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101Soft tissue sarcomas: The multidisciplinary approach to treatment
S28 100
101
The three A's of normal tissue repopulation: acceleration, _asymmetry loss, and _abortive divisions
SOFT TISSUE SARCOMAS: THE MULTIDISCIPLINARY APPROACH TO TREATMENT
Woffgang DOrr Dept. Radiation Therapy, Technical University Dresden, Germany Radiation-induced repopulation is a major factor of radiation tolerance in turnover tissues like oral mucose. It is often described as increased proliferation, but the changes are more complex. In undisturbed tissue, the equilibrium of production and superficial loss of cells is well regulated. Cell divisions on average era asymmetrical, resulting in one proliferating and one differentiating daughter. During radiotherapy, substantial dose compensation is observed with longer overall treatment times, yielding an increase in residual tissue tolerance, which - regarding stem cell number the predominant factor of radiation tolerance - must be based on net production of stem cells. A general response of turnover tissues to damage is acceleration of cell production. However, by a higher rate of asymmetrical divisions, with one stem cell generating one stem cell, only faster turnover but no amplification of stem cell numbers can be achieved. Hence, loss of the division asymmetry is a prerequisite of effective rapopulation, with symmetrical mitoses producing two stem call daughters. In addition, substantial production of differentiating cells is observed, ff solely based on the low number of stem cells surviving the first treatment weeks, this would require unrealistically short cell cycle times of only few hours. Therefore, it must be assumed that damaged cells, although having lost their stem cell character, perform a limited number of abortive divisions before terminal differentiation. In conclusion, the basis of radiation-induced repopulation is a complex reorganization of the proliferative tissue structure best described by three A's: accelerated stem call divisions, asymmetry loss, and abortive divisions.
O.S. Nielsen Department of Oncology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. Significant progress has been made in the management of patients with soft tissue sarcomas. New histopathology as well as imaging techniques have been developed. A number of staging systems have also been developed but none have yet been accepted as the single-staging system. Importantly the necessity of treatment planning within the framework of a multidisciplinary approach has been acknowledged by an increasing number of sarcoma centres. Local treatment is still of utmost importance for cure of soft tissue sarcomas. However, the treatment has shifted from radical to more extremity saving procedures by the use of combined surgery and adjuvant radiotherapy, thereby improving the functional outcome and probably also quality of life. The optimal timing of radiotherapy has not been settled. In locally advanced sarcomas other modalities such as hyperthermia and local perfusion are being studied. The role of adjuvant chemotherapy is continously debated. A recent metaanalysis showed an improved disease free survival but no effect on overall survival. Therefore, the results of ongoing randomized studies should awaited. Despite improved local control many patients will develop metastasis and thus need systemic treatment. Unfortunately, only few cytostatic drugs are active, the most important being ifosfamide and doxorubicin. Presently single-agent is likely as effective as combination chemotherapy. The effect of several new drugs are under investigation. Although definite progress has been made within the field of soft tissue sarcomas, continued efforts in studying this disease are unequivocally needed.
102
103
A L T E R E D FRACTIONATION: T H E PAST AND T H E FUTURE
INVERSE THERAPY PLANNING AND TREATMENT O~IION
H.D. Thames (M.D. Anderson Cancer Center, Houston TX 77030 )
The term Altered Fractionation carries with it the idea that something (fractionation) is to be changed, which carries with it the idea of confilet and disagreement, and these words best characterize the long history of the subject. In the early days arguments between proponents of large single doses and those of multiple doses given daily were settied in the 1920s by the results of Coutard at the Curie Institute in Paris, which showed that deep-seated tumors of the larynx could be cured by daily exteroal-beam doses. In 1963 Fowler and colleagues showed that the number of fractions could be separated, in its influence on isocffect dose, from overall time, and together with the results of Strandqvist and Cohen this led Ellis to formulate his NSD concept (1968). Argument soon followed: a 1971 issue of the British Journal of Radiology was filled with pro and con over the NSD formula. But it was not until the late 1970s that the deleterious effect of large fraction sizes, not predicted by the NSD concept, was recognized. The opposite side of this coin is that small fraction sizes are relatively sparing, and in fact that different tissues react