Athena
12-17-2008, 04:13 PM
IMRT: next move, biological optimization?
The development of intensity-modulated radiation therapy (IMRT) represents an important advance in the precision treatment of cancers, providing a more conformal dose to the tumour while preserving surrounding healthy tissue. To date, the demonstrated benefits of IMRT have been attributed to the improved geometrical dose distribution. But there’s another, as yet unexplored, opportunity offered by IMRT: the ability to optimize the tumour’s biological response.
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Unlike the case in conventional radiation therapy, the dose distributions in IMRT are highly variable in both time and space. The overall time taken to deliver the IMRT treatment (beam-on time), as currently practised, can be significantly longer than for conventional radiotherapy. But there is strong evidence to show that a protracted fraction treatment time allows repair of cellular damage, while the treatment is being delivered.
Research has shown that delivery times shorter than 10 minutes are more effective at killing cells and that this effect increases continuously with faster dose delivery.1, 2 Recent data have emphasized the importance of repair within a fraction, with experiments showing that a reduction in fraction delivery time - from 17 minutes to a minute - can increase the effectiveness of a given dose by up to 20%, depending on the tumour type.3 If the delivery time is longer than 10 to 15 minutes, it is proposed that the dose should be increased to compensate for the reduction in cell death due to such repair effects.4
While there is little experimental evidence as yet for the effects of faster delivery on healthy tissue, it is likely that the therapeutic ratio may be improved. This provides a strong incentive for faster IMRT delivery systems, underlining the importance of initiatives such as RapidArc, volumetric modulated arc therapy (VMAT) and tomotherapy. The fast throughput of patients facilitated by these approaches may eventually only be a minor benefit compared with the improved biological outcomes.
Bystander bearings
The unique aspect of IMRT beam delivery, where the dose rate changes rapidly with time and varies strongly from one point in the tumour to another, means that neighbouring cells can have very different dose histories. Their response and repair opportunities can thus also be very different. Bystander effects - non-local effects that result from intercellular communication - have been observed following cell irradiation.5 For the case of IMRT, the different dose histories of neighbouring cells can lead to unexpected survival fractions, as the bystander signals received by a cell affect its response to the dose it receives.
Depending on the distribution of dose, bystander signalling can either increase or decrease the net cell survival fraction.6 Recently, Claridge-Mackonis et al. classified the bystander effect into three types, based on experimental evidence of in vitro radiation responses in spatially modulated fields.7 The classical bystander effect (type I), as first described by Mothersill et al., is characterized by a reduction in cell survival of unirradiated cells when in communication with cells that have been irradiated.8 Two new types of bystander effect (types II and III) manifest themselves as an increase in cell survival for a given dose.
The type II bystander effect results in an increased survival in cells receiving a small radiation dose when their neighbours receive a lethal dose. Clinically, this means that if a region receives a lethal dose, surrounding peripheral cells will exhibit an increase in survival and possibly even proliferation, despite receiving a small dose of scattered radiation. If the peripheral cells are healthy, this is beneficial. But if the peripheral cells are micro-extensions of the tumour or precursors for secondary cancers, the type II bystander effect could be a problem. This highlights the significance of careful planning of the treatment volume and the need for caution when reducing margin size.
The type III bystander effect is characterized by an increase in survival of irradiated cells within the treatment field when neighbouring cells receive a reduced dose. In IMRT, where the dose distribution within the tumour volume is less uniform than for conventional treatments and where the dose distribution varies with time, the consequences of the type III effect may require a compensating increase in dose to provide the same biological effect. Clinically, this effect may already be counteracted by the dose escalation permitted by IMRT.
Figuring it out
The mechanisms underlying bystander signalling are not well understood and are likely to be multifaceted, involving direct communication between adjacent cells through the membranes and molecular vectors in the intercellular medium. If we fully understood the mechanisms of the bystander effects, repair processes and their interplay, we would have a powerful vehicle by which to enhance the therapeutic outcome of radiation therapy.
The lack of knowledge at the molecular level, however, does not prevent the effects from being incorporated into clinical planning strategies. A mathematical de******ion of the overall bystander response and its interplay with the ionizing-radiation response would provide a means of exploiting the biological opportunities offered by the spatial and temporal modulation of IMRT.
Our research group has taken the first steps in building a mathematical framework, benchmarked against experimental data, with which to incorporate bystander signalling into radiobiological modelling. By applying the framework to experimental results for both uniform and modulated therapeutic radiation exposures, we find that bystander signalling makes a substantial contribution to cell death, even when the field is spatially uniform.
The geometrical optimization of dose delivery through IMRT is a major achievement and one that’s widely exploited in many treatment centres. The next step is a better understanding of the biological mechanisms involved in response and the opportunities to manipulate them. Maybe then, the true promise of IMRT will be within our grasp.
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About the author
Natalka Suchowerska is associate professor in the Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney, Australia. This article was co-authored by David R McKenzie, professor of materials physics in the School of Physics, University of Sydney, Australia.
