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382 RECENT DEVELOPMENTS IN IMAGING AND TRANSLATIONAL RESEARCH IN RADIOTHERAPY
S194 includes the remaining glandular tissue behind the NAC. Breast reconstruction is performed immediately after irradiation. From this experience we conclude that for large or multicentric tumors and/or diffuse microcalcifications far from the NAC, NSM with ELIOT of the NAC obtain good local control and satisfactory cosmetic results. 381 FAILURE MODE AND EFFECT ANALYSIS-BASED QUALITY ASSURANCE FOR DYNAMIC MLC TRACKING SYSTEMS: PATIENT SAFETY IN THE ERA OF REAL-TIME RADIOTHERAPY P. Keall1, A. Sawant2 1 University of Sydney, Australia 2 UT Southerwestern, Dallas, USA Purpose: The era of real-time radiotherapy is upon us. Robotic and gimballed linac systems have been implemented clinically: intense research and development is occurring for dynamic mulitleaf collimator (DMLC) and couch-based systems. DMLCbased systems have been demonstrated in large animal experiments and have been integrated with a large number of real-time target position monitoring systems. In order to maximise patient safety prior to the clinical advent of DMLC tumor tracking, this work aims to develop and implement a failure mode and effect analysis (FMEA)-based commissioning and quality assurance framework. Methods: A systematic failure mode and effect analysis was performed for a prototype real-time tumor tracking system that uses implanted electromagnetic transponders for tumor position monitoring and a DMLC for real-time beam adaptation. A detailed process tree of DMLC tracking delivery was created and potential tracking-specific failure modes were identified. For each failure mode, a risk probability number (RPN) was calculated from the product of the probability of occurrence, the severity of effect, and the detectibility of the failure. Based on the insights obtained from the FMEA, commissioning and QA procedures were developed to check (i) the accuracy of coordinate system transformation, (ii) system latency, (iii) spatial and dosimetric delivery accuracy, (iv) delivery efficiency, and (v) accuracy and consistency of system response to error conditions. The frequency of testing for each failure mode was determined from the RPN value. Results: Failures modes with RPN í 125 were recommended to be tested monthly. Failure modes with RPN í 125 were assigned to be tested during comprehensive evaluations, e.g., during commissioning, annual quality assurance, and after major software/hardware upgrades. System latency was determined to be ~193 ms. The system showed consistent and accurate response to erroneous conditions. Tracking accuracy was within 3%Ä3 mm (100% pass rate) for sinusoidal as well as a wide variety of patient-derived respiratory motions. The total time taken for monthly QA was ~35 min, while that taken for comprehensive testing was ~3.5 h. Conclusions: FMEA proved to be a powerful and flexible tool to develop and implement a quality management (QM) framework for DMLC tracking. The authors conclude that the use of FMEA based QM ensures efficient allocation of clinical resources because
ICTR-PHE 2012 the most critical failure modes receive the most attention. It is expected that the set of guidelines proposed here will serve as a living document that is updated with the accumulation of progressively more intrainstitutional and interinstitutional experience with DMLC tracking. 382 RECENT DEVELOPMENTS IN IMAGING AND TRANSLATIONAL RESEARCH IN RADIOTHERAPY L. Pylkkanen, I. Hristova, J. Hall, J. Bean, D. Lacombe EORTC, Brussels, Belgium An important question for future research in radiotherapy is whether information obtained from translational research (TR) and imaging studies could be used to individualise treatment and minimise toxicity without hampering efficacy. Further, as our understanding of cancer biology deepens, this opens avenues for the exploitation of disease mechanisms to improve radiation response in tumours. This will increasingly allow the development of combined drug/radiation treatments (1). Biomarkers resulting from TR studies conducted using human biospecimens may lead to improvements in radiotherapy. Predictive assays of intrinsic radiosensitivity, e.g., the radiation-induced Iymphocyte apoptosis test (2), are expected to predict the risk of late radiation-induced toxicity. The ability to Identify patients at risk for severe normal tissue toxicities could allow selection of patients who are suitable candidates for preventive measures. Another potential therapeutic implication is sensitising cancers for radiotherapy; e.g., the discovery that cancers with deficiency in DNA double-strand break repair capacity are sensitive to PARP-inhibitors (3, 4) could potentially be used to sensitise cancers to radiotherapy. We can also ask if biomarkers could be used to guide radiation dosing for individual patients? Examples of TR activities on human biospecimens in EORTC studies will be presented. Concerning new imaging TR modalities, the use of 4D PET/CT for target volume delineation and the role of MRI for target definition and response assessment are of interest to investigators. 4D MRI for radiation treatment planning is a very promising approach; however MRI's temporal and spatial resolution is still inferior e.g., to 4D CT and 4D PET/CT (5). Another clinical implication is the use of PET/CT, and more recently DCE-CT, for distinguishing between disease progression and normal tissue toxicity. The use of DWI, DCE and DSC MRI can also help distinguish tissue necrosis versus progression, particularly in brain tumours (6). Currently the use of PET/CT and novel imaging biomarkers in early response evaluation after chemotherapy and with targeted agents is becoming increasingly assessed in clinical studies. Whether these approaches could be used for evaluation of response to radiotherapy and dose modification, and thus personalised treatment planning and monitoring, is a paramount question. In upcoming EORTC trials 4D PET/CT would be used for radiation therapy planning, and DCE/DWI MRI for differentiating necrosis from progression. Examples from ongoing and planned radiotherapy trials within EORTC will be reviewed. Despite the recent developments in both TR and imaging in radiotherapy, more research is still required
