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142 oral Radiation therapy in T1–T2 glottic carcinoma: influence of various treatment parameters on local control — complications
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interruptions on local tumor control (LTC) in postoperative radiotherapy (PRT) for squamous cell head and neck cancer (SCHNC). Material/methods: The retrospective analysis included 305 patients with SCHNC in various locations and stages treated in Gliwice between 1980 and 1998. Mean total radiation dose, dose per fraction, treatment time, interval surgery-radiotherapy (S-RT), age of patients were 63,4 Gy, 2,1 Gy, 46 days, 61,1 days, and 55,3 years respectively. No interruptions during PRT (except for weekend brakes) appeared in 29% of patients, while 28% had more than 5 days of gap. The data were classified into seven categories depending on the position of treatment gap (weeks 1-7). Results: A univariate model has shown that during the first two weeks of PRT treatment gaps did not significantly influence LTC, unlike gaps at weeks 3-7 which had significantly impaired LTC. There was only 1,5% decrease in LTC per 10 day extension of interval S-RT. A multivariate proportional hazard regression analysis indicated that increase in treatment brakes, the presence of tumor recurrence after surgery, stage N1-3, and extra-laryngeal site of cancer were significantly related to decrease in LTC, while interval S-RT, age, sex, T stage, hemoglobin concentration, total radiation dose, and dose per fraction did not appear significant. Consideration of seven time intervals for treatment gaps in the multivariate model has shown a significant progressive increase in the hazard of recurrence for gap in the respective weeks 3 to 7. Conclusions: Lack of critical decline in LTC from modest increase in time interval S-RT, and lack of treatment gap effect during first two weeks of PRT may suggest that certain radiation dose (and time) is required to reduce the number of surviving tumor cells in surgical bed to the levels which may activate rapid repopulation. The estimated lag period for accePerated repopulation during PRT of approximately 2 weeks seems, however, to be considerably shorted than that postulated for radiation treatment for primary SCHNC (3-4 weeks). 140
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The D A H A N C A 6 & 7 trial of 5 versus 6 fractions per week of conventional radiotherapy of squamous cell carcinoma (SCC) of the head and neck. A randomized study w i t h 1485 patients. J. Overgaard, H. Sand Hansen, W. Sapru, M. Overgaard, C. Grau, L. Specht, E. Andersen, L. Bastholt, K. Jorgensen, O. Hansen, L. Andersen, J. Evensen Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark Purpose: to examine whether reduction of the oveerall treatment time by increasing the number of weekly radiotherapy fractions from 5 to 6 (and maintaining same total dose and fraction number) improve the tumor response in squamous cell carcinoma of the head and neck, and is such treatment principle acceptable with regard to early and late morbidity. Material and methods: patients eligible for primary radiotheray alone were randomized between 5 or 6 weekly fractions of conventional radiotherapy (66-68 Gy in 33 to 34 fx to all tumors except well differentiated T1 glottic which were treated with 62 Gy). All patients, except those with glottic cancers (DAHANCA 6, 694 pts), were also treated with the hypoxic radiosensitizer Nimorazole (DAHANCA 7, 791 pts). The data are updated per September 2000. The results are reported as 5-year actuarial values, and differences estimated by log-rank analysis. Results: between January 1992 and December 1999, 1485 patients were included in the study. More than 97% of the patients received the planned total dose. The median overall treatment time were 46 and 39 days in the 5 and 6 fx/wk arm, respectively. The outcome were correated to classical prognostic parameters (T and N stage, sex, hemoglobin and tumor site). Overall, the results showed a benefit in 5-year Ioco-regional control (59% vs 68% (p=0.006) for the 5 vs 6 fx/week arm, respectively. The effect of overall treatment time appears especially to occur in the T-site (65% vs 75% for 5 vs 6 fx/wk respectively, p<0.001), whereas the response in the neck nodes was not significant different. The benefit in tumor control resulted in a significant better oveerall disease-specific survival (65% vs 72% for 5 vs 6 fx/week respectively), whereas there was no significant difference in overall survival. Acute morbidity in the form of severe mucositJs and dysphagia were significantly more frequent in the 6 fx/wk group, but there were no difference in the incidence of late oedema or fibrosis. Conclusion: reducing the overall treatment time in radiotherapy of squaincus cell carcinoma of the head and neck, by increasing the weekly number of fractions from 5 to 6 and maintaining the same overall dose resulted in a significant increase in tumor control, and disease-free survival. This was associated with an increased, but tolerable, acute morbidity and with no sign of increased late radiation complications. The 6 fx/wk regime has now become a new standard baseline treatment in Denmark. Supported by the Danish Cancer Society.
