has assumed a leading role in global cancer practice. Modest gains in Iocoregional disease control and overall survival have been achieved, although generally at the expense of higher acute and sometimes chronic toxicities. The prospect that new molecular therapies might complement or augment conventional cancer treatment modalities is under active investigation for many tumor types. Inhibitors of the epidermal growth factor receptor (EGFR) represent a particularly promising class of agents currently under examination. The first randomized clinical trial (Phase III) to identify a survival advantage combining an EGFR inhibitor with conventional cancer therapy has emerged in the context of high dose radiation (ASCO 2004). The biological rationale for the EGFR/radiation combination has been well studied with evidence that EGFR blockade can complement radiation effects on cell cycle inhibition, enhance radiation-induced apoptosis, interfere with radiation-induced damage repair and induce antiangiogenic effects as well as anti-metastatic effects. The clinical trial randomized 424 advanced H&N cancer patients to curative-intent radiation alone +/- weekly cetuximab (anti-EGFR mAb). There was a near doubling of the median survival from 28 to 54 months, and a statistically significant improvement (p = 0.02) in Iocoregional disease control (8% at 2 years) and overall survival (13% at 3 years) favoring the experimental arm. Cetuximab treatment was generally well tolerated with the most common adverse event being that of skin reaction. There are several potential, implications of this new trial. First, the results identify the capacity of a molecular targeted growth inhibitor
$30 September 9-12
(cetuximab in this case) to augment survival outcome in a curative cohort of patients treated with radiation alone. This finding suggests that other epithelial cancers treated with dominant radiation approaches may warrant clinical investigation regarding the addition of EGFR inhibitors. Second, the results suggest that cetuximab (and possibly other EGFR inhibitors) warrants clinical evaluation regarding capacity to enhance outcome when added to chemoradiation regimens. Finally, the similar survival gains observed with cetuximab/radiation to those observed with chemoradiation (compared against radiation alone) suggest the potential for cetuximab to substitute for chemotherapy; a concept that warrants systematic clinical evaluation. 98 HOW Can We Use Genomics to Understand Non-targeted effects of Radiotherapy?
C. Mothersi//, C. O'Shea, M. Moriarty, C. Seymour. Medica/ Physics and Applied Radiation Sciences Unit, McMaster University, Hamilton, Ontario; St Luke's /nstitute of Cancer Research, Dublin, ~re~and Radiation-induced bystander effects are the subject of intense investigation in radiation protection. While the effects are produced in cells not directly hit by radiation and not in the radiation field, they clearly have a genetic basis in that different strains of mice, cell lines or human patients express different types of "out-of-field" effects. The effects predominate at low doses and have been discussed mainly in terms of the impact on low-dose risk assessment. Possible therapeutic implications have been alluded to, but not discussed in any detail. The purpose of this presentation is to consider the possible areas where genomics could be applied to bystander biology in areas of major importance or interest in radiotherapy. These include consideration of radiation-induced bystander effects during the cell cycle, under hypoxic conditions, when fractionated therapy modalities are used, or when combined radio-chemotherapy is given. Also discussed are individual variations in toxicity of bystander factors and normal tissue "collateral" damage. The importance of considering the tumor in the context of the organ, and even the organism that supports it, is also discussed. Direct clinical radiotherapy studies that consider bystander effects are not in the public domain at the time of writing, although a clinical study is being analysed by this group at present. Many in vitro studies are available that are relevant; some preliminary animal data have also been published. Because radiation-induced bystander effects appear to challenge many of the central assumptions that underlie radiotherapy practice, it is important to consider what unexplored treatment avenues might result from a consideration of these effects. The final part of this presentation is devoted to this point. 99 Acute Genitourinary (GU) Toxicity in Prostate Cancer Patients Treated with External Beam Radiotherapy (EBRT) is Due to the Dose to the Urethra.
