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Prophylaxis of intimal hyperplasia after stent-implantation in peripheral arteries using endovascular irradiation
Proceedings
of the 34th Annual ASTRO
treatment time (~6 vs 6 to <6 vs 8 to
Meeting
169
(PCS point A) dose (~7500 vs 27500.
Conclusions: This study demonstrates a significant adverse effect on surUval and pelvic control with prolongation of total radiation treatment time for squamous cell cancer of the uterine cervix in multivariate analysis. This finding indicates total treatment time should be kept to a minimum by eliminating unplanned treatment breaks during external beam treatment and avoiding unnecessary delays prior to and between IC placements. In the future design of clinical trials, limitations on total treatment time should be rigorously controlled, and the effect of variations in this important factor by attered fractionation schemes should be studied.
76 RESULTS OF TWO RANDOMIZED TOTAL BODY IRRADIATION DOSE RATES IN 56 PATIENTS WITH ACUTE NON-LYMPHOBLASTIC LEUKEMIA B. Gindrey-Vie*, J.N. Foulquier*, L.H. Schwartz*, L. Vitu-Loas*, C. Uzal*, M. Ozsahin*, F. P&ne*, E. ToubouI*, Y. Belkacemi*, B. Rio$, N. C. Gotiny, V. Leblondt, M. Schlienger*, A. Laugler* From the Departments of *Radiation Oncology of the HBpital Tenon, §Hematology of HBtel-Dieu, JHematoIogy of the HBpital Saint-Antoine, and tHematology of the Groupe Hospitalier Pit&Salp&i&e, Paris, France Purpose: In order to assess the influence of instantaneous total body irradiation leukemia (ANLL), we randomized 56 patients according to two different dose rates.
(TBI) dose rate in acute
non-Iymphoblastic
Materials & Methods: Between December 10, 1986 and December 31, 1989 fifty-six patients with ANLL in complete remisslon induced by chemotherapy (44 with cyclophosphamide alone, 7 with cyclophosphamide in combination with other drugs, and 5 without cyclophosphamide) received TBI before undergoing bone marrow transplantation (allogeneic in 18, autologous in 38 patients). Two techniques were used but not randomized between the two groups of patients : either 12 Gy were delivered In 6 fictions over three consecutive days to mid-plane at ti and 9 Gy to the lungs, or 10 Gy m one fraction to mid-plane at I_4 and 8 Gy to the lungs. The patients were randomized according to two instantaneous dose rates, called LOW (6 cGy/min in single-dose and 3 cGy/min in hexafractionated) and HIGH (15 cGy/min in single-dose and 6 cGy/min in hexafractionated) for each TBI technique. Twenty-SIX patients received single-dose TBI (11 LOW, 15 HIGH), and 30 patients were treated using fractionated TBI (14 LOW, 16 HIGH). Results: In April 1991, the 4-year leukemia-free and overall survival rates were 48% and 51%. respectively. The same survival rates were 47% and 48% in the LOW group, while they were 48% and 55% in the HIGH group (p=O.94 and 0.68, respectively). Considering the LOW two different techniques, these rates were found to be 46% and 53% in the HIGH single-dose TBI group, while they were both 50% in the fractionated TBI group (p=O.91 and 0.49, respectively). No difference w’as observed in the incidence of interstitial pneumonitls, graft-vs.-host disease, and veno-occlusive disease either between the LOW and the HIGH groups, or between the single-dose and fractionated TBI groups. The only two patients who developed a cataract were treated by single-dose high instantaneous dose rate TBI. MultIvariate analyses showed that instantaneous dose rate and fractionation did not influence either the leukemia-free and overall survival, or the incidence of complications. ‘Conclusion: The results of this randomized prospective study of 56 0 0 patients showed that, in ANLL patients conditioned with TBI, neither the 12 24 36 48 0 instantaneous dose rate (6 vs. 15 cGy/min in single-dose, and 3 vs. 6 months cGy/min in fractionated TBI), influence the survival and the complication rates.
