- Email: [email protected]
217 Invited Breast cancer in the elderly: when radiotherapy in early stages?
$74 Friday, 20 September 2002
tify the evaluation of therapy for all elderly patients. SlOG ( International Society for Geriatric Oncology ) and the EORTC Task Force Cancer in the Elderly are among the many groups which dedicate their efforts to this area. References: Extermann M, Aapro M., Assessment of the older cancer patient. Hematol Oncol Clin North Am 14:63-77,2000 Kohne CH, Grothey A, Bokemeyer C, Bontke N, Aapro M., Chemotherapy in elderly patients with colorectal cancer. Ann Onco112:435-42, 2001 Samain E, Schauvli~ge F, Marty J. Anesthesia for breast cancer surgery in the elderly, in press. Critical Reviews in Oncol Hematol, 2002 217 Invited B r e a s t cancer in the elderly: when radiotherapy in early
Symposia
bidity, income level, and year of diagnosis were not. Some Authors claim the use of a Comprehensive Geriatric Assessment score systems to evaluate the attitude of aged patients to receive combined treatments (L.Repetto, JCO 2002). Comorbidity remains the main factor determining the tolerability of treatments, included surgery: activity of daily living scales and performance status can integrate the scales for selection of patients. Because local pelvic recurrences are a substantial cause of morbidity, furthor efforts are needed to discriminate between aged patients who are suitable for combined treatments according to the best ongoing treatment approach to rectal cancer therapyof each Centre and patients who need palliative care to improve and to maintain their quality of life as long as possible.
stages? P. Olmi 1, M. Daidone2, A. Cerrotta 1, D. Corradini2, C. Fallai 1, D. Badii 1 l lstituto Nazionale dei Tumod, Radiotherapy Department, Milano, Italy 21stituto nazionale dei Tumori, Experimental oncology Dept, Milano, Italy Before to answer to the question of the paper, we must be able to answer two main questions: 1)Is the breast cancer in the elderly from biological point of view similar to the cancer of adult patients? 2)Does it exist an evidence about the best local treatment after surgery based on literature data in the elderly? 1)The biology of breast cancer in elderly patients seems to be favourable in advanced age from data of the literature. In our experience, based on 14.000 recruited in our institution in 20 years the breast cancer are characterized by a lower proliferative rate (3H-thymidine labelling index -TLI) a higher positivity for estrogen receptors (ER>10fmol/mg protein), a lower p53 overexpression (>5%of immunostained nuclei), by trends in favour of a more frequent presence of progesterone receptors (PgR>25 fmol/mg protein) and of diploid clones, an overexpression of the anti-apoptosis protein bcl2 (>30% of immunostained cells) than tumors from younger patients. The integration of pathologic and biologic variables significantly improved the predictive resolution of each variable singly considered either for identification of the low-risks or of the high-risk patients: it is possible to identify patients with an aggressive patho-biologic profile with the presence of 2 or 3 out 4 unfavourable factors and conversely the patients with favourable profile, 2)The current information shows many data in favour of radiation therapy after conservative surgery in the elderly. We'll analyse the data from a Canadian study published in 1999, the experience of MD Anderson pubIished in 2001 and of Chicago Northwestern University published in 2001 and finally two retrospective analyses of two series of patients (746 pts aged 70+ referred from 1970 to 1998 at the Radiotherapy Dept. of University of Florence and 1229 pts aged 70+ treated from 1981 to 1996 at the of Ist. Naz. dei Tumori di Milano. From the first series we obtain a median survival of 10 years, a DFS at 10 yrs of 78%, a time to LRR of 86% and a time to DM of 78%. From the second series we observe a RFS of 68%,a DFS of 78%, a LRFS of 89%. We'll try to delineate an algorithm for the best local treatment of early breast cancer in the elderly, 218
Invited