S195 to validate the utility of these new concepts in radiotherapy planning, response evaluation, and distinguishing between progression and radiation induced toxicity. References 1. Harrington K. et al., Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer. Clin Oncol 2007; 8:561-571. 2. Ozsahin M. et al., Rapid assay of intrinsic radiosensitivity based on apoptosis in human CD4 and CD8 T-lymphocytes. Int J Radiat Oncol Biol Phys 1997; 38(2):429-40. 3. Calabrese C. R. et al., Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 2004; 96:56-67. 4. Tutt A. et al., Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol 2009; 27:18s (suppl; abstract CRA501). 5. Dinkel et al., 4D-MRI analysis of lung tumor motion in patients with hemidiaphragmatic paralysis. Radiotherapy and Oncology 2009; 91:449-454. 6. Friso W.A. et al., Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 2009; 256(6):878-887. 383 TARGETED ALPHA THERAPY M.R. Zalutsky, G. Vaidyanathan Duke University Medical Center, Durham, North Carolina 27514 USA Targeted radionuclide therapy (also known as targeted radiotherapy or molecular radiotherapy) is an exciting strategy for cancer treatment that is similar to external beam therapy in that malignant cells primarily are destroyed by means of radiation induced damage to their DNA. Targeted radiotherapy is like chemotherapy because it uses a molecule, in this case bearing a radionuclide, to deliver a cytotoxic substance to disease sites. However, unlike conventional drugs and toxins, which kill only the directly targeted cells, a unique feature of radionuclides is that they can exert a “bystander” or “crossfire” effect, potentially destroying adjacent tumor cells even if they lack the specific tumor-associated receptor, enzyme or antigen. Furthermore, a systemically administered targeted radiotherapeutic, which combines the exquisite specificity of molecular specific cellular recognition with the anti-neoplastic effects of ionizing radiation, has the potential to simultaneously eliminate both a primary tumor site and metastatic disease, including malignant cell populations undetectable by diagnostic imaging. Radionuclides that decay by the emission of α-particles offer the exciting prospect of combining cellspecific molecular targets with radiation having a range in tissue of only a few cell diameters. On the other hand, a potential problem resultant from this short range is the effect of heterogeneities in dose deposition on therapeutic efficacy. Alpha particles are radiation of high linear energy transfer, offering important radiobiological advantages for cancer therapy. These include a therapeutic effect that is nearly independent of dose rate, presence of oxygen, and cell cycle status. The properties of α-emitters are best suited for the treatment of compartmentally spread neoplasms such
ICTR-PHE 2012 as ovarian carcinoma and neoplastic meningitis, as well as tumors of the circulation such as lymphoma and leukemia. In addition, targeted anti-vascular radiotherapy is a particularly attractive application of alpha emitters because of the possibility of achieving more efficient cell kill than might be possible with strategies requiring direct binding of the labeled compound to the tumor cells themselves. Alpha emitting radionuclides that have now been evaluated in patients are 46-min 213Bi, 7.2-h 211At, 11-day 223Ra and 10-day 225Ac. Our own work has focused on the heavy halogen 211At, and studies with this radionuclide will be used to illustrate the promise and limitations of alpha emitters for radionuclide therapy. In common with most other α-emitters with realistic clinical potential, lack of reliable availability is one of the biggest hurdles in the use of 211At for targeted radiotherapy. However, in the case of 211At, it is not a question of production cost or availability of target material, because 211At can be produced in reasonable yield from natural bismuth targets. Rather, the difficulty is the lack of cyclotrons equipped with the medium energy α-particle beams required for its production. The Arronnax cyclotron in Nantes is an important step in addressing this problem. Because of the short half-life of 211At and its chemical properties, it will be essential to not only be able to produce clinically relevant levels of 211At but also to be able to ship it to remote locations in chemically tractable form. Approaches that have been investigated include compensating for radiolysis-mediated effects and the consideration of alternative chemistries. In common with other α-particle emitters, strategies for compensating for heterogeneities in dose deposition also must be developed, hopefully in a way that is compatible with approval for human use. Finally, it is essential that more clinical trials be performed with αparticle emitting radiotherapeutics, particularly in settings of minimum residual disease where the radiobiological advantages of α-particles can be best exploited. Clinical studies that have been completed or are on-going include the evaluation of 223Ra chloride for treatment of bone metastases in patients with prostate cancer, 213Bi- and 225Ac-labeled Hu195 monoclonal antibody (mAb) for acute myeloid leukemia, 213BiDOTA-TOC for treating neuroendocrine tumors, 213BiDOTA-substance P and 211At-labeled 81C6 mAb for glioma therapy and 211At-labeled MX-35 F(ab’)2 for treatment of ovarian carcinoma. Currently, we are acquiring the remaining data needed to initiate clinical evaluation of meta-[211At]astatobenzylguanidine and 211 At-labeled trastuzumab in patients with neuroblastoma and breast cancer neoplastic meningitis, respectively. In summary, although the results of most clinical trials performed to date indicate that targeted α-particle therapy is a promising strategy for cancer treatment, practical problems must be overcome before this approach has a meaningful clinical impact. 384 PRECLINICAL IMAGING AND THERAPY M. de Jong Erasmus MC Rotterdam, The Netherlands Preclinical PET, SPECT and CT small animal imaging platforms provide insight into disease biology as well as evaluation of novel imaging and therapeutic options in small animal mouse and rat disease models.