77 TOTAL BODY IRRADIATION AND CATARACT INCIDENCE : A COMPARISON OF TWO RANDOMIZED DIFFERENT INSTANTANEOUS DOSE RATES A. Laugier*, M. Ozsahin*, E. Touboul*, F. P&ne*, Y. BeIkacemi*, C. Dominique *, L.H. Schwartz*, J.L. Marin*, L. Vitu-Loas*, L. IsikIi*, E. Ozyar*, B. Riog, N. C. Goring, V. Leblondt, M. Schlienger* From the Departments of *Radiation Oncology of the HBpital Tenon, §Hematology of HGtel-Dieu, JHematoIogy of the HBpital Saint-Antoine, and tHematology of the Groupe Hospitalier PitiC-SaIp&itre, Paris, France Purpose: A randomized prospective clinical trial on instantaneous order to evaluate its influence on survival and complications. Materials
St Methods:
One hundred
lifty-seven
patients
total body irradiation
have undergone
(TBI) dose rate has been conducted
a TBI before bone marrow
transplantation
according
in to
170
Radiation
Oncology,
Biology, Physics
Volume 24, Supplement
1
two different techniques: either in one fraction (10 Gy given to mid-plane at LA, and 8 Gy to the lungs) or in SIX fractions (12 Gy dose over 3 consecutive days to mid-plane at LA, and 9 Gy to the lungs). Patients were randomized according to two instantaneous rates, called LOW and HIGH, m single-dose (6 vs. 1.5 cGy/mm) and hexafractionated (3 vs. 6 cGy/min) TBI groups; there were 77 cases for the LOW and 80 for the HIGH groups, wlith 57 patients receiving single-dose TBI (28 LOW, 29 HIGH) and 100 patients recelvmg fractionated TBI (49 LOW, 51 HIGH). Results: The 4-year relapse-free and overall survival rates were 58% and 52%, respectively. There was no difference in the incidence of graft-vs.-host disease, interstitial pneumonitis, veno-occlusive disease either between the LOW and the HIGH groups, Nine (5.7%) of 157 patients developed cataracts after 17 to 44 &on&s, or between the single-dose and fractionated TBI groups. with an estimated incidence of 27% at four years. Two (2.6%) of 77 patients in the LOW group, and 7 (8.6%) of 80 patients in the HIGH ~~ HIGH "1 group developed cataracts, with 4-year estimated incidence of 15% and 39% respectively (p=O.C68). Five of 57 patients (8.7%) in the single-dose TBI group, and 4 of 100 patients (4%) m the fractionated group developed cataracts, with estimated lnctdences of 53% and 13% respectively (p=O.26). When the subgroups were considered, in the single-dose TBI group, one (3.57~) of 28 LOW patients, and 4 (14%) of 29 HIGH patlcnts 20 developed cataracts, with estimated incidences of 33% and 77% respectively (p=O.O49). In the fracttonated group, one (2%) of 49 LOW patients, and 3 (5.8%) of 51 HIGH patrents developed cataracts, with 10 4-year estimated incidences of 4% and 22% (p=O.40). Conclusion: In this randomized study of 157 patients, It IS found that 0 tngh instantaneous dose rate (about 15 cGy/mln) In single-dose TBI leads 12 24 36 48 0 to higher incidence of cataracts when compannp to other regimens. months
78 A PHASE I PILOT STUDY TO EVALUATE INTRAOPERATIVE RADIATION THERAPY (IORT) AND THE HYPOXIC CELL SENSITIZER ETANIDAZOLE (ETA) IN PATIENTS WITH LOCALLY ADVANCED MALIGNANCIES (RTOG PROTOCOL 89-t)@.