Rectum cancer: which is the best strategy of treatment in the elderly. Preop/postop. radiotherapy with concomitant chemotherapy or n o t ? V. Valentini Universit~ Cattolica S.Cuore, /st. Radiologia - Div. Radioterapia, Roma, Italy Cancer in the elderly~is a major health problem because of increased age of people in western Countries and because of prolonged life in the cancer population. Several Authors have noted the relative lack of studies regarding the treatments in the elderly and very often their efficacy and toxicity are controversial. A meta-analysis on the role of adjuvant radiotherapy in rectal cancer (Lancet 2001) showed that the age is a risk factor of non-rectal cancer death for patients who underwent to radiotherapy. On the contrary, a meta-analysis on the role of adjuvant chemotherapy in colorectal patients (D.J. Sargent et al., NEJM 2001.) demonstrated that selected elderly patients can receive the same benefit from chemotherapy as their younger counterparts, without a significant increase in toxic effects. A retrospective population-based study utilizing Medicare linked data identified 1.411 patients aged 65 and older operated on for stage I1-111rectal cancer between 1992-1996 in USA (BMinsky, ASCO 2001 ). Radiotherapy was used in 57% of patients, 12% had pre- and 88% postoperative treatment and 75% also received adjuvant chemotherapy. Age at the diagnosis was the strongest determinant of treatment; an APR, a stage Ill tumour, or T4 lesions were each independently associated with treatment, whereas, sex, race, comor-
MOLECULAR
ONCOLOGY
FOR CLINICIANS
219 Invited T h e basic tools of molecular ontology
M. Pruschy, S. Bodis Universit&tsSpital ZOrich Klinik for Radio-Onkologie, R~mistrasse 100, CH8091 ZQrich Further progress in clinical oncology requires optimal integration of basic molecular research tools relevant for cancer screening, early detection and therapy. Radiation Biology deserves credit for the systematic quantification of the interaction of fractionated ionizing radiation with normal tissue and tumour cells both in vitro and in vivo. The knowledge from this field should be combined with the rapidly increasing knowledge in the area of molecular biology and clinical radiotherapy. The Radiation oncologist has to be aware of the technical and methodological limitations of molecular techniques and their application in the clinical setting. Many methods are successfully used and have been integrated into clinical routine for over 2 decades. DNA, RNA and Protein analysis have provided insight into mechanisms of radiation-induced cell damage and damage repair. Modern DNA-analysis detects residual tumour cells, a treatment resistant tumor celt clone or a distinct chromosomal translocation, respectively, with direct consequences for the treatment strategy. For the molecular analysis of radiation responsiveness more sophisticated and computer assisted molecular methods are indispensable. The "Array Technology" is only the beginning. This expensive and complex method gives the "genetic footprint" of a specific tumour cell (and to a lesser extent of a specific tumour). Simultaneously the concerted interaction of genes and proteins can be analysed. Expression analysis of thousands of genes or proteins can be obtained in a specific tumour and the results can be analysed in regard of prognostic or predictive endpoints. The challenges are to understand the hierarchy of the cellular gene-protein network and, ultimately, to identify molecular key targets relevant for clinical decision making progresses. Proper patient selection, state of the art biopsies, biopsy documentation, appropriately chosen molecular methods, bioinformatics but also more basic research input is important to translate this algorithm into clinical routine. The reproducibility, the processing of the data and the correct selection of key information is another challenge. Before we can celebrate the breakthrough of molecular target radiotherapy more basic normal tissue and tumour-biology information is needed. The correct choice of the most appropriate, least expensive and least time consuming molecular method for a clinically relevant question is one important step in this direction. 220
Invited
A c l i n i c i a n ' s l o o k at molecular ontology
J.R. Yamold The Royal Marsden NHS Trust, Academic Un_it of Radiotherapy, Sutton, United Kingdom After 50 years of steady increase, breast cancer mortality fell by 30% between 1988 and 1998 in the UK, a trend repeated in other countries. The change is attributed to conventional interventions viz. population-based mammographic screening, co-ordinated delivery of modern surgery and radiotherapy plus the benefits of adjuvant tamoxifen and cytotoxic therapies. Further reductions in mortality are projected in the current decade, even without taking into account the role of oestrogen blockade in the preventive setting. Examining the history of standard treatments, they were established empirically over several decades by global collaboration using the rigorous, if cumbersome, technology of the randomised controlled clinical trial. The research outcomes stimulated an explosion of translational and basic research exploiting techniques of molecular genetics, biochem-