ICTR-PHE 2012 the most critical failure modes receive the most attention. It is expected that the set of guidelines proposed here will serve as a living document that is updated with the accumulation of progressively more intrainstitutional and interinstitutional experience with DMLC tracking. 382 RECENT DEVELOPMENTS IN IMAGING AND TRANSLATIONAL RESEARCH IN RADIOTHERAPY L. Pylkkanen, I. Hristova, J. Hall, J. Bean, D. Lacombe EORTC, Brussels, Belgium An important question for future research in radiotherapy is whether information obtained from translational research (TR) and imaging studies could be used to individualise treatment and minimise toxicity without hampering efficacy. Further, as our understanding of cancer biology deepens, this opens avenues for the exploitation of disease mechanisms to improve radiation response in tumours. This will increasingly allow the development of combined drug/radiation treatments (1). Biomarkers resulting from TR studies conducted using human biospecimens may lead to improvements in radiotherapy. Predictive assays of intrinsic radiosensitivity, e.g., the radiation-induced Iymphocyte apoptosis test (2), are expected to predict the risk of late radiation-induced toxicity. The ability to Identify patients at risk for severe normal tissue toxicities could allow selection of patients who are suitable candidates for preventive measures. Another potential therapeutic implication is sensitising cancers for radiotherapy; e.g., the discovery that cancers with deficiency in DNA double-strand break repair capacity are sensitive to PARP-inhibitors (3, 4) could potentially be used to sensitise cancers to radiotherapy. We can also ask if biomarkers could be used to guide radiation dosing for individual patients? Examples of TR activities on human biospecimens in EORTC studies will be presented. Concerning new imaging TR modalities, the use of 4D PET/CT for target volume delineation and the role of MRI for target definition and response assessment are of interest to investigators. 4D MRI for radiation treatment planning is a very promising approach; however MRI's temporal and spatial resolution is still inferior e.g., to 4D CT and 4D PET/CT (5). Another clinical implication is the use of PET/CT, and more recently DCE-CT, for distinguishing between disease progression and normal tissue toxicity. The use of DWI, DCE and DSC MRI can also help distinguish tissue necrosis versus progression, particularly in brain tumours (6). Currently the use of PET/CT and novel imaging biomarkers in early response evaluation after chemotherapy and with targeted agents is becoming increasingly assessed in clinical studies. Whether these approaches could be used for evaluation of response to radiotherapy and dose modification, and thus personalised treatment planning and monitoring, is a paramount question. In upcoming EORTC trials 4D PET/CT would be used for radiation therapy planning, and DCE/DWI MRI for differentiating necrosis from progression. Examples from ongoing and planned radiotherapy trials within EORTC will be reviewed. Despite the recent developments in both TR and imaging in radiotherapy, more research is still required
S195 to validate the utility of these new concepts in radiotherapy planning, response evaluation, and distinguishing between progression and radiation induced toxicity. References 1. Harrington K. et al., Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer. Clin Oncol 2007; 8:561-571. 2. Ozsahin M. et al., Rapid assay of intrinsic radiosensitivity based on apoptosis in human CD4 and CD8 T-lymphocytes. Int J Radiat Oncol Biol Phys 1997; 38(2):429-40. 3. Calabrese C. R. et al., Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 2004; 96:56-67. 4. Tutt A. et al., Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol 2009; 27:18s (suppl; abstract CRA501). 5. Dinkel et al., 4D-MRI analysis of lung tumor motion in patients with hemidiaphragmatic paralysis. Radiotherapy and Oncology 2009; 91:449-454. 6. Friso W.A. et al., Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol 2009; 256(6):878-887. 