- Email: [email protected]
306 speaker REAL TIME IGART WITH LINAC MR HYBRID
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 122
P ROFFERED PAPER
T UESDAY, M AY 10, 2011
Proffered paper Clinical Proffered Papers 4: Breast Cancer 307 oral RISK OF SECOND MALIGNANCIES (SM) AFTER BREAST CANCER (BC) TREATMENT AND THEIR RELATIONSHIP WITH THE ADJUVANT RADIOTHERAPY: LONG TERM RESULTS Y. Kirova1 , Y. de Rycke2 , C. Gautier2 , C. François1 , B. Asselain1 , A. Fourquet1 1 I NSTITUT C URIE, Paris, France 2 I NSTITUT C URIE, Statistics, Paris, France Purpose: To assess the role of radiation therapy (RT) and others adjuvant treatments in the development of SM after longer follow-up and continued monitoring of these patients to confirm the validity and stability of previously published results. Materials: A study of a large single institutional registry-based cohort was conducted on 24,682 women treated for early stage BC at the Institut Curie between 1981 and 2000. Of them 17,745 were analyzed (excludes male, metastatic and bilateral BC and patients who had already diagnosis of other cancer before BC): 14,512 patients were treated with radiation therapy (RT) and 3,233 without RT. Incidence of various types of second malignancies were measured, and the age-standardized incidence ratios (SIRs) for each malignancy were estimated, using data for the general French population. Results: At a median follow-up of 13.4 years (range 2-29), 2370 patients had developed SM as follows: 2010 (13.8%) patients with SM in RT and 360 (11.1%) in no RT group. The 13.4 -year risk of any second malignancy was nearly identical for both cohorts (8.6% v 7.5%, respectively, NS). The 13.4year risk of a second nonbreast malignancy was 5% for the RT and 4% for the no RT group. In comparison with the general population, the studied population had a higher risk of SM (SIR: 2.96 [2.81-3.11]). The greatest risk increases were seen in hematological malignancies (SIR: 2.4 [1.85-3.03]), gynecological (SIR: 1.31 [1.14-1.49]), and lung cancers (SIR 1.39 [1.12-1.72], none of them related to RT. The incidences of gastrointestinal and head and neck cancers were lower in the studied population in comparison with the general French population. No increased risk was observed for malignant melanoma, genito-urinary, and thyroid cancers. Conclusions: With a median follow up of 13.4 years, women treated for breast cancer had a significantly increased risk of several kinds of SM, compared to the general population. The magnitude of this absolute risk was small in the various types of malignancies studied. 308 oral SECOND PRIMARY CANCER AMONG DANISH WOMEN WITH EARLY BREAST CANCER TREATED WITH POSTOPERATIVE RADIOTHERAPY T. Grantzau1 , M. S. Thomsen2 , L. Mellemkjær3 , J. Overgaard1 1 A ARHUS U NIVERSITY H OSPITAL, Department of Experimental Clinical Oncology, Aarhus C, Denmark 2 A ARHUS U NIVERSITY H OSPITAL, Department of Oncology, Aarhus C, Denmark 3 DANISH C ANCER S OCIETY, Institute of Cancer Epidemiology, Copenhagen, Denmark Purpose: To evaluate long-term second primary cancer risk among women treated for early breast cancer with postoperative radiotherapy. Materials: We conducted a cancer-registry based cohort study that included all Danish women without a prior malignancy who had been treated for early breast cancer in the period from 1982 to 2008. The data used in this study was supplied by The Danish Breast Cancer Cooperative Group (DBCG). In order to identify the primary second malignancies the DBCG registry was linked to The Danish Cancer Registry. The Danish Cancer Registry is nationwide and population based. Second primary breast cancer was not considered an outcome in this study. If women were diagnosed with two or more second primary cancers only the first cancer was included in order to avoid the additional effect of any treatment given. Results: The cohort included 46,176 one-year survivors: 23,627 (51%) women had received postoperative radiotherapy (RT) and 22,549 (49%) were non-irradiated. By the end of 2008 with a median follow-up of 6 years (range 1-26) 2,595 second primary cancers had occurred, including 1,148 second cancers located in or close to the treatment field. Second primary cancers located in or close to the treatment field were classified as potentially radiotherapy induced. We included among other the following sites: Pharynx, Larynx, Lung, Pleura, Esophagus, Stomach, Thyroid gland, Pancreas, Colon, Bone and Connective tissue. The Standardized incidence ratio (SIR) for the potentially RT induced sites was 1.2 (95% CI 1.1-1.3) among the irradiated women and 1.0 (95% 0.9-1.1) among the non-irradiated women. The risk of getting a second primary cancer increased over time since treatment. SIR for potentially RT induced sites at a latency of +15 years after breast cancer diagnosis was 1.9 (95%CI 1.4-2.4) among the irradiated women vs. 1.1 (95% CI 0.9-1.3) among the non-irradiated. Further, the risk of getting a potentially
