- Email: [email protected]
Impact of Breast Radiotherapy on Quality of Life in Older Patients: A Phase III Trial
S12
CLINICAL ONCOLOGY
in developing local plans to deliver effective skill mix, service improvements and increased capacity in response to local demand. Exciting new projects for training as well as new models of career structure will be discussed. 21 Future Technologies A. Barrett Norfolk and Norwich University Hospital, Norwich, UK The National Radiotherapy Advisory Group working party on new technology has recommended 4D image guided radiotherapy as the standard of care for UK radiotherapy in the next five years. It has studied available technology and tried to assess its current and future role. It has made recommendations on the introduction of new technology, development of national protocols for commissioning and evaluation, collaboration with ACORRN and manufacturers. These recommendations will be presented as part of a symposium to be organised by Peter Kirkbride. They are currently confidential pending ministerial release.
22 NRAG Recommendations for Developing Radiotherapy in England M. Williams Addenbrooke’s Hospital, Cambridge, UK Abstract not published
23 ACCORN d Revitalising Radiotherapy in England P. Price Ralston Paterson Professor of Radiation Oncology & Principal Clinical Scientist, The Wolfson Molecular Imaging Centre, Manchester, UK Abstract not published T10 Target Theory Revisited: Why Physicists are Essential for Radiobiology Research J. D. Chapman CRM Consulting Services, Penticton, BC, Canada V2A 8N1 Douglas E. Lea’s legacy as an eminent radiation biophysicist is well documented. His textbook, Action of Radiation on Living Cells, became an important part of my graduate and post-graduate training in this field. My PhD supervisor, Dr E. C. Pollard, was a contemporary of Dr Lea at Cambridge University and Lea’s teachings were passed on faithfully to all of Ernie’s students. My post-doctoral research was performed at the Gray Laboratory in Northwood, England where Sir Oliver Scott, Ged Adams and Jack Boag fostered the Douglas Lea and Hal Gray vision of radiobiology research. On several occasions, I have overheard other scientists referring to Douglas Lea, Hal Gray and Ernie Pollard as ‘latter day saints’ of target theory. So just what is target theory? In its minimal form, radiation physicists envisioned microscopic volumes (targets) of radiosensitive molecules in cells that, if ‘hit’ by some energy deposition ‘event’ could lead to the death of that specific cell. Target theory was built upon quantitative and mathematical descriptions of the kinetics of cell killing revealed in cell survival curves. Cell survival was considered to result from the Poisson probability of no radiation events occurring within any of the cells target volumes. These considerations led to the mathematical description of singlehit/single-target, single-hit/multi-target, multi-hit/single-target and multi-hit/multi-target possibilities to describe the different shapes of cell survival curves (see Elkind and Whitmore, The Radiobiology of Cultured Mammalian Cells, Gordon and Breach, 1967). It is safe to say that for some time the mathematical descriptions of cell killing ‘outpaced’ the discovery of what
constituted a ‘target volume’ and the ‘radiation event’ of importance. And of course, molecular biology research with its promise to explain cell killing by radiation in terms of specific genes became fashionable and has consumed most of recent research funding. Research from my laboratory contributed at least four new insights into radiation mechanisms that help us to better define the basic elements of target theory. Firstly, the linear-quadratic equation was shown to be the most efficient descriptor of tumor cell killing and the characteristics of single-hit and double-hit inactivation to be distinctively different. Furthermore, the intrinsic radiosensitivity of most human tumor cell lines indicates that it is the single-hit mechanism of cell killing that produces the bulk of tumor response produced by current fractionated radiotherapy procedures. Secondly, the indirect effects of hydroxyl radicals produce the majority of cell killing in oxygenated cells by both single-hit and double-hit events. In fact, indirect effect is more prominent in single-hit compared to double-hit events. This discovery has reshaped our understanding of radiation damages produced by electron track-end, Auger electrons and high-LET radiations. Thirdly, the molecular target(s) in mammalian cells were shown to ‘morph’ throughout the cell division cycle so that the relative importance of single-hit and double-hit killing changes dramatically. In fact, at mitosis when cellular chromatin is maximally compacted, the increased RBE of high-LET is profoundly reduced. In other words, photon and charged-particle radiations have quite similar killing effectiveness, per unit of total absorbed dose, when cells are in mitosis. And fourthly, the proportion of a cell’s chromatin in ‘compacted form’ during inter-phase (G1-, S- and G2phases) correlates with its intrinsic radiosensitivity defined by single-hit killing. This discovery opens up a new approach by which tumor cells might be manipulated to a higher radiosensitivity state at the time of