Proffered papers
141
oral
Cell kinetic changes in human squamous cell carcinomas during radiotherapy studied using in vivo administration of two halogenated pyrimidines B. Zackrisson 1, P. Flygare 1, B. Sj6str6m 2, H. Gustafsson 2, G.D. Wilson 3 1Umea University, Dept. of Oncology, Umea, Sweden 2Umea University, Dept. of Oto rhino laryngology , Umea, Sweden 3Mount Vemon Hospital, Gray Laboratory Cancer Research Trust, Northwood, England Purpose: This study investigated treatment-induced cell kinetic changes during the first week of conventional radiotherapy in advanced head and neck cancer patients using the administration of two halogenated pyrimidines and flow cytometry. The purpose was to assess whether proliferation was still evident and if any cell kinetic changes predicted outcome and therefore be used as a rationale for considering treatment intervention. Methods: 33 patients with advanced head and neck cancer were administered an injection of iododeoxyuridine prior to treatment 4 to 8.2 hours before surgical biopsy. A second administration of bromodeoxyuridine was given immediately prior to the fifth fraction of 2 Gy and 3.7 to 9.2 hours before a second biopsy. All patients were planned for radical treatment (66-70 Gy in 2 Gy fractions over 6.5-7 weeks). As a part of the primary therapy, 21 patients had surgery of the site of the primary tumour and nodal metastasis after completion of the radiation therapy. Flow cytometry was used to calculate changes in cell kinetics including a novel approach to measure cell cycle delay in vivo. The changes were correlated with clinical outcome. Results: The cell kinetic response of tumours was variable some showed an increase in proliferation during the first week of treatment whilst the majority showed inhibition of proliferation. Reduction of LI and pro-treatment DNA ploidy status were the only parameters to correlate with overall survival. Although G2 delays were measurable during treatment, they did not provide any clinical discrimination. Conclusions: Some degree of proliferation was evident in all patients after one week of radiotherapy and the response to treatment was variable. Reduction in LI appears to be able discriminate patients who do better and, when combined with DNA ploidy information, it was able to identify a cohort of patients with particularly good outcome. In contrast, lack of LI reduction and DNA aneuploidy predicted a group of paUents who responded poorly to treatment; this information could be helpful in planning treatment intervention and an alternative treatment strategy may have had better chance of success. 142
oral
Radiation therapy in T1-T2 glottic carcinoma: influence of various treatment parameters on local control - complications. V. Sharma K.A. Dinshaw, J.P. Agarwal, S. Ghosh, R. Havaldar Radiation Oncology, Tata Memorial Hospital, Mumbai, India Purpose: to evaluate the influence of various treatment parameters on local control as well as complications in T1 and T2 glottic carcinomas. Methods: between 1975 and 1989, 676 patients with early glettic carcinoma (460 T1 and 216 T2) received curative radiation with 3 dNerent treatment regimens. The regimen 1 comprised of 50 Gy/15 fr/ 3 wks (3.33 Gy/daily) for 192 patients, 60-62.5 Gy / 24-25 fr / 5 wks (2.5Gy/daily) for 352 patients (regimen 2) and 55-60 Gy/ 25-30 fr/ 5 - 6 wks (2-2.25 Gy/daily) for 132 patients (regimen 3). Results: the local control at 10 years was 82% and 57% for T1 and T2 lesions respectively (p=0.0). For T1NOM0 group, field size had significant impact on local control both with univadate (0.05) and multivariate (p=0.03) analysis. For T2NOM0 group field size (p=0.03) was significant in univariate as well as multivariate analysis. Persistant radiation edema was noted in 146 (22%) patients and was significantly worse with larger field size (p=O.O00). Conclusions: The shorter fractionation schedule had comparable local control, without increased complications than the protracted shcedule and is best suited for a busy department. 143
oral
Consequential late effects in altered radiotherapy for head and neck cancer - incidence and risk factors T. Rutkowski, L. Miszczyk, B. Maciejewski, R. Tamawski Cancer Centre, MSC Institute, Gfiwice, Poland Purpose: the aim of this paper is to evaluate the risk of consequential late effects (CLE) in relation to dose fractionation and to establish physical and clinical risk factors. Material and methods: results of the CAIR trial on 7-days/week accelerat-
