- Email: [email protected]
116 Invited Biological modifiers in radiation oncology
Symposia
Thursday, 19 September 2002 $39
lowed by TME surgery with TME surgery alone. Of these 1530 patients 1414 patients were assessable. Toxicity from RT, surgery characteristics and postoperative complications and mortality were compared. Through an extensive quality control system, all data have been checked for inconsistencies, Toxicity during RT hardly occurred. Irradiated patients had 100 ml more blood loss during the operation (p<0.001) and showed more perineal cornplications (p=0.008) in cases of abdominoperineal resection. The total number of complications was slightly increased in the irradiated group (p=0.008). No difference was observed in postoperative mortality (4.0% vs. 3.3%) or in the number of reinterventions. These data suggest that TME surgery is not hampered by the application of short-term preoperative radiotherapy, In addition to this, long-term morbidity will be discussed.
Results: Up to date (April 2002), 780 pts. have been recruited in 26 institutions: 393 pts. received adjuvant RCT (aCR), 397 pts. neoadjuvant RCT (nRCT). Acute toxicity of RCT was reduced in the preoperative setting: WHO-grade 3/4-diarrhea 9% versus 13% in the aRCT-group, grade-3-erythema 14% vs. 16%, grade 3-1eucopenia 2% vs. 3%. Postoperative complications were not increased after nRCT: wound infection 5% vs. 6% in the aRCT arm, 12% anastomotic leakage in both arms, fistula 1% vs. 4% in the aRCT-arm. With a median follow-up of 26 months, the actuarial five-year overall-survival rate (blinded evaluation) was 74%, the 5-year local failurerate t 1% and the 5-year distant failure rate 30%. Conclusion: The accrual is going well, neoadjuvant CR is tolerated excellently and bears no higher risk for perioperative morbidity. This trial will close recruitement in July 2002 with more than 800 patients randomized.
114
B I O L O G I C A L M O D I F I E R S C O M I N G TO Y O U R CLINIC
Invited
Preoperative radiotherapy for resectable rectal cancer - What evidence remains to be collected? B. G/ime/ius University Hospital, Dept of Oncol, Biol and C/in Immunol, Uppsala, Sweden Karolinska Hospital, Radiumhemmet, Stockholm, Sweden A number of large randomised trials have compared preoperative radiotherapy (RT) and surgery with surgery alone in rectal cancer with the aim of decreasing local failure rates and secondary to that improve survival. The results of the trials performed more than a decade ago, when surgery was not optimally performed, were recently subject to a meta-analyses based upon individual patient data (Colorectal Cancer Collaborative Group, Lancet 2001; 358: 1291-1304). Collectively, the trials showed that local recurrences were reduced and survival improved in a dose-dependent way and that unacceptable acute/subacute toxicity was seen when the RT meant irradiation of large tissue volumes. The local recurrence rate was reduced by preop RT also in connection with better surgery or TME, as recently shown in a randomised trial (Kapiteijn et al, NEJM 2001 ; 345: 638-46). The relative reduction was actually higher by the preop RT (5 x 5 Gy) with TME than with standard surgery, as could be anticipated. Since much fewer recurrenSes occur after TME, the absolute reduction, and thus cost-effectiveness, will, however, be lower. The acute toxicity to properly given preop RT, whether conventionally fractionated or using 5 Gy fractions is low, and late toxicity is likely also low, although less well studied. The knowledge about the value of RT with surgery for rectal cancer is extensive. Still, major controversies exist and clinical routines vary widely world-wide. These issues relate to selection of the groups of patients at risk for a local failure, timing and fractionation of the RT, target volumes and doses, concomitant chemotherapy or not, and whether the chance of preserved sphincter function also after tong follow-up for the very low rectal cancers increases, 115
Invited
Adjuvant and neoadjuvant radiochemotherapy for advanced rectal cancer - First results of the German mulUcenter phaseIll-Trial ( p r o t o c o l C A O / A R O / A I O - 9 4 )