irradiation. The research and exploitation of DNA conformation and tertiary structure falls mainly within the domain of biophysics. So, modern target theory is now based upon two different mechanisms of cell killing (a- and b-inactivation) whose dependence upon repair, dose-rate, indirect effect and molecular oxygen are distinct and different chromatin targets whose structures are changing throughout the cell cycle and are different in different tumor cells. Future studies require an improved description of the microdosimetric events (particularly electron track-ends) produced in mammalian cells by different radiations and the chromatin structures (10e30 nm diameter) that appear to be the hypersensitive radiation targets. These studies suggest that physicists are urgently needed for the modern radiobiology research that could impact most profoundly on the clinical practice of radiation oncology. 24 Impact of Breast Radiotherapy on Quality of Life in Older Patients: A Phase III Trial I. Kunkler University of Edinburgh, UK Background: Breast cancer in older patients presents an increasing health care burden. There is little data on the impact of adjuvant whole breast radiotherapy (WBRT) on quality of life (QoL) in older patients. The PRIME I trial presents the first level I data on the impact of WBRT in such patients. Patients and methods: After breast conserving therapy with clear margins, women 65 years or older with pT0-2, pN0,M0 breast cancer receiving endocrine therapy were randomised to WBRT (40e 50 Gy in 15e25 fractions) or no further treatment. Primary endpoints were QoL, anxiety and depression and cost effectiveness. QoL was measured over 15 months by EORTC QLQ C30 and BR23 modules, mental state by HADS and Philadelphia Geriatric Center Morale Scale, physical functioning by Barthel Activity of Daily Living Index (BADLI) and Clackmannan Scale and costeffectiveness with EuroQol scale to calculate QALYs. Results: 255 patients were randomised. Improvements in QoL with the omission of radiotherapy were not seen in the EuroQol
CLINICAL ONCOLOGY assessment or in the functionality or symptom domains of EORTC scales. RT was associated with increased breast symptoms and fatigue but with less insomnia or endocrine side effects. The BADLI indicated a small but significant fall in functionality in the RT compared to no RT . Up to 15 months, there were no recurrences and QoL utilities from EuroQol were almost identical. Conclusions: Although there are no global differences in quality of life scores between patients treated with and without RT, there are several dimensions which exhibit significant advantage to the omission of radiotherapy. Within this time frame, no radiotherapy is the cost-effective choice. Extrapolations from these data suggest RT may not be a cost effective treatment unless it results in a recurrence rate of at least 5% lower in absolute terms than those treated without radiotherapy. 25 How to use ‘Total-QALYs’ to Make the Treatment Justifications Required by IRMER A. McKenzie Bristol Oncology Centre, Horfield Road, Bristol, UK Background: The requirements of the Ionising Radiation (Medical Exposure) Regulations (IRMER) include a duty on the doctor prescribing radiotherapy to justify the treatment by ‘showing a sufficient net benefit giving appropriate weight’ to the therapeutic benefits and ‘the individual detriment that the exposure may cause’. No guidance is given, either in the regulations or elsewhere, on how to decide this balance between benefit and detriment. No prosecutions were brought by the Department of Health under this regulation for unjustifiable damage to normal tissue as a side effect of treatment, but, with the transfer of the enforcement powers to the Healthcare Commission, there is a need to agree on a common approach for demonstrating justifications of treatments. Method: In order to quantify the balance between opposing factors, the factors need to be expressed in the same units. The benefit of a radiotherapy treatment is easily expressed in terms of QALYs (quality-adjusted life-years), by multiplying together the tumour control probability (TCP), the ‘utility value’ for diseasefree life at the average age of the survivors and the number of years that survivors would be expected to gain because of the radiotherapy. It is proposed that the detriment for a disease-free person may be deduced from a utility value, U, where U ¼ 1 e g . NTCP. NTCP is normal-tissue complication probability and g is a constant close to unity. As the prescription dose increases, U decreases from unity to nearly zero. The ‘Total QALYs’ are found by multiplying U by the benefit in QALYs gained from treating the patients. A further consideration is the likelihood of the treatment technique inducing second malignancy. Results and conclusion: Using, as an example, relevant prostate TCP and NTCP data to calculate the Total QALYs, the method indicates that it is difficult to justify a treatment regimen producing Grade 2 or higher rectal toxicity in more than about 10% of patients. This is not inconsistent with current clinical practice, which therefore lends support for the methodology. In this justification process, consideration of second malignancy induction turns out to be less important, but not negligible.