differendy to changes in fraction size. In 1982 Thames and Withers showed that the effect of changes in fraction size (the "fractionation sensitivity") could be characterized by the ratio a/l~ of linear-quadratic target-cell survival parametexs, and that late-responding tissues were characterized by small all~ values as opposed to acutely reacting tissues and many tumors (large oJl~ values). A therapeutic gain from hyperfractionation (dose escalation by means of small doses per fraction given twice daily) is predicted, and this has been borne out in phase I]1 trials. A second radiobiologically based alteration is acceleratedfractionation, whose rationale is to limit the opportunity for tumor clonogen proliferation by shortmaing the overall treatment time. This is currently undergoing phase 111 trials. The outlook for these and other strategies, and arguments pro and con, will be discussed. Supported in part by CA-29026 from the National Cancer Institute
Anders Brahma Dept. of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Stockholm, Sweden
Background: Radiation therapy of cancer is today going through a very dynamic development with the introduction of a large number of new treatment principles, new types of treatment units and new radiobioingicallybased optimization algorithms for treatment planning. All of these make use of the recent developments in three dimensional tumor diagnostics, molecular biology of cancer, the fractiunation sensitivity of different tissues and most recently predictive assays of radiation sensitivity. Results: The most efficient but also least developed area of treatment optimization is to use a few (-3) non uniform radiation beams directed towards the tumor. Such few field techniques are also optimal from a radiobiological point of view, particularly if the recently inthcated increase in radiation sensitivity at low doses (RBE = 1O; D < 0.5 Gy) also is relevant for therapy related radiation damage. Today patient individual collimation with beam blocks or maltileaf collimators protect organs at risk laterally outside the tumor volume. Non uniform dose delivery also allows protection of normal tissues anterior, posterior and even inside the target volume by shaping the isodose.s tightly around the tumor tissues and thereby also allowing longitudinal protection of normal tissues. Some of the most advanced new algorithms are even treating therapy optimization as an inverse problem where the optimal incident beam shapes are determined directly from the location of gross disease, presumed microscopic tumor spread and organs at risk. The optimization is then performed such that the probability, P+, to eradicate all clonogeaic tumor cells without severely damaging healthy normal tissues is as high as possible. Conclusion: Already with a few non uniform beams the treatment outcome is within a few percent of what can be achieved with infinitely many co-planar beams in a dynamic mood. With such optimized non uniform treatments it should be possible to improve the treatment outcome by as much as 20 % and more, paRicularly in patients with a complex local spread of the disease or several organs at risk.
101
The three A's of normal tissue repopulation: acceleration, _asymmetry loss, and _abortive divisions
SOFT TISSUE SARCOMAS: THE MULTIDISCIPLINARY APPROACH TO TREATMENT
Woffgang DOrr Dept. Radiation Therapy, Technical University Dresden, Germany Radiation-induced repopulation is a major factor of radiation tolerance in turnover tissues like oral mucose. It is often described as increased proliferation, but the changes are more complex. In undisturbed tissue, the equilibrium of production and superficial loss of cells is well regulated. Cell divisions on average era asymmetrical, resulting in one proliferating and one differentiating daughter. During radiotherapy, substantial dose compensation is observed with longer overall treatment times, yielding an increase in residual tissue tolerance, which - regarding stem cell number the predominant factor of radiation tolerance - must be based on net production of stem cells. A general response of turnover tissues to damage is acceleration of cell production. However, by a higher rate of asymmetrical divisions, with one stem cell generating one stem cell, only faster turnover but no amplification of stem cell numbers can be achieved. Hence, loss of the division asymmetry is a prerequisite of effective rapopulation, with symmetrical mitoses producing two stem call daughters. In addition, substantial production of differentiating cells is observed, ff solely based on the low number of stem cells surviving the first treatment weeks, this would require unrealistically short cell cycle times of only few hours. Therefore, it must be assumed that damaged cells, although having lost their stem cell character, perform a limited number of abortive divisions before terminal differentiation. In conclusion, the basis of radiation-induced repopulation is a complex reorganization of the proliferative tissue structure best described by three A's: accelerated stem call divisions, asymmetry loss, and abortive divisions.