M. Schwartz 7, S. Pater, R. Corns2, I. Lavoie2, J. Ske//7, B. Bahoric I, L. Souhami ~. ~McGi// University Department of Radiation Onco/ogy, Montrea/, Quebec; 2McGill University Department of Medical Physics, Montreal, Quebec Objectives: To analyze the dose to the urethra and bladder in relation to acute GU toxicity. Methods: Following CT simulation with a urethrogram, sixteen patients each had three plans generated: i) the original plan that each patient was treated with, ii) a plan from a reduced field technique, and iii) a plan from an anterior urethral block technique. The reduced field and anterior urethral block
CARO 2004
techniques were designed to decrease the dose to the urethra outside of the planning target volume (urethral dose) while maintaining the dose to the PTV. The doses to the urethra, bladder, and urethral volume from the original plan were correlated to acute GU toxicities, and a logistic fit model was generated. Results: The rates of grade 1, 2, and 3 acute GU toxicity were 13.0%, 62.5%, and 13.0%, respectively. The urethral dose significantly correlated with acute GU toxicity (p = 0.0056), but the doses to the bladder and urethral volume did not. The difference of the urethral dose between the anterior urethral block vs. original plan was 14.3% (p < 0.0001) and the reduced field vs. original 10% (p < 0.0001). There were no differences between the three plans in regards to the dose to the PTV, rectum or bladder. Using our predictive model, a dose decrease from 44 to 38.6 Gy using an anterior urethral block would decrease the risk of acute GU grade 3 toxicity by 50%. Conclusions: The dose to the bladder does not correlate with acute GU toxicity. We found a significant correlation with the dose to the urethra and acute GU toxicity, showing that the urethral dose is the limiting factor for acute effects. By using the reduced field or anterior urethral block techniques, the dose to the urethra can be easily decreased without compromising coverage to the PTV. 100 Smoking Increases the Risk of Developing Metastatic Disease in Prostate Cancer Patients Treated with Radical Radiotherapy.
J. Pantarotto', S. Dahrouge 1, L. Eapen ~, Y. Mac2, A.M. Ugnat2, L. Xiez, V. Gallant 1, S. Malone 7. 1The Ottawa Hospital, University of Ottawa, Ottawa, Ontario; 2Centre for Chronic Disease Prevention and Control, Health Canada, Ottawa, Ontario Background: Population-based studies have suggested that smoking is related to an increased risk of developing fatal disease. We evaluated the impact of smoking on long-term outcome in a cohort of men treated at one institution with a uniform radical radiotherapy protocol. Methods: The study is a retrospective cohort review of 313 cT1-T4 NO M0 patients. Treatment consisted of a curative course of external beam radiotherapy (6600 cGy/33) with 44% treated with short course. Results: Median age at treatment was 69. Clinical stage on presentation was 43% T1-T2a, 35% T2b-c, and 22% T3-T4. Gleason scores of < 6 observed in 69%, 7 in 18% and > 8 in 13%. Median PSA was 10.5 ng/mL. 54% of the population were former smokers and 17% were current smokers. Tobacco history was not correlated with stage, Gleason score or pretreatment PSA. Median follow-up was 5.8 years. Smoking was associated with an elevated risk of metastatic failure in the univariate analysis. This association was maintained in the multivariate analysis for former smokers (HR = 2.8, p = 0.11) and for current smokers (HR = 5.7, p = 0.015) when compared to non-smokers. A history of smoking (former and current) was associated with reduced disease-specific survival (HR = 2.20) but this was not statistically significant (p = 0.17). Conclusions: Smoking is associated with an increased risk of developing metastatic disease and may impact on disease specific survival in prostate cancer patients treated with curative radiotherapy.
