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221 Invited Signal transduction and radiation survival: is there a common pathway?
Symposia
istry and cellular biology which have been highly successful in shedding light on molecular processes regulating cancer development and treatment responses. One of the most fruitful areas of interaction between molecular and clinical oncology relates to a very old clinical observation, namely the oestrogen dependency of breast cancer. The molecular endocrinology of the oestrogen receptor underpins a new understanding of endocrine effects, including recent insight into the role of plasma membrane growth factor receptor pathways (HER-2 and EGFR) in modulating tumour responsive to oestrogen blockade. The growth factor receptor HER-2 (or c-orB-2) is also the target of one of the first anti-cancer pharmaceuticals (trastuzumab) whose development was based on an understanding of molecular structuret~unction relationships. These are exciting times for molecular oncology as it enters the post-genomic era, but it will have to get a move on; breast cancer will be a much less common cause of death in developed countries by the end of the current decade, 221 Invited Signal transduction and radiation survival: is there a common
pathway'?, W.G. McKenna, R.J. Muschel, A. Gupta, E.J. Bemhard University of Pennsylvania, Radiation Oncology, Philadelphia PA 19104, USA Some evidence suggests that there may be a common signaling pathway that regulates the survival of cells after radiation. Ras has been shown to increase radiation resistance. Downstream pathways from Ras could thus be targets for manipulation of radiosensitivity. Also, since signaling cascades may converge from multiple upstream mediators, identification of the downstream elements may give insights into cases where radioresistance is seen in the absence of a Ras mutation. To identify the pathways that contribute to sensitization, we screened a panel of agents known to block at specific points. The data pointed to PI3K as a mediator of Ras-induced radiation resistance. These results were confirmed using an inducible vector for PI3K. PI3K pathway may also affect radioresistance independently of Ras activation, since EGF can also signal through PI3K. We asked whether EGFR expression and Akt phosphorylation(since Akt is downstream of PI3K) measured in both in human head and neck cancers and in tissue culture were associated with the response to radiation. Association between staining of EGFR, Pan Akt, P-Akt and outcome was tested in patients with head and neck cancer. We found P-Akt was a significant predictor for local control, This idea was tested using H&N cancer cells that have active EGFR and WT Ras, we found that Akt was constitutively phosphorylated. Treatment of the cells with an EGFR inhibitor, a farnesyltransferase inhibitor of Ras, or a PI3K inhibitor resulted in both reduced Akt phosphorylation and caused radiosensitization. This retrospective study evaluating EGFR and Akt in H&N cancer patients treated with multimodality therapy found a significant association between P-Akt and treatment failure. These results implicate PAkt in radiation resistance since failures were all local. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, ras, PI3K, and Akt radiosensitized H&N squamous cancer cell lines, We have previously shown that PI3K is a mediator of Ras-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through this common pathway. In addition to EGFR and Ras, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, Ras, or PTEN that results in radiation resistance may uncover targets for developing molecular based radiosensitization protocols for tumors resistant to radiation and thus improve local control,
Friday, 20 September 2002 $75
waveform from a position-sensitive respiration monitor placed on the patient, are recorded synchronously during acquisition and are used to correlate CT slice with respiration phase. Following spiral acquisition, one selects those reconstructed slices that occur at the same phase in the respiration waveform, yielding 3D image sets at typically 8-10 different phases. Choosing a small spiral pitch results in acceptable (-5mm) resolution along the patient axis. Initial patierlt studies with this technique show good agreement in observed anatomical variation with phase compared to fluoroscopic imaging, as well as the current technique of axial CT acquisition at a single phase. The RCCT data can be analyzed to identify the phase of minimum tumor motion, determine the residual tumor motion within the treatment gate interval to define appropriate treatment apertures, and cornpare treatment plans at different phases. In addition to intra-fractional variation, there can also be inter-fractional organ variation during gated treatment; however, lung tumors are often difficult or impossible to discern in portal images. Megavoltage cone-beam CT using an amorphous silicon electronic portal imaging device is a promising alternative for tumor localization and position correction during gated treatments. Phantom studies demonstrate that by using small imaging fields that conform to the planning target volume, sufficient contrast and spatial resolution is achieved to discorn tumor-like objects in lung. For example, we have observed contrast differences of 10% in CBCT reconstructions with 100 image projections totaling -60cGy at isocenter. Furthermore, the radiation dose from such imaging fields can be accounted for in the treatment plan, with no significant additional dose to surrounding non-target tissues. Such an approach can be used, for example, to image the lung GTV on a daily basis early on in treatment and correct for any systematic error in its position. 223
Invited
