- Email: [email protected]
304 speaker TRANSLATING MOLECULAR IMAGING INTO THE CLINIC: FROM MOUSE TO MAN
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or recurrent disease. The treatment consisted of chemotherapy concomitant with pelvic radiation of 45Gy/25fr to the vulva and loco-regional areas. A boost dose was given to the inguinal nodes by electron or conformal therapy. Boost dose to the vulvar area was achieved by interstitial brachytherapy. Implant was according to the localisation of the primary. Dosimetry was CT scan based and an Iridium-192 afterloading system was used to deliver a boost dose of 20Gy/10fr/55 hours. Results: From November 1997 and December 2006, 41 patients median age 65 years were included in this prospective study. Patients were stage according to the FIGO system: 13- stage II, 25-stage III, 3- IV and 2 had recurrent disease. There were 37 squamous cell carcinomas and 4 adenocarcinomas. Chemotherapy consisted of platinum (n= 16) or mitomicin (n=25) based regimen. With a median follow-up of 80 months, the local control rate and loco-regional control rate are 85% and 96% respectively. The diseasefree survival, the overall survival and the disease-specific survival are respectively 79%, 90% and 92% at 5 years. Sphincter preservation rate is 100%. There was no treatment related death. The most common acute toxicities were: grade 2 genito-urinary (73%), grade 2 gastrointestinal (70.8%), Grade 3 dermatologic (50%) and febrile neutopenia (5%). Late toxicity mostly consisted of skin fibrosis, telangiectasia in 25% and Grade 2 vaginal atrophy, 3 patients had soft tissues necrosis treated by hyperbaric oxygen Conclusions: Interstitial HDR brachytherapy used as a boost to concomitant chemoradiation provides good results as a sphincter sparing approach in selected patients with vulvar cancer.
T UESDAY, M AY 10, 2011
Symposium ESTRO - CARO Joint Symposium: Translating research in imaging into clinical practice 303 speaker FROM GENOMICS TO INDIVIDUALIZED TREATMENT B. Wouters1 1 P RINCESS M ARGARET H OSPITAL, Toronto, Canada
Important advances in a variety of human diseases including cancer have been made through the development and implementation of standardized, evidenced based, treatment protocols. However, implicit in such standardization is an assumption that the nature of the disease amongst different individuals is similar, and that patients have similar probabilities of benefiting from the treatment in question. For cancer therapy in general, and radiation therapy in particular, this assumption holds only to a first approximation, as several known biological variables that influence treatment response vary significantly both within and amongst different tumors. For radiotherapy, these include differences in proliferation, hypoxic fraction, and even the intrinsic radiosensitivity of the tumor cells in question. Recent advances in molecular imaging have provided tools to assess these properties, particularly their spatial variation within tumors, and to aid in delivering individualized treatment. However, the underlying basis for differences in the biological properties amongst tumors lies in the recent observation that at the genetic level, individual tumors show an extremely high level of heterogeneity. Rapid technological advances have revealed that individual tumors often contain thousands of mutations and that the number of different genes that contribute to cancer development is much higher than previously thought. Consequently, the number of shared mutations in tumors from individual patients is very small, limited to a few commonly mutated genes. These observations suggest that deep genomic characterization of individual tumors is necessary to both understand their relevant biological characteristics and to predict the effectiveness of available treatment options. It is likely that genomic characterization of individual tumors will also provide a better context for interpreting observations made through molecular imaging, such that they can be used more effectively for guiding treatment in the future. 304 speaker TRANSLATING MOLECULAR IMAGING INTO THE CLINIC: FROM MOUSE TO MAN P. Lambin1 , L. Dubois1 , J. Eriksson2 , A. Windhorst2 , D. De Ruysscher1 , G. Van Dongen2 1 MAASTRO C LINIC, GROW, U NIVERSITY M EDICAL C ENTRE M AAS TRICHT, Radiation Oncology, Maastricht, Netherlands 2 VUMC, Nuclear Medicine, Amsterdam, Netherlands
