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143 Preclinical requirements for a successful clinical trial: present and future
$68 Tuesday, October 26, 2004
that a target volume extending 20 mm breast tissue around the primary tumor, assured either by tumor free margins beyond the primary, or by radiotherapy should adequately cover the target. Exact localization of the target is mandatory and should take account of all the available information: clinical examination before and after surgery, specimen orientation, pathology reports with special emphasis on the tumor free margins in different directions, clip localization on simulator, seroma localization, with ultrasound, or with or without contrast filling on CT. Critical organs in breast radiotherapy are the lung, the heart, as well as the skin in breast conserving therapy. Skin doses should not exceed 45 Gy (2Gy) equivalent. 143
Preclinical requirements for a successful clinical trial: present and future P. Lambin 1, B.G. Weuters ~, L. Colette 2, D. de Ruysscher ~ ~MAASTRO GROW Research Institute, Department of Radiation Oncology, Maastricht, The Netherlands 2EORTC, Data Center, Brussels, Belgium The first question to be asked is how do we define a successful clinical trial? Several answers are possible. A trial that leads to an increase in knowledge? A trial in which the hypothesis is confirmed? A trial that shows a significant difference with the control arm? A trial that has an influence on the standard treatment of care. A trial that is published? etc? Of course, everyone hopes that a trial will lead to an improvement in the way we treat cancer. However, from both an ethical and a scientific viewpoint, a clinical trial should, at the minimum, meet the first definition a n d - p r o v i d e a significant increase in knowledge. This makes it very important to include translational in any trial. The challenge facing translational researchers is in the design of "SMART" clinical trials , in which each patient serves as his or her own control e.g. by comparing a biopsy before and after treatment. This type of trial ensures a flow of information from the bedside back to the lab. With the realization that most trials will be negative, coupled with the high costs of developing and testing new drugs, it is imperative that trials are designed with a goal to increase our basic understanding of disease. Historically, clinical trials have been the last -step in the development of a new therapy in which the primary goal was simply to determine if the new therapy was better than the old. This approach may have been logical in the past, when the method of action of many drugs was poorly understood, but it is much less useful today when looking at drugs designed to target specific molecular pathways. One critical component of new trials is thus the collection of biological tissue. In the case of a classical 'negative' trial, this tissue might be used to identify biological differences (geneticproteomic profiles), which subsequently might identify a subset of patients who can benefit from the new treatment. Similarly, in the case of a 'positive' trial, this tissue might be used to identify those patients who do not benefit and who would otherwise experience unnecessary treatment and its associated toxicity. 144 Review of today's treatment planning algorithms T. KndSs, E. Wieslander Lund University Hospital, Dept.of Radiation Physics, Lund, Sweden The development of computers has made it possible to use much more accurate methods than earlier. These new methods are usually based on measurements just as the older ones. The old algorithms did many times use these data in direct ways but
Teaching lectures
the new ones only use the data to adjust parameters in the used model. It is also common that the Inhomogeneity correction is inherent in the model based algorithm instead of the correction factor technique used in the older methods. This lecture will review both existing algorithms used in common available treatment planning systems as well as the latest developments. Their advantages and limitations will be discussed. The main part of the lecture will concentrate on the latest developments as convolution/superposition and Monte Carlo methods. The physics of photon beams relevant to radiation therapy will also be reviewed in a descriptive way. Clinical dose distribution produced by several commercial systems for some common treatment sites will be benchmarked against Monte Carlo calculations. Implications on IMRT and other forth coming treatment modalities will be discussed based on the accuracy of the dose calculation engine. 145 Radiobiology for treatment planning
J. Deasy, J. Bradley, I. El Naqa Mallinckrodt Institute of Radiology, Washington Univ. School of •-Medicine, St Louis, U.S.A. We will review radiobiological issues in 3-D conformal radiotherapy (3-D CRT) and intensity modulated radiation therapy (IMRT) treatment planning. 3-D CRT and IMRT represent a leap in the radiation oncologist's ability to shape the dose distribution and control dose-volume tradeoffs which may have a profound impact on treatment outcome. In addition to still-crucial time-dose factors, we will review data and models of dose-volume factors, and ways they may be used directly in treatment planning systems. Technically, IMRT allows for dose shaping or sculpting, both in terms of isodose contour shape, and the spatial placement of non-uniform doses within the target. IMRT can therefore be seen as minimizing the volume of the target which receives a lower than desired (prescribed) dose, due to required avoidance of normal tissues. Conversely, IMRT can reduce the fractional volume of nearby sensitive normal tissues which are irradiated, potentially reducing complication rates or types of complications observed. Although clinical data on the response of tumors to nonuniform dose distributions continues to be sparse, there is a growing body of data which is better defining dose-volume effects in the treatment of lung tumors (pneumonitis, lung fibrosis, esophagitis), head and neck tumors (xerostomia), prostate treatment (rectal tolerance), partial small bowel irradiation, and other endpoints. Typically, there are many ways to mathematically model the data for possible use in treatment planning systems. This review will focus on new and increasingly powerful datasets and derived models of dosevolume effects and normal tissue complication probability, as well as the potential of refining and using the models to guide prospective, customized, treatment planning. 146 Physical and clinical aspects of proton therapy H. Meertens Groningen University Hospital, Radiation Oncology, Groningen, The Netherlands The physical characteristics of protons result in an intrinsic advantage compared to photons for the deposition in of a high dose of ionising radiation with high precision at the tumour site. The advantages of a single proton beam compared to a single photon beam comprise: (1) a lower dose deposition to normal tissues proximal to the tumour, (2) a uniform dose distribution