T11 Accounting for Target Motion due to Breathing in the Treatment of Lung Cancer with Radiotherapy E. Lynn Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK Three dimensional conformal radiotherapy where dose is shaped to disease with the intention of giving a high dose to the disease with minimal dose to adjacent normal tissues is now standard. The exact position of disease needs to be accurately defined to avoid geometric miss. Lung cancers move with breathing. The movement is variable and unpredictable making allowance for such movement
S13
in the planning and administration of radiotherapy difficult. External immobilisation to reduce set-up error is important. Strategies to account for motion of the lung cancer with breathing include performance of a ‘slow’ planning CT scan while the patient is breathing, abdominal compression, deep inspiration or expiration breath hold without any special apparatus, assisted breath hold using a spirometric device, gating while free breathing, moving gantry or multi-leaf collimation. The relative merits of the different techniques will be discussed.
26 Feasibility of Free-breathing Respiratory Gated Liver Radiotherapy with MRI-derived Models C. Coolens*, M. J. Whitey, W. R. Crumy, L. Charles-Edwards*, B. O’Neillz, D. Taitz, M. Hawkinsz *Department of Physics, Royal Marsden NHS Foundation Trust, Fulham Road, London, UK; yCentre for Medical Image Computing, University College London, Malet Place, London, UK; zDepartment of Radiotherapy, Royal Marsden NHS Foundation Trust, Fulham Road, London, UK Purpose: To assess the feasibility of guiding free-breathing respiratory gated radiotherapy of the liver with MRI derived models of hepatic motion. Methods: Prediction of liver position via skin markers for gated radiotherapy is investigated for reproducibility using 4D MRI. Initial work assesses different scanning protocols (based on 3D multi-shot echo planar imaging) with parallel imaging techniques to achieve an image of the liver with temporal resolution of 1 s. Volunteers were imaged during breath-hold (for high resolution registration quality) and in free-breathing with MR-visible skin markers in place; models describing the resulting liver motion and relating it to the position of the skin markers were built using two non-rigid registration methods (B-spline interpolation and fluid flow model). The MR-visible markers are used to synthesize a gating signal such as that obtained during radiotherapy from e.g. a Varian RPM marker. The second stage verifies the accuracy of predicted motion via repeat MRI scans and fluoroscopic imaging (patients only). Results: The chosen MR imaging protocol consisted of a 15-s breathhold high resolution scan followed by a lower resolution 1.5 s dynamic free-breathing scan, with roughly 3 mm isotropic resolution acquired for a total of 1e2 min. Using fluid registration on volunteers, average modulus error between predicted and realized deformations was !1 mm where the model was based on internal diaphragm. The RMS error based on an external signal was 2e3 mm. Conclusion: Results for healthy volunteers suggest that liver deformations may be predicted using a simple skin-marker-system combined with a previously acquired MRI model. This may allow a more controlled delivery of gated radiotherapy of the liver based on external surface marker only. In addition, due to superior softtissue contrast the 4D MR data itself allows better motion visualization for liver target definition compared to 4D CT.
27 On-board Imaging d the Ipswich Experience R. A. Perry Radiotherapy Department, Ipswich Hospital, Heath Road, Ipswich, UK Introduction: At Ipswich Hospital megavoltage (MV) portal images are routinely used for verification of the radiotherapy treatment position in addition to other quality assurance checks. We are always looking at ways of improving the quality and clinical benefit of these portal images. Image-guided radiotherapy (IGRT) systems give the potential to obtain diagnostic quality kV images with vastly reduced dose compared to MV images on the treatment unit. With the installation of a new Varian linac with on-board imaging (OBI) facilities in December 2005, kV imaging and cone beam CT (CBCT) became a clinical option in Ipswich.