The development of intensity-modulated radiation therapy (IMRT) represents an important advance in the precision treatment of cancers, providing a more conformal dose to the tumour while preserving surrounding healthy tissue. To date, the demonstrated benefits of IMRT have been attributed to the improved geometrical dose distribution. But there’s another, as yet unexplored, opportunity offered by IMRT: the ability to optimize the tumour’s biological response.
---
Unlike the case in conventional radiation therapy, the dose distributions in IMRT are highly variable in both time and space. The overall time taken to deliver the IMRT treatment (beam-on time), as currently practised, can be significantly longer than for conventional radiotherapy. But there is strong evidence to show that a protracted fraction treatment time allows repair of cellular damage, while the treatment is being delivered.
Research has shown that delivery times shorter than 10 minutes are more effective at killing cells and that this effect increases continuously with faster dose delivery.1, 2 Recent data have emphasized the importance of repair within a fraction, with experiments showing that a reduction in fraction delivery time - from 17 minutes to a minute - can increase the effectiveness of a given dose by up to 20%, depending on the tumour type.3 If the delivery time is longer than 10 to 15 minutes, it is proposed that the dose should be increased to compensate for the reduction in cell death due to such repair effects.4
While there is little experimental evidence as yet for the effects of faster delivery on healthy tissue, it is likely that the therapeutic ratio may be improved. This provides a strong incentive for faster IMRT delivery systems, underlining the importance of initiatives such as RapidArc, volumetric modulated arc therapy (VMAT) and tomotherapy. The fast throughput of patients facilitated by these approaches may eventually only be a minor benefit compared with the improved biological outcomes.
Bystander bearings
The unique aspect of IMRT beam delivery, where the dose rate changes rapidly with time and varies strongly from one point in the tumour to another, means that neighbouring cells can have very different dose histories. Their response and repair opportunities can thus also be very different. Bystander effects - non-local effects that result from intercellular communication - have been observed following cell irradiation.5 For the case of IMRT, the different dose histories of neighbouring cells can lead to unexpected survival fractions, as the bystander signals received by a cell affect its response to the dose it receives.
Depending on the distribution of dose, bystander signalling can either increase or decrease the net cell survival fraction.6 Recently, Claridge-Mackonis et al. classified the bystander effect into three types, based on experimental evidence of in vitro radiation responses in spatially modulated fields.7 The classical bystander effect (type I), as first described by Mothersill et al., is characterized by a reduction in cell survival of unirradiated cells when in communication with cells that have been irradiated.8 Two new types of bystander effect (types II and III) manifest themselves as an increase in cell survival for a given dose.
The type II bystander effect results in an increased survival in cells receiving a small radiation dose when their neighbours receive a lethal dose. Clinically, this means that if a region receives a lethal dose, surrounding peripheral cells will exhibit an increase in survival and possibly even proliferation, despite receiving a small dose of scattered radiation. If the peripheral cells are healthy, this is beneficial. But if the peripheral cells are micro-extensions of the tumour or precursors for secondary cancers, the type II bystander effect could be a problem. This highlights the significance of careful planning of the treatment volume and the need for caution when reducing margin size.
The type III bystander effect is characterized by an increase in survival of irradiated cells within the treatment field when neighbouring cells receive a reduced dose. In IMRT, where the dose distribution within the tumour volume is less uniform than for conventional treatments and where the dose distribution varies with time, the consequences of the type III effect may require a compensating increase in dose to provide the same biological effect. Clinically, this effect may already be counteracted by the dose escalation permitted by IMRT.
Figuring it out
The mechanisms underlying bystander signalling are not well understood and are likely to be multifaceted, involving direct communication between adjacent cells through the membranes and molecular vectors in the intercellular medium. If we fully understood the mechanisms of the bystander effects, repair processes and their interplay, we would have a powerful vehicle by which to enhance the therapeutic outcome of radiation therapy.
The lack of knowledge at the molecular level, however, does not prevent the effects from being incorporated into clinical planning strategies. A mathematical de******ion of the overall bystander response and its interplay with the ionizing-radiation response would provide a means of exploiting the biological opportunities offered by the spatial and temporal modulation of IMRT.
Our research group has taken the first steps in building a mathematical framework, benchmarked against experimental data, with which to incorporate bystander signalling into radiobiological modelling. By applying the framework to experimental results for both uniform and modulated therapeutic radiation exposures, we find that bystander signalling makes a substantial contribution to cell death, even when the field is spatially uniform.
The geometrical optimization of dose delivery through IMRT is a major achievement and one that’s widely exploited in many treatment centres. The next step is a better understanding of the biological mechanisms involved in response and the opportunities to manipulate them. Maybe then, the true promise of IMRT will be within our grasp.
----
About the author
Natalka Suchowerska is associate professor in the Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney, Australia. This article was co-authored by David R McKenzie, professor of materials physics in the School of Physics, University of Sydney, Australia.