Classically modern translational research tries to bridge two gaps: a) the gap between in vitro biomedical research and in vivo imaging and b) the gap between preclinical imaging and clinical imaging. In this paper we will focus on the last one. Clinical translation of scientific discoveries is often the long-term goal of academic medical research. However, this goal is not always realized due to the complicated path between bench research and clinical use. In this abstract, we outline the fundamental steps required for first-in-human testing of a new imaging biomarker with [18F]HX4 and [89Zr]Cetuximab as examples. In theory the regulation for new imaging biomarkers is the same as for therapeutic drugs: after promising preclinical testing, the imaging biomarker has to be synthesized according to Good Manufacturing Practice guidelines (GMP) and tested for toxicity. An extensive "Investigator Brochure" as well as an "Investigational Medicinal Product Dossier" (IMPD) have to be registered and approved centrally at the national and the European (http://eudract.emea.eu.int) level. After approval, a "first in human trial" has to be performed. The development follows four discovery and four development steps, being ESD = Exploratory Screen Development, SDS = Screening/Designed Synthesis, LD = Lead Development, CS = Candidate Seeking for the discovery steps and CAN = Clinical Candidate, phase 0 (pharmacodynamics and -kinetics at very low doses), phase I (toxicity) and phase II (effectiveness) trials as development steps. Developing and understanding of clinical significance for specific imaging biomarkers can be a difficult process. There are two main steps of certification for a surrogate endpoint to be fully established: Qualification and Validation. For an imaging biomarker to become qualified, it must go through a somewhat formal qualification process. After qualification, an imaging biomarker may have limited use as a surrogate endpoint. They may be used in phase I and II clinical trials for correlative studies, but can only be used in phase III trials for early hypothesis generating studies. There are two steps for validation, probable validation and known validation. "Probable validation" requires widespread agreement in the medical or scientific community as to its efficacy, which it is linked to the presence of the target disease or condition (we speak also of biological validation). "Known validation" requires a scientific framework or body of evidence that appears to
T UESDAY, M AY 10, 2011
elucidate the marker’s efficacy. For full validation, an imaging biomarker must for example demonstrate it is accurate, reproducible, and feasible over time, that measured changes over time in the imaging biomarker are closely coupled or linked to the success or failure of the therapeutic effect. In other words the imaging biomarker must have therapeutic consequences. Only after that stage, the imaging biomarker can be used for treatment or trial selection, randomization, stratification or as main endpoint. During the presentation we will focus on two examples: a) a biomarker of hypoxia [18F]HX4 1. Preclinical evaluation and validation of [18F]HX4, a novel promising hypoxia marker for PET imaging. Dubois et al, PNAS submitted 2. PET imaging of hypoxia using [18F]HX4: a phase I trial. van Loon J et al Eur J Nucl Med Mol Imaging. 2010 Aug;37(9):1663-8. b) a labeled drug ([89Zr]Cetuximab). 1. Disparity between in vivo EGFR expression and 89Zr-labeled cetuximab uptake assessed with PET. Aerts HJ et al. P. J Nucl Med. 2009 Jan;50(1):12331. 2. Development and evaluation of a cetuximab-based imaging probe to target EGFR and EGFRvIII. Aerts HJ et al. Radiother Oncol. 2007 Jun;83(3):32632.