F. Halberg, D. Cosmatoa, L.L. Gunderson, D. Noyes, G. Hanks, C.N. Coleman Univ. of Calif. SF; RTGG Statistical Unit; Mayo Clinic; LDS Hospital; Fox Chase Cancer Center; Harvard Joint Center for Radiation Therapy Purpose: This was a Phase I study conducted as a limited institution pilot tnal within the Radiation Therapy Oncology Group (RTOG protocol 89-M). This study sought to identify the maximum tolerated dose (MTD) of the oxygen-mimetic sensitizer ETA (SR-2508) when used concurrenlly with surgery and IORT (12.0 gm/m* previously shown to be the MTD of ETA as single dose with chemotherapy). Materials & Methods: A total of 42 patients were entered onto the study according to an escalating dose scheme (4.4.6.7 and 21 patients were entered on the 5.5,7.5,9. 10.5 and 12.0 gm/m2 dose arms, respectively). The drug was given via IV infusion over 15 minutes followed by IORT (lo-20 Gy) administered within 20-30 minutes from the end of the infusion. Multiple tissue samples from tumor, tumor bed and/or normal tissue were obtamed 20 and 45 minutes from start of infusion and just prior to wound closure, with simultaneous plasma samples. ETA concentrations in tumor tissue and serum was determined for 33 of the 42 patients. Assessment of treatment toxicity was made during treatment and at regular follow-up intervals thereafter. Severe or unexpected toxicities were reported immediately. Results: ETA serum and tissue concentrations were assessed on all patients entered on the 9.0 and 10.5 gm/m2 dose arms and on 20 of the 21 patients on the maximum dose arm (12.0 gm/m*). Results were as follows: ETA dose gm/m2 (assigned and given) Mean ETA serum cont. (@ml) Mean ETA tissue cont. @g/ml)
9.0 535 547
10.5 645 414
12.0 715 988
Median time to maximum serum concentration: 25 minutes. Median time to maximum tumor concentration: 42 minutes. The tissue concentration began falling approximately one hour after end of infusion. Adipose tissue had the lowest normal tissue concentration, validating ETA’s lower Iipophilicity. As evidenced by the fact that the highest dose arm was reached, acute drug induced toxicities were minimal. Few limited toxicities were observed during drug administration. Acute IORT-induced toxicities were also minimal with only two patients developing grade 1 toxicities. More severe toxicities were reported during follow-up but all were believed to bc related to surgery and/or radiation, not drug-related. A total of three patients reported grade 3 toxicities 3+ months post treatment, that persist through their last follow-up at 6-8 months post treatment. Three other patients reported grade 4 toxicities. One patient on the 9.0 gm/mzdose arm developed a grade 3 small bowel toxicity at five months that escalated to grade 4 two months later. One patient on the 10.5 gm/m2dose arm experienced simultaneous grade 4 subcutaneous and skin toxicities, related to high dose reirmdiation. and a grade 2 peripheral neuropathy, at 7.6 months post treatment. The third patient was on the 12.0 gm/m2 dose arm and experienced a small bowel fistula which resolved without surgery. Conclusions: IORT is an ideal setting for addressing hypoxic cell radioresistance. ‘I%eserum and tissue concentrations of ETA observed in this trial were substantially higher than expected, and 5-10 times the levels seen with ETA doses given with fractionated external beam RT. With 15 min. infusion duration, IORT should be given 40 min. after the start of the infusion, allowing time for increased intracellular uptake and treatment prior to decline of tissue ETA levels. With a projected sensitizer enhancement ratio of 2.5-3, IORT with ETA is expected to improve local tumor control, thereby improving quality of life and potentially survival in selected patients. A subsequent Phase III trial involving IORT +/- Etanidazole (at 12.0 gm/m2) for patients with locally recurrent rectosigmoid carcinoma is now being planned and will be conducted as a group-wide RTOG trial.
of the 34th Annual ASTRO
treatment time (~6 vs 6 to <6 vs 8 to
Meeting
169
(PCS point A) dose (~7500 vs 27500.
Conclusions: This study demonstrates a significant adverse effect on surUval and pelvic control with prolongation of total radiation treatment time for squamous cell cancer of the uterine cervix in multivariate analysis. This finding indicates total treatment time should be kept to a minimum by eliminating unplanned treatment breaks during external beam treatment and avoiding unnecessary delays prior to and between IC placements. In the future design of clinical trials, limitations on total treatment time should be rigorously controlled, and the effect of variations in this important factor by attered fractionation schemes should be studied.
76 RESULTS OF TWO RANDOMIZED TOTAL BODY IRRADIATION DOSE RATES IN 56 PATIENTS WITH ACUTE NON-LYMPHOBLASTIC LEUKEMIA B. Gindrey-Vie*, J.N. Foulquier*, L.H. Schwartz*, L. Vitu-Loas*, C. Uzal*, M. Ozsahin*, F. P&ne*, E. ToubouI*, Y. Belkacemi*, B. Rio$, N. C. Gotiny, V. Leblondt, M. Schlienger*, A. Laugler* From the Departments of *Radiation Oncology of the HBpital Tenon, §Hematology of HBtel-Dieu, JHematoIogy of the HBpital Saint-Antoine, and tHematology of the Groupe Hospitalier Pit&Salp&i&e, Paris, France Purpose: In order to assess the influence of instantaneous total body irradiation leukemia (ANLL), we randomized 56 patients according to two different dose rates.