383 TARGETED ALPHA THERAPY M.R. Zalutsky, G. Vaidyanathan Duke University Medical Center, Durham, North Carolina 27514 USA Targeted radionuclide therapy (also known as targeted radiotherapy or molecular radiotherapy) is an exciting strategy for cancer treatment that is similar to external beam therapy in that malignant cells primarily are destroyed by means of radiation induced damage to their DNA. Targeted radiotherapy is like chemotherapy because it uses a molecule, in this case bearing a radionuclide, to deliver a cytotoxic substance to disease sites. However, unlike conventional drugs and toxins, which kill only the directly targeted cells, a unique feature of radionuclides is that they can exert a “bystander” or “crossfire” effect, potentially destroying adjacent tumor cells even if they lack the specific tumor-associated receptor, enzyme or antigen. Furthermore, a systemically administered targeted radiotherapeutic, which combines the exquisite specificity of molecular specific cellular recognition with the anti-neoplastic effects of ionizing radiation, has the potential to simultaneously eliminate both a primary tumor site and metastatic disease, including malignant cell populations undetectable by diagnostic imaging. Radionuclides that decay by the emission of α-particles offer the exciting prospect of combining cellspecific molecular targets with radiation having a range in tissue of only a few cell diameters. On the other hand, a potential problem resultant from this short range is the effect of heterogeneities in dose deposition on therapeutic efficacy. Alpha particles are radiation of high linear energy transfer, offering important radiobiological advantages for cancer therapy. These include a therapeutic effect that is nearly independent of dose rate, presence of oxygen, and cell cycle status. The properties of α-emitters are best suited for the treatment of compartmentally spread neoplasms such
ICTR-PHE 2012 as ovarian carcinoma and neoplastic meningitis, as well as tumors of the circulation such as lymphoma and leukemia. In addition, targeted anti-vascular radiotherapy is a particularly attractive application of alpha emitters because of the possibility of achieving more efficient cell kill than might be possible with strategies requiring direct binding of the labeled compound to the tumor cells themselves. Alpha emitting radionuclides that have now been evaluated in patients are 46-min 213Bi, 7.2-h 211At, 11-day 223Ra and 10-day 225Ac. Our own work has focused on the heavy halogen 211At, and studies with this radionuclide will be used to illustrate the promise and limitations of alpha emitters for radionuclide therapy. In common with most other α-emitters with realistic clinical potential, lack of reliable availability is one of the biggest hurdles in the use of 211At for targeted radiotherapy. However, in the case of 211At, it is not a question of production cost or availability of target material, because 211At can be produced in reasonable yield from natural bismuth targets. Rather, the difficulty is the lack of cyclotrons equipped with the medium energy α-particle beams required for its production. The Arronnax cyclotron in Nantes is an important step in addressing this problem. Because of the short half-life of 211At and its chemical properties, it will be essential to not only be able to produce clinically relevant levels of 211At but also to be able to ship it to remote locations in chemically tractable form. Approaches that have been investigated include compensating for radiolysis-mediated effects and the consideration of alternative chemistries. In common with other α-particle emitters, strategies for compensating for heterogeneities in dose deposition also must be developed, hopefully in a way that is compatible with approval for human use. Finally, it is essential that more clinical trials be performed with αparticle emitting radiotherapeutics, particularly in settings of minimum residual disease where the radiobiological advantages of α-particles can be best exploited. Clinical studies that have been completed or are on-going include the evaluation of 223Ra chloride for treatment of bone metastases in patients with prostate cancer, 213Bi- and 225Ac-labeled Hu195 monoclonal antibody (mAb) for acute myeloid leukemia, 213BiDOTA-TOC for treating neuroendocrine tumors, 213BiDOTA-substance P and 211At-labeled 81C6 mAb for glioma therapy and 211At-labeled MX-35 F(ab’)2 for treatment of ovarian carcinoma. Currently, we are acquiring the remaining data needed to initiate clinical evaluation of meta-[211At]astatobenzylguanidine and 211 At-labeled trastuzumab in patients with neuroblastoma and breast cancer neoplastic meningitis, respectively. In summary, although the results of most clinical trials performed to date indicate that targeted α-particle therapy is a promising strategy for cancer treatment, practical problems must be overcome before this approach has a meaningful clinical impact. 384 PRECLINICAL IMAGING AND THERAPY M. de Jong Erasmus MC Rotterdam, The Netherlands Preclinical PET, SPECT and CT small animal imaging platforms provide insight into disease biology as well as evaluation of novel imaging and therapeutic options in small animal mouse and rat disease models.