305 speaker DOSE PAINTING: HOW AND FOR WHICH TUMOURS? V. Khoo1 1 R OYAL M ARSDEN H OSPITAL T RUST & I NSTITUTE OF C ANCER R ESEARCH, London, United Kingdom
In the optimisation of radiotherapy, it is evident that the ability to modulate our dose provides improved dose distributions. This has developed sequentially from the traditional use of simple wedges to inverse planning for intensity modulated radiotherapy (IMRT). Clinically IMRT has been used to permit safe dose escalation in several tumour sites such as prostate cancer with improvements in local control that is hoped will translate into overall survival. IMRT can also offer a substantial reduction in normal tissue toxicity (eg prostate and head and neck radiotherapy) and improve quality of life indices for these patients. More recently imaging modalities can provide functional and molecular information to better assess tumour heterogeneity and function. Recognised issues for tumour radioresistance such as hypoxia, enhanced tumour proliferation, and surrogates of tumour activity such as angiogenesis and amino acid metabolism can now be assessed and evaluated by positron emission tomography (PET) and functional magnetic resonance imaging (MRI). IMRT provides the opportunity to create substantial inhomogenous dose distributions with strategies such as simultaneous integrated boosts or zones of de-escalation of dose. Together with the ability to define subtumour volumes, the concept of dose painting was developed. A further refinement of this regional subtumour volume dose painting or dose painting by contours is dose painting by numbers or by voxels where dose is allocated according to quantitative imaging parameters of the imaged voxels within the target. Dose painting can thus provide the most personalised treatment strategy for any individual and may ideally, in the future, target individual molecular lesions. Underpinning the strategy of dose painting is the ability to validate that the imaged regions or voxels do represent suitable biological targets that will benefit from alterations in dose delivered such as increased dose or larger dose fractions. Appropriate histopathological-imaging studies are needed to quantify the imaging correlates. Careful prospective studies with patterns of failure evaluation are necessary to quantify the potential benefit of these strategies. Critical to any sophisticated treatment strategy such as IMRT and particularly when there are subtarget dose volumes being dose painted is the need for accuracy and to incorporate image guided radiotherapy methods to ensure
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reliability for dose painting. Future developments should address assessment of tumour response during therapy to enable the opportunity to implement changes in the treatment schema for both favourable and unfavourable patient scenarios. 306 speaker REAL TIME IGART WITH LINAC MR HYBRID G. Fallone1 1 C ROSS C ANCER I NSTITUTE, Department of Medical Physics, Edmonton, Canada Purpose/Objective: IGRT attempts to address the uncertainties of the target’s topography during the course of the treatment. Present techniques are limited by poor soft-tissue visualization and do not allow real-time imaging during linac/source irradiation. Since MRI provides superior soft-tissue contrast (most cancers are of soft-tissue type), 3 D imaging without gantry rotation and fast imaging, integrating an MRI with a linac/other radiation source would offer significant advantages for IGRT. At the Cross Cancer Institute, Edmonton Canada, we designed, studied and developed an integrated linac-MR system consisting of an open bi-planar (split magnet) with a 6 MV linac with two configuration options (Fig). The MR’s magnetic field runs perpendicularly to the magnet planes and either transversely or longitudinally to the linac central axis.. The Lorentz force in the transverse option does not change dosimetry significantly for homogeneous tissue, but does change it significantly for inhomogeneous tissues (eg, lungs) at magnetic fields greater than 0.2T. These dosimetric changes are eliminated or considerably reduced in the longitudinal option for higher fields. In addition, this option provides an increase in dose to the PTV, because the magnetic field confines the electrons to the forward direction, and can thus potentially reduce dose to the surrounding tissues. The longitudinal option is only possible in our design. Results/Discussion: Our first prototype is a 6 MV linac mounted onto the open end of a biplanar 0.2 T permanent MR system with a 30 cm pole-topole gap in the transverse option. Present MR imaging is operational during linac irradiation and MR images produced during irradiation were visually and quantitatively similar to those taken with the linac turned off. It provides 4 