R. Sauer1, R. Fietkau2, C. RSdel1, C. Wittekind3, P. Martus 4, R. Raab5 1University of Erlangen, Department of Radiation Therapy, Erlangen, Getmany 2University of Rostock, Department of Radiation Therapy, Rostock, Germany 3University of Leipzig, Institute of Pathology, Leipzig, Germany 4University of Berlin, Dep. of Medical Informatics, Biometry and Epidemiology, Berlin, Germany 5University of Hannover, Department of Surgery, Hannover, Germany Purpose: Postoperative radiochemotherapy (RCT) is recommended for patients with advanced rectal cancer in the USA and in Germany. In recent years, encouraging results of preoperative radiotherapy have been reported. This phase-Ill study compares the efficacy of neoadjuvant to standard postoperative RCT. Patients and Methods: Pts. with rectal cancer (uT3/4 or uN+) were assigned to pre- or postoperative RCT: 50,40 Gy were applied in conventional fractionation. 5-FU (lg/m=/d) was administered in the 1. and 5. week as 120hcontinuous infusion. RCT was identical in both arms except for a boost of 5,40 Gy in the postoperative setting. Techniques of surgery were strictly standardised and included total mesorectal excision. Endpoints of the study were 5-year-survival, local and distant control, rate of curative resections and sphincter preservation, toxicity of RCT, surgical complications.
SOON 116
Invited
Biological modifiers in radiation ontology Ph. Lambin, B.G. Wouters RTIL/UH Maastricht, The Netherlands The combination of promising new biological modifying drugs with radiotherapy has significant potential for improving anti-tumour responses over radiation treatment alone. This philosophy is based on the tenet that although new agents are often highly tumour specific and exhibit very good toxicity profiles, they are unable to kilt the 9 to 10 logs of tumour ceils required to cure a tumour. Thus, it is possible that promising new therapeutic compounds which could benefit standard therapies may be missed in poorly designed or single therapy trials. The likelihood of this type of scenario is increasing as the costs associated with clinical trials of new biological agents are continuing to escalate. This puts pressure on pharmaceutical companies to abandon drugs that do not show some efficacy in early trials. Therefore, there is a strong rationale to combine these new compounds with high quality modern radiotherapy. We propose the following classification of new potential biological modifiers of radiation according to their main mechanism of action: I Modifiers of tumour response: 1) Proliferation a. Growth factor receptors (EGFR, Her2Neu) 2) Radiosensitivity a. Modification of intrinsic radiosensitivity i. Increase apoptotic threshold ii. Decrease DNA repair b. Complementary cell kill i. S-phase specific cytotoxins c. Additive cell kill 3) Hypoxia a. Hypoxic radiosensitizers (nimorazole, etc) b. Oxygenators (EPO, oxygen carriers, etc) c. Decrease oxygen consumption (hyperglycemia, etc) d. Hypoxia directed therapy i. cytotoxins, bioreductive drugs (tirapazamine, etc) ii. hyperthermia iii. bacteria gene therapy vectors (clostridia, salmonella, etc) e. Hypoxia response modifiers (Glycolysis, VEGF, HiF, etc...) f. Vascular targeting drugs, inhibitors of angiogenesis (combretastatin, etc) II Modifiers of normal tissue 1) Modifiers of survival or the number of clonogenic cells a. Increase proliferation (KGF, etc) b. Block apoptosis (pifithrin, etc) 2) Modifiers of the function-differentiation of normal cells a. Stem cell therapy b. Cytokine therapy Many of the new drugs have been developed at high cost and are often tested with radiation at a very late stage, tested in inadequate experimental models or in some cases not tested at all due to lack of communication between pharmaceuticals companies and the academic world of Radiation Oncology. A successful framework for screening new biological modifiers with radiation does not yet exist within Europe. The EORTC RT group has recently launched an initiative called the "Virtual European laboratory of radiation Biology" in order to address this deficiency and promote new therapeutic options for patients.