September 9-12 $29
93 Radiation-Induced Apoptosis of Lymphocytes to Predict Late Toxicity from Radiotherapy.
95 Toxicity From Radiation Therapy Associated with Abnormal Transcriptional Responses to DNA Damage.
K. Schnarr ~, L. Ryan ~, N. McFar/ane ~, N.E.A. Crompton2, J. Sathya 3, I. Dayes~, D. Boreham ~. ~Department of Medical Physics, McMaster University, Hamilton, Ontario; 2Sir John Eccles Professor of Philosophy of Science, Cornerstone University, Grand Rapids, Michigan; ~Department of Radiation Oncology, Juravinski Cancer Centre, Department of Medicine, McMaster University, Hamilton, Ontario; 4Department of Medical Physics, McMaster University, Hamilton, Ontario
K. E. Rieger I, W.J. Hong 1, V. G. Tusher ~, J. Tang~, R. Tibshiranf, and G. Chu ~ 1Departments of Medicine and Biochemistry, Stanford University School of Medicine, Stanford, Califomia; 2Health Research & Policy and Statistics, Stanford University School of Medicine, Stanford, Cafifomia
An important challenge arises in radiotherapy when certain individuals present with abnormal radiosensitivities. Radiosensitive individuals may not tolerate normal therapy and encounter complications whereas radioresistant patients may not respond adequately to standard treatments regimes because of intrinsic cellular resistance. Crompton et al. (IJROBP 1999; 45:707-714 and IJROBP 2001; 49:547-554) have performed retrospective studies that suggest 1-lymphocytes (CD4/CD8) can be used to predict normal tissue adverse response based on lymphocyte radiosensitivity among a patient group. These studies showed late normal tissue toxicity was correlated to low level apoptosis in CD4 and CD8 lymphocytes. The assay developed by this group used a simple flow cytometry based assay. Our group has researched the sensitivity of alternative apoptosis assays (DiOC6, Caspase-3, Annexin-V, PI, 7AAD and Comet), and have shown that FITC conjugated caspase-3 and Annexin V-FITC assays had the greatest sensitivity. However, the caspase-3 assay is more labour intensive, and therefore we are using Annexin V-FITC for speed, simplicity and sensitivity and comparing this assay (Annexin-V) with Crompton et al. for suitability in clinical use. In the present study, 80 prostate cancer patients will be tested for radiosensitivity using lymphocyte apoptosis assays. These patients were formerly enrolled in a randomized doseescalation study by Sathya et al. (unpublished data). Toxicity was recorded prospectively. The aim of this study is to determine a correlation between the proportion of Tlymphocytes undergoing apoptosis when irradiated (2 and 9 Gy) and the occurrence of late toxicity (Grade II and above). We will report our preliminary data that shows individual radioresponses have small intra-individual and large interindividual variation and attempt to correlate this to clinical outcome. 94 Practical Lessons From the Molecular Biology of Head and Neck Cancer Development
J. Ca~llano. Department Of Otolaryngology-Head And Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland Recent investigations have provided a more precise understanding of early molecular events and their impact on biologic behavior in the development of head and neck squamous cell carcinoma. This understanding has significant implications for directing future advances in surgical and radiation therapy, chemoprevention, and molecular targeted therapy. These findings also provide a more complete understanding of the biology underlying the concept of "field cancerization" and risk of second primary tumor after treatment of primary head and neck cancer.
Toxicity from radiation therapy is a grave problem for cancer patients. We hypothesized that some cases of toxicity are associated with abnormal transcriptional responses to radiation. We used microarrays to measure responses to ionizing and ultraviolet radiation in lymphoblastoid cells derived from 14 patients with acute radiation toxicity. The analysis utilized a new method, heterogeneity-associated transformation of the data, to account for a clinical outcome arising from more than one underlying cause. To compute the risk of toxicity for each patient, we applied nearest shrunken centroids, a method that identifies and cross-validates predictive genes. Transcriptional responses in 24 genes predicted radiation toxicity in 9 of 14 patients with no false positives among 43 controls (p = 2.2¥107). The responses of these 9 patients displayed significant heterogeneity. Of the 5 patients with toxicity and normal responses, 2 were treated with protocols that proved to be highly toxic. These results may enable physicians to predict toxicity and tailor treatment for individual patients. 96 Molecular Target Radiosensitization: From Laboratory to Phase III Clinical Trial.