MR images/second with tumours that are automatically countoured, tracked, and followed by the linac beam through MLC motion. The shape of the contour is also followed. We have eliminated mutual interferences between the linac and the MRI systems: 1) RF Issues: The linac 3 GHz RF from the microwave generator does not interfere with the MRI because it is electro-magnetically contained within the closed linac system. However, we found that the pulsed power modulator creates pulses containing low level MHz harmonics which are specific to the linac and the treatment room. We implemented configurations to reduce RF interferences resulting in MR images obtained during linac irradiation to be the same as those obtained when the linac is off. The effects of RF from the MLC motors were also determined and eliminated. 2) Magnetic Issues: We simulated/optimized/ measured the 3D linac waveguide and Monte-Carlo -simulated the resultant radiation distribution within a subject. We modeled the 3D magnetic fields emanating from the MRI, and optimized the size and distance of shielding to reduce the field within the waveguide to avoid significant displacement of the electron trajectory in the linac. We investigated the magnetic effects on the linac waveguide for both the transverse and longitudinal options. In the transverse option, beam loss depends on the field (eg, 45 % at 6 G, 100 % at 14 G), with the production of a highly asymmetric focal spot (13 % profile asymmetry at 6 G). Profile symmetry is regained at the expense of a lateral shift in the dose profiles by translating the focal spot with respect to the target coordinates. The lateral profile shifts were corrected by adjusting the jaw positions asymmetrically. In the longitudinal option, only the electron gun optics that is affected. Although, the longitudinal magnetic fields cause large beam losses within the electron gun, these losses may be eliminated through a redesign of the electron gun optics or through magnetic shielding. We optimized passive and active magnetic designs to shield the linac against magnetic interferences, and found that very simple passive and/or active shielding designs can easily magnetically decouple the linac from the MR imager. We also found that commercial MLC system motors can be used if the magnetic fields at their locations are below tolerances, which in extreme cases can easily be provided with magnetic shielding. Our system involves the physical coupling of a linac with a rotating biplanar MR system to prevent image distortion resulting from relative motion between the magnet and the linac. However, since the magnet rotates with respect to the patient, there may be a change in tissue magnetic susceptibility as the magnet rotates resulting in image distortion. We have shown that MRIs with fields below 1.5 T can still maintain acceptable geometric accuracy with rotation. Conclusion: We are presently implementing the longitudinal option integrating a 6 MV linac to a 0.5 MR system with a 60 cm pole-to-pole gap with, at the very least, the same imaging and auto-tracking-radiation features of our present prototype.
S YMPOSIUM
or recurrent disease. The treatment consisted of chemotherapy concomitant with pelvic radiation of 45Gy/25fr to the vulva and loco-regional areas. A boost dose was given to the inguinal nodes by electron or conformal therapy. Boost dose to the vulvar area was achieved by interstitial brachytherapy. Implant was according to the localisation of the primary. Dosimetry was CT scan based and an Iridium-192 afterloading system was used to deliver a boost dose of 20Gy/10fr/55 hours. Results: From November 1997 and December 2006, 41 patients median age 65 years were included in this prospective study. Patients were stage according to the FIGO system: 13- stage II, 25-stage III, 3- IV and 2 had recurrent disease. There were 37 squamous cell carcinomas and 4 adenocarcinomas. Chemotherapy consisted of platinum (n= 16) or mitomicin (n=25) based regimen. With a median follow-up of 80 months, the local control rate and loco-regional control rate are 85% and 96% respectively. The diseasefree survival, the overall survival and the disease-specific survival are respectively 79%, 90% and 92% at 5 years. Sphincter preservation rate is 100%. There was no treatment related death. The most common acute toxicities were: grade 2 genito-urinary (73%), grade 2 gastrointestinal (70.8%), Grade 3 dermatologic (50%) and febrile neutopenia (5%). Late toxicity mostly consisted of skin fibrosis, telangiectasia in 25% and Grade 2 vaginal atrophy, 3 patients had soft tissues necrosis treated by hyperbaric oxygen Conclusions: Interstitial HDR brachytherapy used as a boost to concomitant chemoradiation provides good results as a sphincter sparing approach in selected patients with vulvar cancer.