interruptions on local tumor control (LTC) in postoperative radiotherapy (PRT) for squamous cell head and neck cancer (SCHNC). Material/methods: The retrospective analysis included 305 patients with SCHNC in various locations and stages treated in Gliwice between 1980 and 1998. Mean total radiation dose, dose per fraction, treatment time, interval surgery-radiotherapy (S-RT), age of patients were 63,4 Gy, 2,1 Gy, 46 days, 61,1 days, and 55,3 years respectively. No interruptions during PRT (except for weekend brakes) appeared in 29% of patients, while 28% had more than 5 days of gap. The data were classified into seven categories depending on the position of treatment gap (weeks 1-7). Results: A univariate model has shown that during the first two weeks of PRT treatment gaps did not significantly influence LTC, unlike gaps at weeks 3-7 which had significantly impaired LTC. There was only 1,5% decrease in LTC per 10 day extension of interval S-RT. A multivariate proportional hazard regression analysis indicated that increase in treatment brakes, the presence of tumor recurrence after surgery, stage N1-3, and extra-laryngeal site of cancer were significantly related to decrease in LTC, while interval S-RT, age, sex, T stage, hemoglobin concentration, total radiation dose, and dose per fraction did not appear significant. Consideration of seven time intervals for treatment gaps in the multivariate model has shown a significant progressive increase in the hazard of recurrence for gap in the respective weeks 3 to 7. Conclusions: Lack of critical decline in LTC from modest increase in time interval S-RT, and lack of treatment gap effect during first two weeks of PRT may suggest that certain radiation dose (and time) is required to reduce the number of surviving tumor cells in surgical bed to the levels which may activate rapid repopulation. The estimated lag period for accePerated repopulation during PRT of approximately 2 weeks seems, however, to be considerably shorted than that postulated for radiation treatment for primary SCHNC (3-4 weeks). 140
oral
The D A H A N C A 6 & 7 trial of 5 versus 6 fractions per week of conventional radiotherapy of squamous cell carcinoma (SCC) of the head and neck. A randomized study w i t h 1485 patients. J. Overgaard, H. Sand Hansen, W. Sapru, M. Overgaard, C. Grau, L. Specht, E. Andersen, L. Bastholt, K. Jorgensen, O. Hansen, L. Andersen, J. Evensen Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark Purpose: to examine whether reduction of the oveerall treatment time by increasing the number of weekly radiotherapy fractions from 5 to 6 (and maintaining same total dose and fraction number) improve the tumor response in squamous cell carcinoma of the head and neck, and is such treatment principle acceptable with regard to early and late morbidity. Material and methods: patients eligible for primary radiotheray alone were randomized between 5 or 6 weekly fractions of conventional radiotherapy (66-68 Gy in 33 to 34 fx to all tumors except well differentiated T1 glottic which were treated with 62 Gy). All patients, except those with glottic cancers (DAHANCA 6, 694 pts), were also treated with the hypoxic radiosensitizer Nimorazole (DAHANCA 7, 791 pts). The data are updated per September 2000. The results are reported as 5-year actuarial values, and differences estimated by log-rank analysis. Results: between January 1992 and December 1999, 1485 patients were included in the study. More than 97% of the patients received the planned total dose. The median overall treatment time were 46 and 39 days in the 5 and 6 fx/wk arm, respectively. The outcome were correated to classical prognostic parameters (T and N stage, sex, hemoglobin and tumor site). Overall, the results showed a benefit in 5-year Ioco-regional control (59% vs 68% (p=0.006) for the 5 vs 6 fx/week arm, respectively. The effect of overall treatment time appears especially to occur in the T-site (65% vs 75% for 5 vs 6 fx/wk respectively, p<0.001), whereas the response in the neck nodes was not significant different. The benefit in tumor control resulted in a significant better oveerall disease-specific survival (65% vs 72% for 5 vs 6 fx/week respectively), whereas there was no significant difference in overall survival. Acute morbidity in the form of severe mucositJs and dysphagia were significantly more frequent in the 6 fx/wk group, but there were no difference in the incidence of late oedema or fibrosis. Conclusion: reducing the overall treatment time in radiotherapy of squaincus cell carcinoma of the head and neck, by increasing the weekly number of fractions from 5 to 6 and maintaining the same overall dose resulted in a significant increase in tumor control, and disease-free survival. This was associated with an increased, but tolerable, acute morbidity and with no sign of increased late radiation complications. The 6 fx/wk regime has now become a new standard baseline treatment in Denmark. Supported by the Danish Cancer Society.
