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1Exploiting scientific progress in radiotherapy
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EXPLOITING SCIENTIRC PROGRESS IN RADIOTHERAPY
Professor Ann Barrett, Beatson Oncology Centre, Glasgow. UK
Impetus for change in the practice of radiotherapy is coming from many directions. This teaching session will consider changes arising from • Better understanding of the biological principles governing turnout and normal tissue response at a molecular and tissue level. We will discuss gene control of radiosensitivity and repair. inherited genetic factors and gene therapy. • Clinical trials of chemotherapy and radiotherapy Where effective chemotherapy has been developed. radiotherapy may have a diminishing role. Clinical trials have led to reduction in radiation volumes and changes in dose and scheduling. • Technological developments. These include ways of Iocalising, defining, speci~'ing and delivering conformal radiotherapy and new modalities such as radiotherapy, intra-operative radiotherapy, high energy and targeted radiotherapy
EPIDEMIOLOGY
FOR
RADIOTHERAPY
AT
REGIONAL
LEVEL JWW Coebergh Dept of Epidemiology & Biostatistics Erasmus University, Rotterdam; Eindhoven Cancer Registry (ECR) Comprehensive Cancer Centre South (IKZ), The Netherlands This contribution describes the application of epiderniological methods in a regional setting of oncological care recorded in a long-standing cancer registry. The ECR originated from the regional department of radiotherapy in 1955 and gradually extended together into a population of one million, two since t982 and within the framework the national cancer registry since 1988. Data collection is active from medical records in (now) 17 hospitals, which also allows for recording of clinical data on stage, primary treatment(s), co-morbidity and, upon demand from clinicians, on items and events related to more/less explicit regional guidelines. Since 1982 the IKZ increasingly served as a facilitating organization within a n(r?)ational policy of enhancing/requiring evidence-based medicine. This was preceded by a phase of national scenario development for long term planning of radiotherapy equipment & staff, based on regional data on incidence and demography. A variety of studies on trends in incidence, survival and patterns of primary treatment" has been carried out, often accompanied by interviews on clinical opinion and communicated within regional tumour study groups." Studies have been or are carried of outcome of all patients with Hodgkin's disease, breast conserving treatment, lung, endometrial and rectal cancer, gastric lymphomas and CNS, often including a review of clinical records and pathological specimens. Participation in EORTC-trials also increased as well as in observational studies of second cancers, recurrence and etiology of cancer. • Radiotherapy & Oncology 1994:31:213-21 "" Cancer Incidence & Sun~ival it1 the SE of the Netherlands. 1955-1994 IIKZ. 1995)
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4
GENETIC ASPECTS OF RADIOTttERAPY
FROM THE DISCOVERY OF RADIOACTIVITY THE DAWN OF CURIETHERAPY
J o h n Y a r n o l d , A c a d e m i c R a d i o t h e r a p y Unit, Royal M a r s d e n NIIS Trust, Downs Road, Sutton, Surrey, UK.
J. Dutrelx Institut Gustave Roussy, Villejuif, FRANCE
Many thousand genes regulate the bchaviour of cells on a day-to-day basis. Changes in the environment evoke cellular responses via alterations in gene expression. The clinical resp~mses of tumours and normal tlSSUt'5to radiotherapy are well-descnbed, but poorly understood in genetic terms. It is hoped that a better understanding of radiation responses at the genetic level will lead to more selective and successful treatments.
The discovery of radioactivity is conventionally associated with an erroneous hypothesis and a fortuitous event. In fact it resulted from a sequence of methodic experiments that Becquerel performed with great skill and deep insighL
Cells that lose clonogenic capacity in response to in uitm irradiation either i) arrest In the cell cycle for an undetermined period, it) undergo al:x~ptosis. or iii) suffer so-called mitotic death. The genetic conlrols of cell cycle arrest
TO"
In his early experiments of 1896 on uranium, which led to the discovery, Becquerel put forward some major features of radioactivity and emitted radiation.
and apoptosis are beginning to be understood. Both depend on recognition of initial damage to DNA and transmissJnn of this information to chemical pathways that determine whether the cell responds by G1 arrest (e.g. fibroblasts) or apoptosis (e.g. lympBocytes). Apoptosis is clearly important in lumours as well as in ~.,me normal tissues.
The discovery of radium by P. and M. Curie in 1898 evidenced a larger dimension to radioactivity. Becquerel, the Curies and Rutherford embraced its exploration as their lifetime endeavour. Their studies opened new concepts of matter and radiation and initiated particule physics and nuclear physics.
The cellular mechanism traditionally considered to account for the greatest loss of clonogenic capaoty after radiotherapy is mitotic death. How, and exactly when, a doomed ceil dies in this fashion is obscure. The simplest model involves no genetic controls, just the loss of essential genetic material in daughter cells when unrejoined chromosome fragments fail to segregate properly at mitosis. However, the recognition of DNA damage and its processing are under genetic controls. New insights have been gained into these processes, including the isolation of genes involved in the recognition and repair of double strand breaks. Last year's cloning of the ataxia telangiectasia gene has added to the sense of excitement.
In contrast with bnght scientific developments, practical applications of natural radioactivity were scarce. Most prospects were delusions. The main application was to be curietherapy. The biological effects, first observed on human skin in 1900, were studied by laborator3' and clinical experiments. The doubtful results of awkward experiments generated phantasms about magic curative virtues of radium. It took 20 years to eradicate irrational convictions, improve the material, establish efficient protx~:ols and turn radium as an efficient tool for cancer treatment.