Thursday, 19 September 2002 $39
lowed by TME surgery with TME surgery alone. Of these 1530 patients 1414 patients were assessable. Toxicity from RT, surgery characteristics and postoperative complications and mortality were compared. Through an extensive quality control system, all data have been checked for inconsistencies, Toxicity during RT hardly occurred. Irradiated patients had 100 ml more blood loss during the operation (p<0.001) and showed more perineal cornplications (p=0.008) in cases of abdominoperineal resection. The total number of complications was slightly increased in the irradiated group (p=0.008). No difference was observed in postoperative mortality (4.0% vs. 3.3%) or in the number of reinterventions. These data suggest that TME surgery is not hampered by the application of short-term preoperative radiotherapy, In addition to this, long-term morbidity will be discussed.
Results: Up to date (April 2002), 780 pts. have been recruited in 26 institutions: 393 pts. received adjuvant RCT (aCR), 397 pts. neoadjuvant RCT (nRCT). Acute toxicity of RCT was reduced in the preoperative setting: WHO-grade 3/4-diarrhea 9% versus 13% in the aRCT-group, grade-3-erythema 14% vs. 16%, grade 3-1eucopenia 2% vs. 3%. Postoperative complications were not increased after nRCT: wound infection 5% vs. 6% in the aRCT arm, 12% anastomotic leakage in both arms, fistula 1% vs. 4% in the aRCT-arm. With a median follow-up of 26 months, the actuarial five-year overall-survival rate (blinded evaluation) was 74%, the 5-year local failurerate t 1% and the 5-year distant failure rate 30%. Conclusion: The accrual is going well, neoadjuvant CR is tolerated excellently and bears no higher risk for perioperative morbidity. This trial will close recruitement in July 2002 with more than 800 patients randomized.
114
B I O L O G I C A L M O D I F I E R S C O M I N G TO Y O U R CLINIC
Invited
Preoperative radiotherapy for resectable rectal cancer - What evidence remains to be collected? B. G/ime/ius University Hospital, Dept of Oncol, Biol and C/in Immunol, Uppsala, Sweden Karolinska Hospital, Radiumhemmet, Stockholm, Sweden A number of large randomised trials have compared preoperative radiotherapy (RT) and surgery with surgery alone in rectal cancer with the aim of decreasing local failure rates and secondary to that improve survival. The results of the trials performed more than a decade ago, when surgery was not optimally performed, were recently subject to a meta-analyses based upon individual patient data (Colorectal Cancer Collaborative Group, Lancet 2001; 358: 1291-1304). Collectively, the trials showed that local recurrences were reduced and survival improved in a dose-dependent way and that unacceptable acute/subacute toxicity was seen when the RT meant irradiation of large tissue volumes. The local recurrence rate was reduced by preop RT also in connection with better surgery or TME, as recently shown in a randomised trial (Kapiteijn et al, NEJM 2001 ; 345: 638-46). The relative reduction was actually higher by the preop RT (5 x 5 Gy) with TME than with standard surgery, as could be anticipated. Since much fewer recurrenSes occur after TME, the absolute reduction, and thus cost-effectiveness, will, however, be lower. The acute toxicity to properly given preop RT, whether conventionally fractionated or using 5 Gy fractions is low, and late toxicity is likely also low, although less well studied. The knowledge about the value of RT with surgery for rectal cancer is extensive. Still, major controversies exist and clinical routines vary widely world-wide. These issues relate to selection of the groups of patients at risk for a local failure, timing and fractionation of the RT, target volumes and doses, concomitant chemotherapy or not, and whether the chance of preserved sphincter function also after tong follow-up for the very low rectal cancers increases, 115
Invited
Adjuvant and neoadjuvant radiochemotherapy for advanced rectal cancer - First results of the German mulUcenter phaseIll-Trial ( p r o t o c o l C A O / A R O / A I O - 9 4 )