tify the evaluation of therapy for all elderly patients. SlOG ( International Society for Geriatric Oncology ) and the EORTC Task Force Cancer in the Elderly are among the many groups which dedicate their efforts to this area. References: Extermann M, Aapro M., Assessment of the older cancer patient. Hematol Oncol Clin North Am 14:63-77,2000 Kohne CH, Grothey A, Bokemeyer C, Bontke N, Aapro M., Chemotherapy in elderly patients with colorectal cancer. Ann Onco112:435-42, 2001 Samain E, Schauvli~ge F, Marty J. Anesthesia for breast cancer surgery in the elderly, in press. Critical Reviews in Oncol Hematol, 2002 217 Invited B r e a s t cancer in the elderly: when radiotherapy in early
Symposia
bidity, income level, and year of diagnosis were not. Some Authors claim the use of a Comprehensive Geriatric Assessment score systems to evaluate the attitude of aged patients to receive combined treatments (L.Repetto, JCO 2002). Comorbidity remains the main factor determining the tolerability of treatments, included surgery: activity of daily living scales and performance status can integrate the scales for selection of patients. Because local pelvic recurrences are a substantial cause of morbidity, furthor efforts are needed to discriminate between aged patients who are suitable for combined treatments according to the best ongoing treatment approach to rectal cancer therapyof each Centre and patients who need palliative care to improve and to maintain their quality of life as long as possible.
stages? P. Olmi 1, M. Daidone2, A. Cerrotta 1, D. Corradini2, C. Fallai 1, D. Badii 1 l lstituto Nazionale dei Tumod, Radiotherapy Department, Milano, Italy 21stituto nazionale dei Tumori, Experimental oncology Dept, Milano, Italy Before to answer to the question of the paper, we must be able to answer two main questions: 1)Is the breast cancer in the elderly from biological point of view similar to the cancer of adult patients? 2)Does it exist an evidence about the best local treatment after surgery based on literature data in the elderly? 1)The biology of breast cancer in elderly patients seems to be favourable in advanced age from data of the literature. In our experience, based on 14.000 recruited in our institution in 20 years the breast cancer are characterized by a lower proliferative rate (3H-thymidine labelling index -TLI) a higher positivity for estrogen receptors (ER>10fmol/mg protein), a lower p53 overexpression (>5%of immunostained nuclei), by trends in favour of a more frequent presence of progesterone receptors (PgR>25 fmol/mg protein) and of diploid clones, an overexpression of the anti-apoptosis protein bcl2 (>30% of immunostained cells) than tumors from younger patients. The integration of pathologic and biologic variables significantly improved the predictive resolution of each variable singly considered either for identification of the low-risks or of the high-risk patients: it is possible to identify patients with an aggressive patho-biologic profile with the presence of 2 or 3 out 4 unfavourable factors and conversely the patients with favourable profile, 2)The current information shows many data in favour of radiation therapy after conservative surgery in the elderly. We'll analyse the data from a Canadian study published in 1999, the experience of MD Anderson pubIished in 2001 and of Chicago Northwestern University published in 2001 and finally two retrospective analyses of two series of patients (746 pts aged 70+ referred from 1970 to 1998 at the Radiotherapy Dept. of University of Florence and 1229 pts aged 70+ treated from 1981 to 1996 at the of Ist. Naz. dei Tumori di Milano. From the first series we obtain a median survival of 10 years, a DFS at 10 yrs of 78%, a time to LRR of 86% and a time to DM of 78%. From the second series we observe a RFS of 68%,a DFS of 78%, a LRFS of 89%. We'll try to delineate an algorithm for the best local treatment of early breast cancer in the elderly, 218
Invited