EXPLOITING SCIENTIRC PROGRESS IN RADIOTHERAPY
Professor Ann Barrett, Beatson Oncology Centre, Glasgow. UK
Impetus for change in the practice of radiotherapy is coming from many directions. This teaching session will consider changes arising from • Better understanding of the biological principles governing turnout and normal tissue response at a molecular and tissue level. We will discuss gene control of radiosensitivity and repair. inherited genetic factors and gene therapy. • Clinical trials of chemotherapy and radiotherapy Where effective chemotherapy has been developed. radiotherapy may have a diminishing role. Clinical trials have led to reduction in radiation volumes and changes in dose and scheduling. • Technological developments. These include ways of Iocalising, defining, speci~'ing and delivering conformal radiotherapy and new modalities such as radiotherapy, intra-operative radiotherapy, high energy and targeted radiotherapy
EPIDEMIOLOGY
FOR
RADIOTHERAPY
AT
REGIONAL
LEVEL JWW Coebergh Dept of Epidemiology & Biostatistics Erasmus University, Rotterdam; Eindhoven Cancer Registry (ECR) Comprehensive Cancer Centre South (IKZ), The Netherlands This contribution describes the application of epiderniological methods in a regional setting of oncological care recorded in a long-standing cancer registry. The ECR originated from the regional department of radiotherapy in 1955 and gradually extended together into a population of one million, two since t982 and within the framework the national cancer registry since 1988. Data collection is active from medical records in (now) 17 hospitals, which also allows for recording of clinical data on stage, primary treatment(s), co-morbidity and, upon demand from clinicians, on items and events related to more/less explicit regional guidelines. Since 1982 the IKZ increasingly served as a facilitating organization within a n(r?)ational policy of enhancing/requiring evidence-based medicine. This was preceded by a phase of national scenario development for long term planning of radiotherapy equipment & staff, based on regional data on incidence and demography. A variety of studies on trends in incidence, survival and patterns of primary treatment" has been carried out, often accompanied by interviews on clinical opinion and communicated within regional tumour study groups." Studies have been or are carried of outcome of all patients with Hodgkin's disease, breast conserving treatment, lung, endometrial and rectal cancer, gastric lymphomas and CNS, often including a review of clinical records and pathological specimens. Participation in EORTC-trials also increased as well as in observational studies of second cancers, recurrence and etiology of cancer. • Radiotherapy & Oncology 1994:31:213-21 "" Cancer Incidence & Sun~ival it1 the SE of the Netherlands. 1955-1994 IIKZ. 1995)
3
4
GENETIC ASPECTS OF RADIOTttERAPY
FROM THE DISCOVERY OF RADIOACTIVITY THE DAWN OF CURIETHERAPY
J o h n Y a r n o l d , A c a d e m i c R a d i o t h e r a p y Unit, Royal M a r s d e n NIIS Trust, Downs Road, Sutton, Surrey, UK.
J. Dutrelx Institut Gustave Roussy, Villejuif, FRANCE
Many thousand genes regulate the bchaviour of cells on a day-to-day basis. Changes in the environment evoke cellular responses via alterations in gene expression. The clinical resp~mses of tumours and normal tlSSUt'5to radiotherapy are well-descnbed, but poorly understood in genetic terms. It is hoped that a better understanding of radiation responses at the genetic level will lead to more selective and successful treatments.
The discovery of radioactivity is conventionally associated with an erroneous hypothesis and a fortuitous event. In fact it resulted from a sequence of methodic experiments that Becquerel performed with great skill and deep insighL
Cells that lose clonogenic capacity in response to in uitm irradiation either i) arrest In the cell cycle for an undetermined period, it) undergo al:x~ptosis. or iii) suffer so-called mitotic death. The genetic conlrols of cell cycle arrest
TO"
In his early experiments of 1896 on uranium, which led to the discovery, Becquerel put forward some major features of radioactivity and emitted radiation.
and apoptosis are beginning to be understood. Both depend on recognition of initial damage to DNA and transmissJnn of this information to chemical pathways that determine whether the cell responds by G1 arrest (e.g. fibroblasts) or apoptosis (e.g. lympBocytes). Apoptosis is clearly important in lumours as well as in ~.,me normal tissues.
The discovery of radium by P. and M. Curie in 1898 evidenced a larger dimension to radioactivity. Becquerel, the Curies and Rutherford embraced its exploration as their lifetime endeavour. Their studies opened new concepts of matter and radiation and initiated particule physics and nuclear physics.
The cellular mechanism traditionally considered to account for the greatest loss of clonogenic capaoty after radiotherapy is mitotic death. How, and exactly when, a doomed ceil dies in this fashion is obscure. The simplest model involves no genetic controls, just the loss of essential genetic material in daughter cells when unrejoined chromosome fragments fail to segregate properly at mitosis. However, the recognition of DNA damage and its processing are under genetic controls. New insights have been gained into these processes, including the isolation of genes involved in the recognition and repair of double strand breaks. Last year's cloning of the ataxia telangiectasia gene has added to the sense of excitement.
In contrast with bnght scientific developments, practical applications of natural radioactivity were scarce. Most prospects were delusions. The main application was to be curietherapy. The biological effects, first observed on human skin in 1900, were studied by laborator3' and clinical experiments. The doubtful results of awkward experiments generated phantasms about magic curative virtues of radium. It took 20 years to eradicate irrational convictions, improve the material, establish efficient protx~:ols and turn radium as an efficient tool for cancer treatment.