(TBI) dose rate in acute
non-Iymphoblastic
Materials & Methods: Between December 10, 1986 and December 31, 1989 fifty-six patients with ANLL in complete remisslon induced by chemotherapy (44 with cyclophosphamide alone, 7 with cyclophosphamide in combination with other drugs, and 5 without cyclophosphamide) received TBI before undergoing bone marrow transplantation (allogeneic in 18, autologous in 38 patients). Two techniques were used but not randomized between the two groups of patients : either 12 Gy were delivered In 6 fictions over three consecutive days to mid-plane at ti and 9 Gy to the lungs, or 10 Gy m one fraction to mid-plane at I_4 and 8 Gy to the lungs. The patients were randomized according to two instantaneous dose rates, called LOW (6 cGy/min in single-dose and 3 cGy/min in hexafractionated) and HIGH (15 cGy/min in single-dose and 6 cGy/min in hexafractionated) for each TBI technique. Twenty-SIX patients received single-dose TBI (11 LOW, 15 HIGH), and 30 patients were treated using fractionated TBI (14 LOW, 16 HIGH). Results: In April 1991, the 4-year leukemia-free and overall survival rates were 48% and 51%. respectively. The same survival rates were 47% and 48% in the LOW group, while they were 48% and 55% in the HIGH group (p=O.94 and 0.68, respectively). Considering the LOW two different techniques, these rates were found to be 46% and 53% in the HIGH single-dose TBI group, while they were both 50% in the fractionated TBI group (p=O.91 and 0.49, respectively). No difference w’as observed in the incidence of interstitial pneumonitls, graft-vs.-host disease, and veno-occlusive disease either between the LOW and the HIGH groups, or between the single-dose and fractionated TBI groups. The only two patients who developed a cataract were treated by single-dose high instantaneous dose rate TBI. MultIvariate analyses showed that instantaneous dose rate and fractionation did not influence either the leukemia-free and overall survival, or the incidence of complications. ‘Conclusion: The results of this randomized prospective study of 56 0 0 patients showed that, in ANLL patients conditioned with TBI, neither the 12 24 36 48 0 instantaneous dose rate (6 vs. 15 cGy/min in single-dose, and 3 vs. 6 months cGy/min in fractionated TBI), influence the survival and the complication rates.
77 TOTAL BODY IRRADIATION AND CATARACT INCIDENCE : A COMPARISON OF TWO RANDOMIZED DIFFERENT INSTANTANEOUS DOSE RATES A. Laugier*, M. Ozsahin*, E. Touboul*, F. P&ne*, Y. BeIkacemi*, C. Dominique *, L.H. Schwartz*, J.L. Marin*, L. Vitu-Loas*, L. IsikIi*, E. Ozyar*, B. Riog, N. C. Goring, V. Leblondt, M. Schlienger* From the Departments of *Radiation Oncology of the HBpital Tenon, §Hematology of HGtel-Dieu, JHematoIogy of the HBpital Saint-Antoine, and tHematology of the Groupe Hospitalier PitiC-SaIp&itre, Paris, France Purpose: A randomized prospective clinical trial on instantaneous order to evaluate its influence on survival and complications. Materials
St Methods:
One hundred
lifty-seven
patients
total body irradiation
have undergone
(TBI) dose rate has been conducted
a TBI before bone marrow
transplantation
according
in to
170
Radiation
Oncology,
Biology, Physics
Volume 24, Supplement
1