Rectum cancer: which is the best strategy of treatment in the elderly. Preop/postop. radiotherapy with concomitant chemotherapy or n o t ? V. Valentini Universit~ Cattolica S.Cuore, /st. Radiologia - Div. Radioterapia, Roma, Italy Cancer in the elderly~is a major health problem because of increased age of people in western Countries and because of prolonged life in the cancer population. Several Authors have noted the relative lack of studies regarding the treatments in the elderly and very often their efficacy and toxicity are controversial. A meta-analysis on the role of adjuvant radiotherapy in rectal cancer (Lancet 2001) showed that the age is a risk factor of non-rectal cancer death for patients who underwent to radiotherapy. On the contrary, a meta-analysis on the role of adjuvant chemotherapy in colorectal patients (D.J. Sargent et al., NEJM 2001.) demonstrated that selected elderly patients can receive the same benefit from chemotherapy as their younger counterparts, without a significant increase in toxic effects. A retrospective population-based study utilizing Medicare linked data identified 1.411 patients aged 65 and older operated on for stage I1-111rectal cancer between 1992-1996 in USA (BMinsky, ASCO 2001 ). Radiotherapy was used in 57% of patients, 12% had pre- and 88% postoperative treatment and 75% also received adjuvant chemotherapy. Age at the diagnosis was the strongest determinant of treatment; an APR, a stage Ill tumour, or T4 lesions were each independently associated with treatment, whereas, sex, race, comor-
MOLECULAR
ONCOLOGY
FOR CLINICIANS
219 Invited T h e basic tools of molecular ontology
M. Pruschy, S. Bodis Universit&tsSpital ZOrich Klinik for Radio-Onkologie, R~mistrasse 100, CH8091 ZQrich Further progress in clinical oncology requires optimal integration of basic molecular research tools relevant for cancer screening, early detection and therapy. Radiation Biology deserves credit for the systematic quantification of the interaction of fractionated ionizing radiation with normal tissue and tumour cells both in vitro and in vivo. The knowledge from this field should be combined with the rapidly increasing knowledge in the area of molecular biology and clinical radiotherapy. The Radiation oncologist has to be aware of the technical and methodological limitations of molecular techniques and their application in the clinical setting. Many methods are successfully used and have been integrated into clinical routine for over 2 decades. DNA, RNA and Protein analysis have provided insight into mechanisms of radiation-induced cell damage and damage repair. Modern DNA-analysis detects residual tumour cells, a treatment resistant tumor celt clone or a distinct chromosomal translocation, respectively, with direct consequences for the treatment strategy. For the molecular analysis of radiation responsiveness more sophisticated and computer assisted molecular methods are indispensable. The "Array Technology" is only the beginning. This expensive and complex method gives the "genetic footprint" of a specific tumour cell (and to a lesser extent of a specific tumour). Simultaneously the concerted interaction of genes and proteins can be analysed. Expression analysis of thousands of genes or proteins can be obtained in a specific tumour and the results can be analysed in regard of prognostic or predictive endpoints. The challenges are to understand the hierarchy of the cellular gene-protein network and, ultimately, to identify molecular key targets relevant for clinical decision making progresses. Proper patient selection, state of the art biopsies, biopsy documentation, appropriately chosen molecular methods, bioinformatics but also more basic research input is important to translate this algorithm into clinical routine. The reproducibility, the processing of the data and the correct selection of key information is another challenge. Before we can celebrate the breakthrough of molecular target radiotherapy more basic normal tissue and tumour-biology information is needed. The correct choice of the most appropriate, least expensive and least time consuming molecular method for a clinically relevant question is one important step in this direction. 220
Invited
A c l i n i c i a n ' s l o o k at molecular ontology
J.R. Yamold The Royal Marsden NHS Trust, Academic Un_it of Radiotherapy, Sutton, United Kingdom After 50 years of steady increase, breast cancer mortality fell by 30% between 1988 and 1998 in the UK, a trend repeated in other countries. The change is attributed to conventional interventions viz. population-based mammographic screening, co-ordinated delivery of modern surgery and radiotherapy plus the benefits of adjuvant tamoxifen and cytotoxic therapies. Further reductions in mortality are projected in the current decade, even without taking into account the role of oestrogen blockade in the preventive setting. Examining the history of standard treatments, they were established empirically over several decades by global collaboration using the rigorous, if cumbersome, technology of the randomised controlled clinical trial. The research outcomes stimulated an explosion of translational and basic research exploiting techniques of molecular genetics, biochem-