O.S. Nielsen Department of Oncology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. Significant progress has been made in the management of patients with soft tissue sarcomas. New histopathology as well as imaging techniques have been developed. A number of staging systems have also been developed but none have yet been accepted as the single-staging system. Importantly the necessity of treatment planning within the framework of a multidisciplinary approach has been acknowledged by an increasing number of sarcoma centres. Local treatment is still of utmost importance for cure of soft tissue sarcomas. However, the treatment has shifted from radical to more extremity saving procedures by the use of combined surgery and adjuvant radiotherapy, thereby improving the functional outcome and probably also quality of life. The optimal timing of radiotherapy has not been settled. In locally advanced sarcomas other modalities such as hyperthermia and local perfusion are being studied. The role of adjuvant chemotherapy is continously debated. A recent metaanalysis showed an improved disease free survival but no effect on overall survival. Therefore, the results of ongoing randomized studies should awaited. Despite improved local control many patients will develop metastasis and thus need systemic treatment. Unfortunately, only few cytostatic drugs are active, the most important being ifosfamide and doxorubicin. Presently single-agent is likely as effective as combination chemotherapy. The effect of several new drugs are under investigation. Although definite progress has been made within the field of soft tissue sarcomas, continued efforts in studying this disease are unequivocally needed.
102
103
A L T E R E D FRACTIONATION: T H E PAST AND T H E FUTURE
INVERSE THERAPY PLANNING AND TREATMENT O~IION
H.D. Thames (M.D. Anderson Cancer Center, Houston TX 77030 )
The term Altered Fractionation carries with it the idea that something (fractionation) is to be changed, which carries with it the idea of confilet and disagreement, and these words best characterize the long history of the subject. In the early days arguments between proponents of large single doses and those of multiple doses given daily were settied in the 1920s by the results of Coutard at the Curie Institute in Paris, which showed that deep-seated tumors of the larynx could be cured by daily exteroal-beam doses. In 1963 Fowler and colleagues showed that the number of fractions could be separated, in its influence on isocffect dose, from overall time, and together with the results of Strandqvist and Cohen this led Ellis to formulate his NSD concept (1968). Argument soon followed: a 1971 issue of the British Journal of Radiology was filled with pro and con over the NSD formula. But it was not until the late 1970s that the deleterious effect of large fraction sizes, not predicted by the NSD concept, was recognized. The opposite side of this coin is that small fraction sizes are relatively sparing, and in fact that different tissues react differendy to changes in fraction size. In 1982 Thames and Withers showed that the effect of changes in fraction size (the "fractionation sensitivity") could be characterized by the ratio a/l~ of linear-quadratic target-cell survival parametexs, and that late-responding tissues were characterized by small all~ values as opposed to acutely reacting tissues and many tumors (large oJl~ values). A therapeutic gain from hyperfractionation (dose escalation by means of small doses per fraction given twice daily) is predicted, and this has been borne out in phase I]1 trials. A second radiobiologically based alteration is acceleratedfractionation, whose rationale is to limit the opportunity for tumor clonogen proliferation by shortmaing the overall treatment time. This is currently undergoing phase 111 trials. The outlook for these and other strategies, and arguments pro and con, will be discussed. Supported in part by CA-29026 from the National Cancer Institute
Anders Brahma Dept. of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Stockholm, Sweden
Background: Radiation therapy of cancer is today going through a very dynamic development with the introduction of a large number of new treatment principles, new types of treatment units and new radiobioingicallybased optimization algorithms for treatment planning. All of these make use of the recent developments in three dimensional tumor diagnostics, molecular biology of cancer, the fractiunation sensitivity of different tissues and most recently predictive assays of radiation sensitivity. Results: The most efficient but also least developed area of treatment optimization is to use a few (-3) non uniform radiation beams directed towards the tumor. Such few field techniques are also optimal from a radiobiological point of view, particularly if the recently inthcated increase in radiation sensitivity at low doses (RBE = 1O; D < 0.5 Gy) also is relevant for therapy related radiation damage. Today patient individual collimation with beam blocks or maltileaf collimators protect organs at risk laterally outside the tumor volume. Non uniform dose delivery also allows protection of normal tissues anterior, posterior and even inside the target volume by shaping the isodose.s tightly around the tumor tissues and thereby also allowing longitudinal protection of normal tissues. Some of the most advanced new algorithms are even treating therapy optimization as an inverse problem where the optimal incident beam shapes are determined directly from the location of gross disease, presumed microscopic tumor spread and organs at risk. The optimization is then performed such that the probability, P+, to eradicate all clonogeaic tumor cells without severely damaging healthy normal tissues is as high as possible. Conclusion: Already with a few non uniform beams the treatment outcome is within a few percent of what can be achieved with infinitely many co-planar beams in a dynamic mood. With such optimized non uniform treatments it should be possible to improve the treatment outcome by as much as 20 % and more, paRicularly in patients with a complex local spread of the disease or several organs at risk.