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
S 121
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 122
P ROFFERED PAPER
T UESDAY, M AY 10, 2011
Proffered paper Clinical Proffered Papers 4: Breast Cancer 307 oral RISK OF SECOND MALIGNANCIES (SM) AFTER BREAST CANCER (BC) TREATMENT AND THEIR RELATIONSHIP WITH THE ADJUVANT RADIOTHERAPY: LONG TERM RESULTS Y. Kirova1 , Y. de Rycke2 , C. Gautier2 , C. François1 , B. Asselain1 , A. Fourquet1 1 I NSTITUT C URIE, Paris, France 2 I NSTITUT C URIE, Statistics, Paris, France Purpose: To assess the role of radiation therapy (RT) and others adjuvant treatments in the development of SM after longer follow-up and continued monitoring of these patients to confirm the validity and stability of previously published results. Materials: A study of a large single institutional registry-based cohort was conducted on 24,682 women treated for early stage BC at the Institut Curie between 1981 and 2000. Of them 17,745 were analyzed (excludes male, metastatic and bilateral BC and patients who had already diagnosis of other cancer before BC): 14,512 patients were treated with radiation therapy (RT) and 3,233 without RT. Incidence of various types of second malignancies were measured, and the age-standardized incidence ratios (SIRs) for each malignancy were estimated, using data for the general French population. Results: At a median follow-up of 13.4 years (range 2-29), 2370 patients had developed SM as follows: 2010 (13.8%) patients with SM in RT and 360 (11.1%) in no RT group. The 13.4 -year risk of any second malignancy was nearly identical for both cohorts (8.6% v 7.5%, respectively, NS). The 13.4year risk of a second nonbreast malignancy was 5% for the RT and 4% for the no RT group. In comparison with the general population, the studied population had a higher risk of SM (SIR: 2.96 [2.81-3.11]). The greatest risk increases were seen in hematological malignancies (SIR: 2.4 [1.85-3.03]), gynecological (SIR: 1.31 [1.14-1.49]), and lung cancers (SIR 1.39 [1.12-1.72], none of them related to RT. The incidences of gastrointestinal and head and neck cancers were lower in the studied population in comparison with the general French population. No increased risk was observed for malignant melanoma, genito-urinary, and thyroid cancers. Conclusions: With a median follow up of 13.4 years, women treated for breast cancer had a significantly increased risk of several kinds of SM, compared to the general population. The magnitude of this absolute risk was small in the various types of malignancies studied. 308 oral SECOND PRIMARY CANCER AMONG DANISH WOMEN WITH EARLY BREAST CANCER TREATED WITH POSTOPERATIVE RADIOTHERAPY T. Grantzau1 , M. S. Thomsen2 , L. Mellemkjær3 , J. Overgaard1 1 A ARHUS U NIVERSITY H OSPITAL, Department of Experimental Clinical Oncology, Aarhus C, Denmark 2 A ARHUS U NIVERSITY H OSPITAL, Department of Oncology, Aarhus C, Denmark 3 DANISH C ANCER S OCIETY, Institute of Cancer Epidemiology, Copenhagen, Denmark Purpose: To evaluate long-term second primary cancer risk among women treated for early breast cancer with postoperative radiotherapy. Materials: We conducted a cancer-registry based cohort study that included all Danish women without a prior malignancy who had been treated for early breast cancer in the period from 1982 to 2008. The data used in this study was supplied by The Danish Breast Cancer Cooperative Group (DBCG). In order to identify the primary second malignancies the DBCG registry was linked to The Danish Cancer Registry. The Danish Cancer Registry is nationwide and population based. Second primary breast cancer was not considered an outcome in this study. If women were diagnosed with two or more second primary cancers only the first cancer was included in order to avoid the additional effect of any treatment given. Results: The cohort included 46,176 one-year survivors: 23,627 (51%) women had received postoperative radiotherapy (RT) and 22,549 (49%) were non-irradiated. By the end of 2008 with a median follow-up of 6 years (range 1-26) 2,595 second primary cancers had occurred, including 1,148 second cancers located in or close to the treatment field. Second primary cancers located in or close to the treatment field were classified as potentially radiotherapy induced. We included among other the following sites: Pharynx, Larynx, Lung, Pleura, Esophagus, Stomach, Thyroid gland, Pancreas, Colon, Bone and Connective tissue. The Standardized incidence ratio (SIR) for the potentially RT induced sites was 1.2 (95% CI 1.1-1.3) among the irradiated women and 1.0 (95% 0.9-1.1) among the non-irradiated women. The risk of getting a second primary cancer increased over time since treatment. SIR for potentially RT induced sites at a latency of +15 years after breast cancer diagnosis was 1.9 (95%CI 1.4-2.4) among the irradiated women vs. 1.1 (95% CI 0.9-1.3) among the non-irradiated. Further, the risk of getting a potentially