Flat-panel Cone-beam CT: an emerging technology of i m a g e guided radiation therapy D. Jaffrav PrincessMargaret Hospital, Radiation Medicine Program, Toronto, Ontario, Canada Localized radiation therapy is often compromised by the substantial margins employed tO guarantee target coverage in the presence of the geometric uncertainty in daily field placement. Additional imaging of soft-tissue structures in the therapy setting would allow daily re-positioning or re-planning with a corresponding reduction in margin size. A novel, volumetric imaging technique based upon flat-panel imager technology and conebeam CT reconstruction methods has been developed for image-guided radiation therapy. Flat-panel cone-beam CT has been made viable through the development of large, robust 2D x-ray detectors (amorphous-silicon photodiode arrays) and high-speed reconstruction hardware for cone-beam CT. Investigations over the past three years have demonstrated the potential of this technology to generate high-resolution (sub-millimeter), low-dose (-0.5 cGy) volumetric ([25cm]3) CT images with soft-tissue contrast sensitivity comparable to conventional CT. Many of the physical challenges of cone-beam CT have been examined and the hypothesis that flat-panel cone-beam CT is a powerful technology for image-guided therapy remains strong. The real test of this technology is beginning, as application specific embodiments of the technology are being explored. At present, two image-guidance system are being constructed based upon this technology - a linear accelerator with on-board cone-beam CT, and an isocentdc, mobile C-arm capable of intra-operative cone-beam CT. Clinical applications for this new technology will be presented, ranging from high-precision radiation therapy of the prostate to C-arm based image-guided brachytherapy. 224
Invited
IMAGE GUIDED RADIOTHERAPY
MRI guided radiotherapy: MRI as position verifcation system for IMRT
222
J.J.W. Laqendijk, B.W. Raaymakers, U.A. van der Heide, R. Topolnjak, H. Dehnad, P. Hofman, A.J. Nederveen, I.M. Schulz, J. Welleweerd, C.J.G. Bakker1 Department of Radiotherapy and Radiology1, University Medical Centre Utrecht,Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Invited
Respiration correlated CT techniques for gated treatment of lung cancer G.S. Maoeras Memorial Sloan-Kettering Cancer Ctr, Dept. of Medical Physics, New York, USA This presentation describes recent developments in imaging techniques at MSKCC to improve tumor localization accuracy during the planning and delivery of respiratory gated radiotherapy of nonsmall cell lung cancer. We have been investigating a technique referred to as respiration-correlated spiral CT (RCCT) to achieve "4-D" imaging, i.e., to provide spatial and ternporal information of the gross tumor volume (GTV) fo[ treatment planning purposes. In RCCT the x-ray on signal from the scanner, and respiration
The integration of a MRI system with a linear accelerator could produce a breakthrough in accurate position verification in radiotherapy. Such a MRI system must be fully integrated with the accelerator system. Both systems must function independently but simultaneously. The MRI system will be able to make fast 2D images of soft tissues with orientation along and perpendicular to the field axis, allowing continuous imaging at critical locations which are predefined during the treatment planning procedure. The major engineering, imaging and clinical problems involved in the design of such
istry and cellular biology which have been highly successful in shedding light on molecular processes regulating cancer development and treatment responses. One of the most fruitful areas of interaction between molecular and clinical oncology relates to a very old clinical observation, namely the oestrogen dependency of breast cancer. The molecular endocrinology of the oestrogen receptor underpins a new understanding of endocrine effects, including recent insight into the role of plasma membrane growth factor receptor pathways (HER-2 and EGFR) in modulating tumour responsive to oestrogen blockade. The growth factor receptor HER-2 (or c-orB-2) is also the target of one of the first anti-cancer pharmaceuticals (trastuzumab) whose development was based on an understanding of molecular structuret~unction relationships. These are exciting times for molecular oncology as it enters the post-genomic era, but it will have to get a move on; breast cancer will be a much less common cause of death in developed countries by the end of the current decade, 221 Invited Signal transduction and radiation survival: is there a common
pathway'?, W.G. McKenna, R.J. Muschel, A. Gupta, E.J. Bemhard University of Pennsylvania, Radiation Oncology, Philadelphia PA 19104, USA Some evidence suggests that there may be a common signaling pathway that regulates the survival of cells after radiation. Ras has been shown to increase radiation resistance. Downstream pathways from Ras could thus be targets for manipulation of radiosensitivity. Also, since signaling cascades may converge from multiple upstream mediators, identification of the downstream elements may give insights into cases where radioresistance is seen in the absence of a Ras mutation. To identify the pathways that contribute to sensitization, we screened a panel of agents known to block at specific points. The data pointed to PI3K as a mediator of Ras-induced radiation resistance. These results were confirmed using an inducible vector for PI3K. PI3K pathway may also affect radioresistance independently of Ras activation, since EGF can also signal through PI3K. We asked whether EGFR expression and Akt phosphorylation(since Akt is downstream of PI3K) measured in both in human head and neck cancers and in tissue culture were associated with the response to radiation. Association between staining of EGFR, Pan Akt, P-Akt and outcome was tested in patients with head and neck cancer. We found P-Akt was a significant predictor for local control, This idea was tested using H&N cancer cells that have active EGFR and WT Ras, we found that Akt was constitutively phosphorylated. Treatment of the cells with an EGFR inhibitor, a farnesyltransferase inhibitor of Ras, or a PI3K inhibitor resulted in both reduced Akt phosphorylation and caused radiosensitization. This retrospective study evaluating EGFR and Akt in H&N cancer patients treated with multimodality therapy found a significant association between P-Akt and treatment failure. These results implicate PAkt in radiation resistance since failures were all local. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, ras, PI3K, and Akt radiosensitized H&N squamous cancer cell lines, We have previously shown that PI3K is a mediator of Ras-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through this common pathway. In addition to EGFR and Ras, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, Ras, or PTEN that results in radiation resistance may uncover targets for developing molecular based radiosensitization protocols for tumors resistant to radiation and thus improve local control,