Proffered papers
141
oral
Cell kinetic changes in human squamous cell carcinomas during radiotherapy studied using in vivo administration of two halogenated pyrimidines B. Zackrisson 1, P. Flygare 1, B. Sj6str6m 2, H. Gustafsson 2, G.D. Wilson 3 1Umea University, Dept. of Oncology, Umea, Sweden 2Umea University, Dept. of Oto rhino laryngology , Umea, Sweden 3Mount Vemon Hospital, Gray Laboratory Cancer Research Trust, Northwood, England Purpose: This study investigated treatment-induced cell kinetic changes during the first week of conventional radiotherapy in advanced head and neck cancer patients using the administration of two halogenated pyrimidines and flow cytometry. The purpose was to assess whether proliferation was still evident and if any cell kinetic changes predicted outcome and therefore be used as a rationale for considering treatment intervention. Methods: 33 patients with advanced head and neck cancer were administered an injection of iododeoxyuridine prior to treatment 4 to 8.2 hours before surgical biopsy. A second administration of bromodeoxyuridine was given immediately prior to the fifth fraction of 2 Gy and 3.7 to 9.2 hours before a second biopsy. All patients were planned for radical treatment (66-70 Gy in 2 Gy fractions over 6.5-7 weeks). As a part of the primary therapy, 21 patients had surgery of the site of the primary tumour and nodal metastasis after completion of the radiation therapy. Flow cytometry was used to calculate changes in cell kinetics including a novel approach to measure cell cycle delay in vivo. The changes were correlated with clinical outcome. Results: The cell kinetic response of tumours was variable some showed an increase in proliferation during the first week of treatment whilst the majority showed inhibition of proliferation. Reduction of LI and pro-treatment DNA ploidy status were the only parameters to correlate with overall survival. Although G2 delays were measurable during treatment, they did not provide any clinical discrimination. Conclusions: Some degree of proliferation was evident in all patients after one week of radiotherapy and the response to treatment was variable. Reduction in LI appears to be able discriminate patients who do better and, when combined with DNA ploidy information, it was able to identify a cohort of patients with particularly good outcome. In contrast, lack of LI reduction and DNA aneuploidy predicted a group of paUents who responded poorly to treatment; this information could be helpful in planning treatment intervention and an alternative treatment strategy may have had better chance of success. 142
oral
Radiation therapy in T1-T2 glottic carcinoma: influence of various treatment parameters on local control - complications. V. Sharma K.A. Dinshaw, J.P. Agarwal, S. Ghosh, R. Havaldar Radiation Oncology, Tata Memorial Hospital, Mumbai, India Purpose: to evaluate the influence of various treatment parameters on local control as well as complications in T1 and T2 glottic carcinomas. Methods: between 1975 and 1989, 676 patients with early glettic carcinoma (460 T1 and 216 T2) received curative radiation with 3 dNerent treatment regimens. The regimen 1 comprised of 50 Gy/15 fr/ 3 wks (3.33 Gy/daily) for 192 patients, 60-62.5 Gy / 24-25 fr / 5 wks (2.5Gy/daily) for 352 patients (regimen 2) and 55-60 Gy/ 25-30 fr/ 5 - 6 wks (2-2.25 Gy/daily) for 132 patients (regimen 3). Results: the local control at 10 years was 82% and 57% for T1 and T2 lesions respectively (p=0.0). For T1NOM0 group, field size had significant impact on local control both with univadate (0.05) and multivariate (p=0.03) analysis. For T2NOM0 group field size (p=0.03) was significant in univariate as well as multivariate analysis. Persistant radiation edema was noted in 146 (22%) patients and was significantly worse with larger field size (p=O.O00). Conclusions: The shorter fractionation schedule had comparable local control, without increased complications than the protracted shcedule and is best suited for a busy department. 143
oral
Consequential late effects in altered radiotherapy for head and neck cancer - incidence and risk factors T. Rutkowski, L. Miszczyk, B. Maciejewski, R. Tamawski Cancer Centre, MSC Institute, Gfiwice, Poland Purpose: the aim of this paper is to evaluate the risk of consequential late effects (CLE) in relation to dose fractionation and to establish physical and clinical risk factors. Material and methods: results of the CAIR trial on 7-days/week accelerat-