T UESDAY, M AY 10, 2011
Symposium ESTRO - CARO Joint Symposium: Translating research in imaging into clinical practice 303 speaker FROM GENOMICS TO INDIVIDUALIZED TREATMENT B. Wouters1 1 P RINCESS M ARGARET H OSPITAL, Toronto, Canada
Important advances in a variety of human diseases including cancer have been made through the development and implementation of standardized, evidenced based, treatment protocols. However, implicit in such standardization is an assumption that the nature of the disease amongst different individuals is similar, and that patients have similar probabilities of benefiting from the treatment in question. For cancer therapy in general, and radiation therapy in particular, this assumption holds only to a first approximation, as several known biological variables that influence treatment response vary significantly both within and amongst different tumors. For radiotherapy, these include differences in proliferation, hypoxic fraction, and even the intrinsic radiosensitivity of the tumor cells in question. Recent advances in molecular imaging have provided tools to assess these properties, particularly their spatial variation within tumors, and to aid in delivering individualized treatment. However, the underlying basis for differences in the biological properties amongst tumors lies in the recent observation that at the genetic level, individual tumors show an extremely high level of heterogeneity. Rapid technological advances have revealed that individual tumors often contain thousands of mutations and that the number of different genes that contribute to cancer development is much higher than previously thought. Consequently, the number of shared mutations in tumors from individual patients is very small, limited to a few commonly mutated genes. These observations suggest that deep genomic characterization of individual tumors is necessary to both understand their relevant biological characteristics and to predict the effectiveness of available treatment options. It is likely that genomic characterization of individual tumors will also provide a better context for interpreting observations made through molecular imaging, such that they can be used more effectively for guiding treatment in the future. 304 speaker TRANSLATING MOLECULAR IMAGING INTO THE CLINIC: FROM MOUSE TO MAN P. Lambin1 , L. Dubois1 , J. Eriksson2 , A. Windhorst2 , D. De Ruysscher1 , G. Van Dongen2 1 MAASTRO C LINIC, GROW, U NIVERSITY M EDICAL C ENTRE M AAS TRICHT, Radiation Oncology, Maastricht, Netherlands 2 VUMC, Nuclear Medicine, Amsterdam, Netherlands
Classically modern translational research tries to bridge two gaps: a) the gap between in vitro biomedical research and in vivo imaging and b) the gap between preclinical imaging and clinical imaging. In this paper we will focus on the last one. Clinical translation of scientific discoveries is often the long-term goal of academic medical research. However, this goal is not always realized due to the complicated path between bench research and clinical use. In this abstract, we outline the fundamental steps required for first-in-human testing of a new imaging biomarker with [18F]HX4 and [89Zr]Cetuximab as examples. In theory the regulation for new imaging biomarkers is the same as for therapeutic drugs: after promising preclinical testing, the imaging biomarker has to be synthesized according to Good Manufacturing Practice guidelines (GMP) and tested for toxicity. An extensive "Investigator Brochure" as well as an "Investigational Medicinal Product Dossier" (IMPD) have to be registered and approved centrally at the national and the European (http://eudract.emea.eu.int) level. After approval, a "first in human trial" has to be performed. The development follows four discovery and four development steps, being ESD = Exploratory Screen Development, SDS = Screening/Designed Synthesis, LD = Lead Development, CS = Candidate Seeking for the discovery steps and CAN = Clinical Candidate, phase 0 (pharmacodynamics and -kinetics at very low doses), phase I (toxicity) and phase II (effectiveness) trials as development steps. Developing and understanding of clinical significance for specific imaging biomarkers can be a difficult process. There are two main steps of certification for a surrogate endpoint to be fully established: Qualification and Validation. For an imaging biomarker to become qualified, it must go through a somewhat formal qualification process. After qualification, an imaging biomarker may have limited use as a surrogate endpoint. They may be used in phase I and II clinical trials for correlative studies, but can only be used in phase III trials for early hypothesis generating studies. There are two steps for validation, probable validation and known validation. "Probable validation" requires widespread agreement in the medical or scientific community as to its efficacy, which it is linked to the presence of the target disease or condition (we speak also of biological validation). "Known validation" requires a scientific framework or body of evidence that appears to