CLINICAL ONCOLOGY
in developing local plans to deliver effective skill mix, service improvements and increased capacity in response to local demand. Exciting new projects for training as well as new models of career structure will be discussed. 21 Future Technologies A. Barrett Norfolk and Norwich University Hospital, Norwich, UK The National Radiotherapy Advisory Group working party on new technology has recommended 4D image guided radiotherapy as the standard of care for UK radiotherapy in the next five years. It has studied available technology and tried to assess its current and future role. It has made recommendations on the introduction of new technology, development of national protocols for commissioning and evaluation, collaboration with ACORRN and manufacturers. These recommendations will be presented as part of a symposium to be organised by Peter Kirkbride. They are currently confidential pending ministerial release.
22 NRAG Recommendations for Developing Radiotherapy in England M. Williams Addenbrooke’s Hospital, Cambridge, UK Abstract not published
23 ACCORN d Revitalising Radiotherapy in England P. Price Ralston Paterson Professor of Radiation Oncology & Principal Clinical Scientist, The Wolfson Molecular Imaging Centre, Manchester, UK Abstract not published T10 Target Theory Revisited: Why Physicists are Essential for Radiobiology Research J. D. Chapman CRM Consulting Services, Penticton, BC, Canada V2A 8N1 Douglas E. Lea’s legacy as an eminent radiation biophysicist is well documented. His textbook, Action of Radiation on Living Cells, became an important part of my graduate and post-graduate training in this field. My PhD supervisor, Dr E. C. Pollard, was a contemporary of Dr Lea at Cambridge University and Lea’s teachings were passed on faithfully to all of Ernie’s students. My post-doctoral research was performed at the Gray Laboratory in Northwood, England where Sir Oliver Scott, Ged Adams and Jack Boag fostered the Douglas Lea and Hal Gray vision of radiobiology research. On several occasions, I have overheard other scientists referring to Douglas Lea, Hal Gray and Ernie Pollard as ‘latter day saints’ of target theory. So just what is target theory? In its minimal form, radiation physicists envisioned microscopic volumes (targets) of radiosensitive molecules in cells that, if ‘hit’ by some energy deposition ‘event’ could lead to the death of that specific cell. Target theory was built upon quantitative and mathematical descriptions of the kinetics of cell killing revealed in cell survival curves. Cell survival was considered to result from the Poisson probability of no radiation events occurring within any of the cells target volumes. These considerations led to the mathematical description of singlehit/single-target, single-hit/multi-target, multi-hit/single-target and multi-hit/multi-target possibilities to describe the different shapes of cell survival curves (see Elkind and Whitmore, The Radiobiology of Cultured Mammalian Cells, Gordon and Breach, 1967). It is safe to say that for some time the mathematical descriptions of cell killing ‘outpaced’ the discovery of what
constituted a ‘target volume’ and the ‘radiation event’ of importance. And of course, molecular biology research with its promise to explain cell killing by radiation in terms of specific genes became fashionable and has consumed most of recent research funding. Research from my laboratory contributed at least four new insights into radiation mechanisms that help us to better define the basic elements of target theory. Firstly, the linear-quadratic equation was shown to be the most efficient descriptor of tumor cell killing and the characteristics of single-hit and double-hit inactivation to be distinctively different. Furthermore, the intrinsic radiosensitivity of most human tumor cell lines indicates that it is the single-hit mechanism of cell killing that produces the bulk of tumor response produced by current fractionated radiotherapy procedures. Secondly, the indirect effects of hydroxyl radicals produce the majority of cell killing in oxygenated cells by both single-hit and double-hit events. In fact, indirect effect is more prominent in single-hit compared to double-hit events. This discovery has reshaped our understanding of radiation damages produced by electron track-end, Auger electrons and high-LET radiations. Thirdly, the molecular target(s) in mammalian cells were shown to ‘morph’ throughout the cell division cycle so that the relative importance of single-hit and double-hit killing changes dramatically. In fact, at mitosis when cellular chromatin is maximally compacted, the increased RBE of high-LET is profoundly reduced. In other words, photon and charged-particle radiations have quite similar killing effectiveness, per unit of total absorbed dose, when cells are in mitosis. And fourthly, the proportion of a cell’s chromatin in ‘compacted form’ during inter-phase (G1-, S- and G2phases) correlates with its intrinsic radiosensitivity defined by single-hit killing. This discovery opens up a new approach by which tumor cells might be manipulated to a higher radiosensitivity state at the time of irradiation. The research and exploitation of DNA conformation