P. M. Harari. University of Wisconsin Comprehensive Madison, Wisconsin
Cancer Center,
For many epithelial cancers (ie, lung, H&N, esophagus, cervix), dominant clinical research strategies in recent decades have involved intensification of radiation and chemotherapy. This effort has commonly taken the form of either altered radiation fractionation or chemoradiation. During recent years in particular, concurrent chemoradiation has assumed a leading role in global cancer practice. Modest gains in Iocoregional disease control and overall survival have been achieved, although generally at the expense of higher acute and sometimes chronic toxicities. The prospect that new molecular therapies might complement or augment conventional cancer treatment modalities is under active investigation for many tumor types. Inhibitors of the epidermal growth factor receptor (EGFR) represent a particularly promising class of agents currently under examination. The first randomized clinical trial (Phase III) to identify a survival advantage combining an EGFR inhibitor with conventional cancer therapy has emerged in the context of high dose radiation (ASCO 2004). The biological rationale for the EGFR/radiation combination has been well studied with evidence that EGFR blockade can complement radiation effects on cell cycle inhibition, enhance radiation-induced apoptosis, interfere with radiation-induced damage repair and induce antiangiogenic effects as well as anti-metastatic effects. The clinical trial randomized 424 advanced H&N cancer patients to curative-intent radiation alone +/- weekly cetuximab (anti-EGFR mAb). There was a near doubling of the median survival from 28 to 54 months, and a statistically significant improvement (p = 0.02) in Iocoregional disease control (8% at 2 years) and overall survival (13% at 3 years) favoring the experimental arm. Cetuximab treatment was generally well tolerated with the most common adverse event being that of skin reaction. There are several potential, implications of this new trial. First, the results identify the capacity of a molecular targeted growth inhibitor
$30 September 9-12
(cetuximab in this case) to augment survival outcome in a curative cohort of patients treated with radiation alone. This finding suggests that other epithelial cancers treated with dominant radiation approaches may warrant clinical investigation regarding the addition of EGFR inhibitors. Second, the results suggest that cetuximab (and possibly other EGFR inhibitors) warrants clinical evaluation regarding capacity to enhance outcome when added to chemoradiation regimens. Finally, the similar survival gains observed with cetuximab/radiation to those observed with chemoradiation (compared against radiation alone) suggest the potential for cetuximab to substitute for chemotherapy; a concept that warrants systematic clinical evaluation. 98 HOW Can We Use Genomics to Understand Non-targeted effects of Radiotherapy?
C. Mothersi//, C. O'Shea, M. Moriarty, C. Seymour. Medica/ Physics and Applied Radiation Sciences Unit, McMaster University, Hamilton, Ontario; St Luke's /nstitute of Cancer Research, Dublin, ~re~and Radiation-induced bystander effects are the subject of intense investigation in radiation protection. While the effects are produced in cells not directly hit by radiation and not in the radiation field, they clearly have a genetic basis in that different strains of mice, cell lines or human patients express different types of "out-of-field" effects. The effects predominate at low doses and have been discussed mainly in terms of the impact on low-dose risk assessment. Possible therapeutic implications have been alluded to, but not discussed in any detail. The purpose of this presentation is to consider the possible areas where genomics could be applied to bystander biology in areas of major importance or interest in radiotherapy. These include consideration of radiation-induced bystander effects during the cell cycle, under hypoxic conditions, when fractionated therapy modalities are used, or when combined radio-chemotherapy is given. Also discussed are individual variations in toxicity of bystander factors and normal tissue "collateral" damage. The importance of considering the tumor in the context of the organ, and even the organism that supports it, is also discussed. Direct clinical radiotherapy studies that consider bystander effects are not in the public domain at the time of writing, although a clinical study is being analysed by this group at present. Many in vitro studies are available that are relevant; some preliminary animal data have also been published. Because radiation-induced bystander effects appear to challenge many of the central assumptions that underlie radiotherapy practice, it is important to consider what unexplored treatment avenues might result from a consideration of these effects. The final part of this presentation is devoted to this point. 99 Acute Genitourinary (GU) Toxicity in Prostate Cancer Patients Treated with External Beam Radiotherapy (EBRT) is Due to the Dose to the Urethra.