Friday, 20 September 2002 $75
waveform from a position-sensitive respiration monitor placed on the patient, are recorded synchronously during acquisition and are used to correlate CT slice with respiration phase. Following spiral acquisition, one selects those reconstructed slices that occur at the same phase in the respiration waveform, yielding 3D image sets at typically 8-10 different phases. Choosing a small spiral pitch results in acceptable (-5mm) resolution along the patient axis. Initial patierlt studies with this technique show good agreement in observed anatomical variation with phase compared to fluoroscopic imaging, as well as the current technique of axial CT acquisition at a single phase. The RCCT data can be analyzed to identify the phase of minimum tumor motion, determine the residual tumor motion within the treatment gate interval to define appropriate treatment apertures, and cornpare treatment plans at different phases. In addition to intra-fractional variation, there can also be inter-fractional organ variation during gated treatment; however, lung tumors are often difficult or impossible to discern in portal images. Megavoltage cone-beam CT using an amorphous silicon electronic portal imaging device is a promising alternative for tumor localization and position correction during gated treatments. Phantom studies demonstrate that by using small imaging fields that conform to the planning target volume, sufficient contrast and spatial resolution is achieved to discorn tumor-like objects in lung. For example, we have observed contrast differences of 10% in CBCT reconstructions with 100 image projections totaling -60cGy at isocenter. Furthermore, the radiation dose from such imaging fields can be accounted for in the treatment plan, with no significant additional dose to surrounding non-target tissues. Such an approach can be used, for example, to image the lung GTV on a daily basis early on in treatment and correct for any systematic error in its position. 223
Invited
Flat-panel Cone-beam CT: an emerging technology of i m a g e guided radiation therapy D. Jaffrav PrincessMargaret Hospital, Radiation Medicine Program, Toronto, Ontario, Canada Localized radiation therapy is often compromised by the substantial margins employed tO guarantee target coverage in the presence of the geometric uncertainty in daily field placement. Additional imaging of soft-tissue structures in the therapy setting would allow daily re-positioning or re-planning with a corresponding reduction in margin size. A novel, volumetric imaging technique based upon flat-panel imager technology and conebeam CT reconstruction methods has been developed for image-guided radiation therapy. Flat-panel cone-beam CT has been made viable through the development of large, robust 2D x-ray detectors (amorphous-silicon photodiode arrays) and high-speed reconstruction hardware for cone-beam CT. Investigations over the past three years have demonstrated the potential of this technology to generate high-resolution (sub-millimeter), low-dose (-0.5 cGy) volumetric ([25cm]3) CT images with soft-tissue contrast sensitivity comparable to conventional CT. Many of the physical challenges of cone-beam CT have been examined and the hypothesis that flat-panel cone-beam CT is a powerful technology for image-guided therapy remains strong. The real test of this technology is beginning, as application specific embodiments of the technology are being explored. At present, two image-guidance system are being constructed based upon this technology - a linear accelerator with on-board cone-beam CT, and an isocentdc, mobile C-arm capable of intra-operative cone-beam CT. Clinical applications for this new technology will be presented, ranging from high-precision radiation therapy of the prostate to C-arm based image-guided brachytherapy. 224
Invited
IMAGE GUIDED RADIOTHERAPY
MRI guided radiotherapy: MRI as position verifcation system for IMRT
222
J.J.W. Laqendijk, B.W. Raaymakers, U.A. van der Heide, R. Topolnjak, H. Dehnad, P. Hofman, A.J. Nederveen, I.M. Schulz, J. Welleweerd, C.J.G. Bakker1 Department of Radiotherapy and Radiology1, University Medical Centre Utrecht,Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Invited
Respiration correlated CT techniques for gated treatment of lung cancer G.S. Maoeras Memorial Sloan-Kettering Cancer Ctr, Dept. of Medical Physics, New York, USA This presentation describes recent developments in imaging techniques at MSKCC to improve tumor localization accuracy during the planning and delivery of respiratory gated radiotherapy of nonsmall cell lung cancer. We have been investigating a technique referred to as respiration-correlated spiral CT (RCCT) to achieve "4-D" imaging, i.e., to provide spatial and ternporal information of the gross tumor volume (GTV) fo[ treatment planning purposes. In RCCT the x-ray on signal from the scanner, and respiration
The integration of a MRI system with a linear accelerator could produce a breakthrough in accurate position verification in radiotherapy. Such a MRI system must be fully integrated with the accelerator system. Both systems must function independently but simultaneously. The MRI system will be able to make fast 2D images of soft tissues with orientation along and perpendicular to the field axis, allowing continuous imaging at critical locations which are predefined during the treatment planning procedure. The major engineering, imaging and clinical problems involved in the design of such