and tertiary structure falls mainly within the domain of biophysics. So, modern target theory is now based upon two different mechanisms of cell killing (a- and b-inactivation) whose dependence upon repair, dose-rate, indirect effect and molecular oxygen are distinct and different chromatin targets whose structures are changing throughout the cell cycle and are different in different tumor cells. Future studies require an improved description of the microdosimetric events (particularly electron track-ends) produced in mammalian cells by different radiations and the chromatin structures (10e30 nm diameter) that appear to be the hypersensitive radiation targets. These studies suggest that physicists are urgently needed for the modern radiobiology research that could impact most profoundly on the clinical practice of radiation oncology. 24 Impact of Breast Radiotherapy on Quality of Life in Older Patients: A Phase III Trial I. Kunkler University of Edinburgh, UK Background: Breast cancer in older patients presents an increasing health care burden. There is little data on the impact of adjuvant whole breast radiotherapy (WBRT) on quality of life (QoL) in older patients. The PRIME I trial presents the first level I data on the impact of WBRT in such patients. Patients and methods: After breast conserving therapy with clear margins, women 65 years or older with pT0-2, pN0,M0 breast cancer receiving endocrine therapy were randomised to WBRT (40e 50 Gy in 15e25 fractions) or no further treatment. Primary endpoints were QoL, anxiety and depression and cost effectiveness. QoL was measured over 15 months by EORTC QLQ C30 and BR23 modules, mental state by HADS and Philadelphia Geriatric Center Morale Scale, physical functioning by Barthel Activity of Daily Living Index (BADLI) and Clackmannan Scale and costeffectiveness with EuroQol scale to calculate QALYs. Results: 255 patients were randomised. Improvements in QoL with the omission of radiotherapy were not seen in the EuroQol
CLINICAL ONCOLOGY assessment or in the functionality or symptom domains of EORTC scales. RT was associated with increased breast symptoms and fatigue but with less insomnia or endocrine side effects. The BADLI indicated a small but significant fall in functionality in the RT compared to no RT . Up to 15 months, there were no recurrences and QoL utilities from EuroQol were almost identical. Conclusions: Although there are no global differences in quality of life scores between patients treated with and without RT, there are several dimensions which exhibit significant advantage to the omission of radiotherapy. Within this time frame, no radiotherapy is the cost-effective choice. Extrapolations from these data suggest RT may not be a cost effective treatment unless it results in a recurrence rate of at least 5% lower in absolute terms than those treated without radiotherapy. 25 How to use ‘Total-QALYs’ to Make the Treatment Justifications Required by IRMER A. McKenzie Bristol Oncology Centre, Horfield Road, Bristol, UK Background: The requirements of the Ionising Radiation (Medical Exposure) Regulations (IRMER) include a duty on the doctor prescribing radiotherapy to justify the treatment by ‘showing a sufficient net benefit giving appropriate weight’ to the therapeutic benefits and ‘the individual detriment that the exposure may cause’. No guidance is given, either in the regulations or elsewhere, on how to decide this balance between benefit and detriment. No prosecutions were brought by the Department of Health under this regulation for unjustifiable damage to normal tissue as a side effect of treatment, but, with the transfer of the enforcement powers to the Healthcare Commission, there is a need to agree on a common approach for demonstrating justifications of treatments. Method: In order to quantify the balance between opposing factors, the factors need to be expressed in the same units. The benefit of a radiotherapy treatment is easily expressed in terms of QALYs (quality-adjusted life-years), by multiplying together the tumour control probability (TCP), the ‘utility value’ for diseasefree life at the average age of the survivors and the number of years that survivors would be expected to gain because of the radiotherapy. It is proposed that the detriment for a disease-free person may be deduced from a utility value, U, where U ¼ 1 e g . NTCP. NTCP is normal-tissue complication probability and g is a constant close to unity. As the prescription dose increases, U decreases from unity to nearly zero. The ‘Total QALYs’ are found by multiplying U by the benefit in QALYs gained from treating the patients. A further consideration is the likelihood of the treatment technique inducing second malignancy. Results and conclusion: Using, as an example, relevant prostate TCP and NTCP data to calculate the Total QALYs, the method indicates that it is difficult to justify a treatment regimen producing Grade 2 or higher rectal toxicity in more than about 10% of patients. This is not inconsistent with current clinical practice, which therefore lends support for the methodology. In this justification process, consideration of second malignancy induction turns out to be less important, but not negligible.