T UESDAY, M AY 10, 2011
elucidate the marker’s efficacy. For full validation, an imaging biomarker must for example demonstrate it is accurate, reproducible, and feasible over time, that measured changes over time in the imaging biomarker are closely coupled or linked to the success or failure of the therapeutic effect. In other words the imaging biomarker must have therapeutic consequences. Only after that stage, the imaging biomarker can be used for treatment or trial selection, randomization, stratification or as main endpoint. During the presentation we will focus on two examples: a) a biomarker of hypoxia [18F]HX4 1. Preclinical evaluation and validation of [18F]HX4, a novel promising hypoxia marker for PET imaging. Dubois et al, PNAS submitted 2. PET imaging of hypoxia using [18F]HX4: a phase I trial. van Loon J et al Eur J Nucl Med Mol Imaging. 2010 Aug;37(9):1663-8. b) a labeled drug ([89Zr]Cetuximab). 1. Disparity between in vivo EGFR expression and 89Zr-labeled cetuximab uptake assessed with PET. Aerts HJ et al. P. J Nucl Med. 2009 Jan;50(1):12331. 2. Development and evaluation of a cetuximab-based imaging probe to target EGFR and EGFRvIII. Aerts HJ et al. Radiother Oncol. 2007 Jun;83(3):32632.
305 speaker DOSE PAINTING: HOW AND FOR WHICH TUMOURS? V. Khoo1 1 R OYAL M ARSDEN H OSPITAL T RUST & I NSTITUTE OF C ANCER R ESEARCH, London, United Kingdom
In the optimisation of radiotherapy, it is evident that the ability to modulate our dose provides improved dose distributions. This has developed sequentially from the traditional use of simple wedges to inverse planning for intensity modulated radiotherapy (IMRT). Clinically IMRT has been used to permit safe dose escalation in several tumour sites such as prostate cancer with improvements in local control that is hoped will translate into overall survival. IMRT can also offer a substantial reduction in normal tissue toxicity (eg prostate and head and neck radiotherapy) and improve quality of life indices for these patients. More recently imaging modalities can provide functional and molecular information to better assess tumour heterogeneity and function. Recognised issues for tumour radioresistance such as hypoxia, enhanced tumour proliferation, and surrogates of tumour activity such as angiogenesis and amino acid metabolism can now be assessed and evaluated by positron emission tomography (PET) and functional magnetic resonance imaging (MRI). IMRT provides the opportunity to create substantial inhomogenous dose distributions with strategies such as simultaneous integrated boosts or zones of de-escalation of dose. Together with the ability to define subtumour volumes, the concept of dose painting was developed. A further refinement of this regional subtumour volume dose painting or dose painting by contours is dose painting by numbers or by voxels where dose is allocated according to quantitative imaging parameters of the imaged voxels within the target. Dose painting can thus provide the most personalised treatment strategy for any individual and may ideally, in the future, target individual molecular lesions. Underpinning the strategy of dose painting is the ability to validate that the imaged regions or voxels do represent suitable biological targets that will benefit from alterations in dose delivered such as increased dose or larger dose fractions. Appropriate histopathological-imaging studies are needed to quantify the imaging correlates. Careful prospective studies with patterns of failure evaluation are necessary to quantify the potential benefit of these strategies. Critical to any sophisticated treatment strategy such as IMRT and particularly when there are subtarget dose volumes being dose painted is the need for accuracy and to incorporate image guided radiotherapy methods to ensure
S YMPOSIUM