R. Sauer1, R. Fietkau2, C. RSdel1, C. Wittekind3, P. Martus 4, R. Raab5 1University of Erlangen, Department of Radiation Therapy, Erlangen, Getmany 2University of Rostock, Department of Radiation Therapy, Rostock, Germany 3University of Leipzig, Institute of Pathology, Leipzig, Germany 4University of Berlin, Dep. of Medical Informatics, Biometry and Epidemiology, Berlin, Germany 5University of Hannover, Department of Surgery, Hannover, Germany Purpose: Postoperative radiochemotherapy (RCT) is recommended for patients with advanced rectal cancer in the USA and in Germany. In recent years, encouraging results of preoperative radiotherapy have been reported. This phase-Ill study compares the efficacy of neoadjuvant to standard postoperative RCT. Patients and Methods: Pts. with rectal cancer (uT3/4 or uN+) were assigned to pre- or postoperative RCT: 50,40 Gy were applied in conventional fractionation. 5-FU (lg/m=/d) was administered in the 1. and 5. week as 120hcontinuous infusion. RCT was identical in both arms except for a boost of 5,40 Gy in the postoperative setting. Techniques of surgery were strictly standardised and included total mesorectal excision. Endpoints of the study were 5-year-survival, local and distant control, rate of curative resections and sphincter preservation, toxicity of RCT, surgical complications.
SOON 116
Invited
Biological modifiers in radiation ontology Ph. Lambin, B.G. Wouters RTIL/UH Maastricht, The Netherlands The combination of promising new biological modifying drugs with radiotherapy has significant potential for improving anti-tumour responses over radiation treatment alone. This philosophy is based on the tenet that although new agents are often highly tumour specific and exhibit very good toxicity profiles, they are unable to kilt the 9 to 10 logs of tumour ceils required to cure a tumour. Thus, it is possible that promising new therapeutic compounds which could benefit standard therapies may be missed in poorly designed or single therapy trials. The likelihood of this type of scenario is increasing as the costs associated with clinical trials of new biological agents are continuing to escalate. This puts pressure on pharmaceutical companies to abandon drugs that do not show some efficacy in early trials. Therefore, there is a strong rationale to combine these new compounds with high quality modern radiotherapy. We propose the following classification of new potential biological modifiers of radiation according to their main mechanism of action: I Modifiers of tumour response: 1) Proliferation a. Growth factor receptors (EGFR, Her2Neu) 2) Radiosensitivity a. Modification of intrinsic radiosensitivity i. Increase apoptotic threshold ii. Decrease DNA repair b. Complementary cell kill i. S-phase specific cytotoxins c. Additive cell kill 3) Hypoxia a. Hypoxic radiosensitizers (nimorazole, etc) b. Oxygenators (EPO, oxygen carriers, etc) c. Decrease oxygen consumption (hyperglycemia, etc) d. Hypoxia directed therapy i. cytotoxins, bioreductive drugs (tirapazamine, etc) ii. hyperthermia iii. bacteria gene therapy vectors (clostridia, salmonella, etc) e. Hypoxia response modifiers (Glycolysis, VEGF, HiF, etc...) f. Vascular targeting drugs, inhibitors of angiogenesis (combretastatin, etc) II Modifiers of normal tissue 1) Modifiers of survival or the number of clonogenic cells a. Increase proliferation (KGF, etc) b. Block apoptosis (pifithrin, etc) 2) Modifiers of the function-differentiation of normal cells a. Stem cell therapy b. Cytokine therapy Many of the new drugs have been developed at high cost and are often tested with radiation at a very late stage, tested in inadequate experimental models or in some cases not tested at all due to lack of communication between pharmaceuticals companies and the academic world of Radiation Oncology. A successful framework for screening new biological modifiers with radiation does not yet exist within Europe. The EORTC RT group has recently launched an initiative called the "Virtual European laboratory of radiation Biology" in order to address this deficiency and promote new therapeutic options for patients.