T11 Accounting for Target Motion due to Breathing in the Treatment of Lung Cancer with Radiotherapy E. Lynn Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK Three dimensional conformal radiotherapy where dose is shaped to disease with the intention of giving a high dose to the disease with minimal dose to adjacent normal tissues is now standard. The exact position of disease needs to be accurately defined to avoid geometric miss. Lung cancers move with breathing. The movement is variable and unpredictable making allowance for such movement
S13
in the planning and administration of radiotherapy difficult. External immobilisation to reduce set-up error is important. Strategies to account for motion of the lung cancer with breathing include performance of a ‘slow’ planning CT scan while the patient is breathing, abdominal compression, deep inspiration or expiration breath hold without any special apparatus, assisted breath hold using a spirometric device, gating while free breathing, moving gantry or multi-leaf collimation. The relative merits of the different techniques will be discussed.
26 Feasibility of Free-breathing Respiratory Gated Liver Radiotherapy with MRI-derived Models C. Coolens*, M. J. Whitey, W. R. Crumy, L. Charles-Edwards*, B. O’Neillz, D. Taitz, M. Hawkinsz *Department of Physics, Royal Marsden NHS Foundation Trust, Fulham Road, London, UK; yCentre for Medical Image Computing, University College London, Malet Place, London, UK; zDepartment of Radiotherapy, Royal Marsden NHS Foundation Trust, Fulham Road, London, UK Purpose: To assess the feasibility of guiding free-breathing respiratory gated radiotherapy of the liver with MRI derived models of hepatic motion. Methods: Prediction of liver position via skin markers for gated radiotherapy is investigated for reproducibility using 4D MRI. Initial work assesses different scanning protocols (based on 3D multi-shot echo planar imaging) with parallel imaging techniques to achieve an image of the liver with temporal resolution of 1 s. Volunteers were imaged during breath-hold (for high resolution registration quality) and in free-breathing with MR-visible skin markers in place; models describing the resulting liver motion and relating it to the position of the skin markers were built using two non-rigid registration methods (B-spline interpolation and fluid flow model). The MR-visible markers are used to synthesize a gating signal such as that obtained during radiotherapy from e.g. a Varian RPM marker. The second stage verifies the accuracy of predicted motion via repeat MRI scans and fluoroscopic imaging (patients only). Results: The chosen MR imaging protocol consisted of a 15-s breathhold high resolution scan followed by a lower resolution 1.5 s dynamic free-breathing scan, with roughly 3 mm isotropic resolution acquired for a total of 1e2 min. Using fluid registration on volunteers, average modulus error between predicted and realized deformations was !1 mm where the model was based on internal diaphragm. The RMS error based on an external signal was 2e3 mm. Conclusion: Results for healthy volunteers suggest that liver deformations may be predicted using a simple skin-marker-system combined with a previously acquired MRI model. This may allow a more controlled delivery of gated radiotherapy of the liver based on external surface marker only. In addition, due to superior softtissue contrast the 4D MR data itself allows better motion visualization for liver target definition compared to 4D CT.
27 On-board Imaging d the Ipswich Experience R. A. Perry Radiotherapy Department, Ipswich Hospital, Heath Road, Ipswich, UK Introduction: At Ipswich Hospital megavoltage (MV) portal images are routinely used for verification of the radiotherapy treatment position in addition to other quality assurance checks. We are always looking at ways of improving the quality and clinical benefit of these portal images. Image-guided radiotherapy (IGRT) systems give the potential to obtain diagnostic quality kV images with vastly reduced dose compared to MV images on the treatment unit. With the installation of a new Varian linac with on-board imaging (OBI) facilities in December 2005, kV imaging and cone beam CT (CBCT) became a clinical option in Ipswich.