M. Schwartz 7, S. Pater, R. Corns2, I. Lavoie2, J. Ske//7, B. Bahoric I, L. Souhami ~. ~McGi// University Department of Radiation Onco/ogy, Montrea/, Quebec; 2McGill University Department of Medical Physics, Montreal, Quebec Objectives: To analyze the dose to the urethra and bladder in relation to acute GU toxicity. Methods: Following CT simulation with a urethrogram, sixteen patients each had three plans generated: i) the original plan that each patient was treated with, ii) a plan from a reduced field technique, and iii) a plan from an anterior urethral block technique. The reduced field and anterior urethral block
CARO 2004
techniques were designed to decrease the dose to the urethra outside of the planning target volume (urethral dose) while maintaining the dose to the PTV. The doses to the urethra, bladder, and urethral volume from the original plan were correlated to acute GU toxicities, and a logistic fit model was generated. Results: The rates of grade 1, 2, and 3 acute GU toxicity were 13.0%, 62.5%, and 13.0%, respectively. The urethral dose significantly correlated with acute GU toxicity (p = 0.0056), but the doses to the bladder and urethral volume did not. The difference of the urethral dose between the anterior urethral block vs. original plan was 14.3% (p < 0.0001) and the reduced field vs. original 10% (p < 0.0001). There were no differences between the three plans in regards to the dose to the PTV, rectum or bladder. Using our predictive model, a dose decrease from 44 to 38.6 Gy using an anterior urethral block would decrease the risk of acute GU grade 3 toxicity by 50%. Conclusions: The dose to the bladder does not correlate with acute GU toxicity. We found a significant correlation with the dose to the urethra and acute GU toxicity, showing that the urethral dose is the limiting factor for acute effects. By using the reduced field or anterior urethral block techniques, the dose to the urethra can be easily decreased without compromising coverage to the PTV. 100 Smoking Increases the Risk of Developing Metastatic Disease in Prostate Cancer Patients Treated with Radical Radiotherapy.
J. Pantarotto', S. Dahrouge 1, L. Eapen ~, Y. Mac2, A.M. Ugnat2, L. Xiez, V. Gallant 1, S. Malone 7. 1The Ottawa Hospital, University of Ottawa, Ottawa, Ontario; 2Centre for Chronic Disease Prevention and Control, Health Canada, Ottawa, Ontario Background: Population-based studies have suggested that smoking is related to an increased risk of developing fatal disease. We evaluated the impact of smoking on long-term outcome in a cohort of men treated at one institution with a uniform radical radiotherapy protocol. Methods: The study is a retrospective cohort review of 313 cT1-T4 NO M0 patients. Treatment consisted of a curative course of external beam radiotherapy (6600 cGy/33) with 44% treated with short course. Results: Median age at treatment was 69. Clinical stage on presentation was 43% T1-T2a, 35% T2b-c, and 22% T3-T4. Gleason scores of < 6 observed in 69%, 7 in 18% and > 8 in 13%. Median PSA was 10.5 ng/mL. 54% of the population were former smokers and 17% were current smokers. Tobacco history was not correlated with stage, Gleason score or pretreatment PSA. Median follow-up was 5.8 years. Smoking was associated with an elevated risk of metastatic failure in the univariate analysis. This association was maintained in the multivariate analysis for former smokers (HR = 2.8, p = 0.11) and for current smokers (HR = 5.7, p = 0.015) when compared to non-smokers. A history of smoking (former and current) was associated with reduced disease-specific survival (HR = 2.20) but this was not statistically significant (p = 0.17). Conclusions: Smoking is associated with an increased risk of developing metastatic disease and may impact on disease specific survival in prostate cancer patients treated with curative radiotherapy.