that a target volume extending 20 mm breast tissue around the primary tumor, assured either by tumor free margins beyond the primary, or by radiotherapy should adequately cover the target. Exact localization of the target is mandatory and should take account of all the available information: clinical examination before and after surgery, specimen orientation, pathology reports with special emphasis on the tumor free margins in different directions, clip localization on simulator, seroma localization, with ultrasound, or with or without contrast filling on CT. Critical organs in breast radiotherapy are the lung, the heart, as well as the skin in breast conserving therapy. Skin doses should not exceed 45 Gy (2Gy) equivalent. 143
Preclinical requirements for a successful clinical trial: present and future P. Lambin 1, B.G. Weuters ~, L. Colette 2, D. de Ruysscher ~ ~MAASTRO GROW Research Institute, Department of Radiation Oncology, Maastricht, The Netherlands 2EORTC, Data Center, Brussels, Belgium The first question to be asked is how do we define a successful clinical trial? Several answers are possible. A trial that leads to an increase in knowledge? A trial in which the hypothesis is confirmed? A trial that shows a significant difference with the control arm? A trial that has an influence on the standard treatment of care. A trial that is published? etc? Of course, everyone hopes that a trial will lead to an improvement in the way we treat cancer. However, from both an ethical and a scientific viewpoint, a clinical trial should, at the minimum, meet the first definition a n d - p r o v i d e a significant increase in knowledge. This makes it very important to include translational in any trial. The challenge facing translational researchers is in the design of "SMART" clinical trials , in which each patient serves as his or her own control e.g. by comparing a biopsy before and after treatment. This type of trial ensures a flow of information from the bedside back to the lab. With the realization that most trials will be negative, coupled with the high costs of developing and testing new drugs, it is imperative that trials are designed with a goal to increase our basic understanding of disease. Historically, clinical trials have been the last -step in the development of a new therapy in which the primary goal was simply to determine if the new therapy was better than the old. This approach may have been logical in the past, when the method of action of many drugs was poorly understood, but it is much less useful today when looking at drugs designed to target specific molecular pathways. One critical component of new trials is thus the collection of biological tissue. In the case of a classical 'negative' trial, this tissue might be used to identify biological differences (geneticproteomic profiles), which subsequently might identify a subset of patients who can benefit from the new treatment. Similarly, in the case of a 'positive' trial, this tissue might be used to identify those patients who do not benefit and who would otherwise experience unnecessary treatment and its associated toxicity. 144 Review of today's treatment planning algorithms T. KndSs, E. Wieslander Lund University Hospital, Dept.of Radiation Physics, Lund, Sweden The development of computers has made it possible to use much more accurate methods than earlier. These new methods are usually based on measurements just as the older ones. The old algorithms did many times use these data in direct ways but
Teaching lectures
the new ones only use the data to adjust parameters in the used model. It is also common that the Inhomogeneity correction is inherent in the model based algorithm instead of the correction factor technique used in the older methods. This lecture will review both existing algorithms used in common available treatment planning systems as well as the latest developments. Their advantages and limitations will be discussed. The main part of the lecture will concentrate on the latest developments as convolution/superposition and Monte Carlo methods. The physics of photon beams relevant to radiation therapy will also be reviewed in a descriptive way. Clinical dose distribution produced by several commercial systems for some common treatment sites will be benchmarked against Monte Carlo calculations. Implications on IMRT and other forth coming treatment modalities will be discussed based on the accuracy of the dose calculation engine. 145 Radiobiology for treatment planning
J. Deasy, J. Bradley, I. El Naqa Mallinckrodt Institute of Radiology, Washington Univ. School of •-Medicine, St Louis, U.S.A. We will review radiobiological issues in 3-D conformal radiotherapy (3-D CRT) and intensity modulated radiation therapy (IMRT) treatment planning. 3-D CRT and IMRT represent a leap in the radiation oncologist's ability to shape the dose distribution and control dose-volume tradeoffs which may have a profound impact on treatment outcome. In addition to still-crucial time-dose factors, we will review data and models of dose-volume factors, and ways they may be used directly in treatment planning systems. Technically, IMRT allows for dose shaping or sculpting, both in terms of isodose contour shape, and the spatial placement of non-uniform doses within the target. IMRT can therefore be seen as minimizing the volume of the target which receives a lower than desired (prescribed) dose, due to required avoidance of normal tissues. Conversely, IMRT can reduce the fractional volume of nearby sensitive normal tissues which are irradiated, potentially reducing complication rates or types of complications observed. Although clinical data on the response of tumors to nonuniform dose distributions continues to be sparse, there is a growing body of data which is better defining dose-volume effects in the treatment of lung tumors (pneumonitis, lung fibrosis, esophagitis), head and neck tumors (xerostomia), prostate treatment (rectal tolerance), partial small bowel irradiation, and other endpoints. Typically, there are many ways to mathematically model the data for possible use in treatment planning systems. This review will focus on new and increasingly powerful datasets and derived models of dosevolume effects and normal tissue complication probability, as well as the potential of refining and using the models to guide prospective, customized, treatment planning. 146 Physical and clinical aspects of proton therapy H. Meertens Groningen University Hospital, Radiation Oncology, Groningen, The Netherlands The physical characteristics of protons result in an intrinsic advantage compared to photons for the deposition in of a high dose of ionising radiation with high precision at the tumour site. The advantages of a single proton beam compared to a single photon beam comprise: (1) a lower dose deposition to normal tissues proximal to the tumour, (2) a uniform dose distribution