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reliability for dose painting. Future developments should address assessment of tumour response during therapy to enable the opportunity to implement changes in the treatment schema for both favourable and unfavourable patient scenarios. 306 speaker REAL TIME IGART WITH LINAC MR HYBRID G. Fallone1 1 C ROSS C ANCER I NSTITUTE, Department of Medical Physics, Edmonton, Canada Purpose/Objective: IGRT attempts to address the uncertainties of the target’s topography during the course of the treatment. Present techniques are limited by poor soft-tissue visualization and do not allow real-time imaging during linac/source irradiation. Since MRI provides superior soft-tissue contrast (most cancers are of soft-tissue type), 3 D imaging without gantry rotation and fast imaging, integrating an MRI with a linac/other radiation source would offer significant advantages for IGRT. At the Cross Cancer Institute, Edmonton Canada, we designed, studied and developed an integrated linac-MR system consisting of an open bi-planar (split magnet) with a 6 MV linac with two configuration options (Fig). The MR’s magnetic field runs perpendicularly to the magnet planes and either transversely or longitudinally to the linac central axis.. The Lorentz force in the transverse option does not change dosimetry significantly for homogeneous tissue, but does change it significantly for inhomogeneous tissues (eg, lungs) at magnetic fields greater than 0.2T. These dosimetric changes are eliminated or considerably reduced in the longitudinal option for higher fields. In addition, this option provides an increase in dose to the PTV, because the magnetic field confines the electrons to the forward direction, and can thus potentially reduce dose to the surrounding tissues. The longitudinal option is only possible in our design. Results/Discussion: Our first prototype is a 6 MV linac mounted onto the open end of a biplanar 0.2 T permanent MR system with a 30 cm pole-topole gap in the transverse option. Present MR imaging is operational during linac irradiation and MR images produced during irradiation were visually and quantitatively similar to those taken with the linac turned off. It provides 4 MR images/second with tumours that are automatically countoured, tracked, and followed by the linac beam through MLC motion. The shape of the contour is also followed. We have eliminated mutual interferences between the linac and the MRI systems: 1) RF Issues: The linac 3 GHz RF from the microwave generator does not interfere with the MRI because it is electro-magnetically contained within the closed linac system. However, we found that the pulsed power modulator creates pulses containing low level MHz harmonics which are specific to the linac and the treatment room. We implemented configurations to reduce RF interferences resulting in MR images obtained during linac irradiation to be the same as those obtained when the linac is off. The effects of RF from the MLC motors were also determined and eliminated. 2) Magnetic Issues: We simulated/optimized/ measured the 3D linac waveguide and Monte-Carlo -simulated the resultant radiation distribution within a subject. We modeled the 3D magnetic fields emanating from the MRI, and optimized the size and distance of shielding to reduce the field within the waveguide to avoid significant displacement of the electron trajectory in the linac. We investigated the magnetic effects on the linac waveguide for both the transverse and longitudinal options. In the transverse option, beam loss depends on the field (eg, 45 % at 6 G, 100 % at 14 G), with the production of a highly asymmetric focal spot (13 % profile asymmetry at 6 G). Profile symmetry is regained at the expense of a lateral shift in the dose profiles by translating the focal spot with respect to the target coordinates. The lateral profile shifts were corrected by adjusting the jaw positions asymmetrically. In the longitudinal option, only the electron gun optics that is affected. Although, the longitudinal magnetic fields cause large beam losses within the electron gun, these losses may be eliminated through a redesign of the electron gun optics or through magnetic shielding. We optimized passive and active magnetic designs to shield the linac against magnetic interferences, and found that very simple passive and/or active shielding designs can easily magnetically decouple the linac from the MR imager. We also found that commercial MLC system motors can be used if the magnetic fields at their locations are below tolerances, which in extreme cases can easily be provided with magnetic shielding. Our system involves the physical coupling of a linac with a rotating biplanar MR system to prevent image distortion resulting from relative motion between the magnet and the linac. However, since the magnet rotates with respect to the patient, there may be a change in tissue magnetic susceptibility as the magnet rotates resulting in image distortion. We have shown that MRIs with fields below 1.5 T can still maintain acceptable geometric accuracy with rotation. Conclusion: We are presently implementing the longitudinal option integrating a 6 MV linac to a 0.5 MR system with a 60 cm pole-to-pole gap with, at the very least, the same imaging and auto-tracking-radiation features of our present prototype.