two different techniques: either in one fraction (10 Gy given to mid-plane at LA, and 8 Gy to the lungs) or in SIX fractions (12 Gy dose over 3 consecutive days to mid-plane at LA, and 9 Gy to the lungs). Patients were randomized according to two instantaneous rates, called LOW and HIGH, m single-dose (6 vs. 1.5 cGy/mm) and hexafractionated (3 vs. 6 cGy/min) TBI groups; there were 77 cases for the LOW and 80 for the HIGH groups, wlith 57 patients receiving single-dose TBI (28 LOW, 29 HIGH) and 100 patients recelvmg fractionated TBI (49 LOW, 51 HIGH). Results: The 4-year relapse-free and overall survival rates were 58% and 52%, respectively. There was no difference in the incidence of graft-vs.-host disease, interstitial pneumonitis, veno-occlusive disease either between the LOW and the HIGH groups, Nine (5.7%) of 157 patients developed cataracts after 17 to 44 &on&s, or between the single-dose and fractionated TBI groups. with an estimated incidence of 27% at four years. Two (2.6%) of 77 patients in the LOW group, and 7 (8.6%) of 80 patients in the HIGH ~~ HIGH "1 group developed cataracts, with 4-year estimated incidence of 15% and 39% respectively (p=O.C68). Five of 57 patients (8.7%) in the single-dose TBI group, and 4 of 100 patients (4%) m the fractionated group developed cataracts, with estimated lnctdences of 53% and 13% respectively (p=O.26). When the subgroups were considered, in the single-dose TBI group, one (3.57~) of 28 LOW patients, and 4 (14%) of 29 HIGH patlcnts 20 developed cataracts, with estimated incidences of 33% and 77% respectively (p=O.O49). In the fracttonated group, one (2%) of 49 LOW patients, and 3 (5.8%) of 51 HIGH patrents developed cataracts, with 10 4-year estimated incidences of 4% and 22% (p=O.40). Conclusion: In this randomized study of 157 patients, It IS found that 0 tngh instantaneous dose rate (about 15 cGy/mln) In single-dose TBI leads 12 24 36 48 0 to higher incidence of cataracts when compannp to other regimens. months
78 A PHASE I PILOT STUDY TO EVALUATE INTRAOPERATIVE RADIATION THERAPY (IORT) AND THE HYPOXIC CELL SENSITIZER ETANIDAZOLE (ETA) IN PATIENTS WITH LOCALLY ADVANCED MALIGNANCIES (RTOG PROTOCOL 89-t)@.
F. Halberg, D. Cosmatoa, L.L. Gunderson, D. Noyes, G. Hanks, C.N. Coleman Univ. of Calif. SF; RTGG Statistical Unit; Mayo Clinic; LDS Hospital; Fox Chase Cancer Center; Harvard Joint Center for Radiation Therapy Purpose: This was a Phase I study conducted as a limited institution pilot tnal within the Radiation Therapy Oncology Group (RTOG protocol 89-M). This study sought to identify the maximum tolerated dose (MTD) of the oxygen-mimetic sensitizer ETA (SR-2508) when used concurrenlly with surgery and IORT (12.0 gm/m* previously shown to be the MTD of ETA as single dose with chemotherapy). Materials & Methods: A total of 42 patients were entered onto the study according to an escalating dose scheme (4.4.6.7 and 21 patients were entered on the 5.5,7.5,9. 10.5 and 12.0 gm/m2 dose arms, respectively). The drug was given via IV infusion over 15 minutes followed by IORT (lo-20 Gy) administered within 20-30 minutes from the end of the infusion. Multiple tissue samples from tumor, tumor bed and/or normal tissue were obtamed 20 and 45 minutes from start of infusion and just prior to wound closure, with simultaneous plasma samples. ETA concentrations in tumor tissue and serum was determined for 33 of the 42 patients. Assessment of treatment toxicity was made during treatment and at regular follow-up intervals thereafter. Severe or unexpected toxicities were reported immediately. Results: ETA serum and tissue concentrations were assessed on all patients entered on the 9.0 and 10.5 gm/m2 dose arms and on 20 of the 21 patients on the maximum dose arm (12.0 gm/m*). Results were as follows: ETA dose gm/m2 (assigned and given) Mean ETA serum cont. (@ml) Mean ETA tissue cont. @g/ml)
9.0 535 547
10.5 645 414
12.0 715 988
Median time to maximum serum concentration: 25 minutes. Median time to maximum tumor concentration: 42 minutes. The tissue concentration began falling approximately one hour after end of infusion. Adipose tissue had the lowest normal tissue concentration, validating ETA’s lower Iipophilicity. As evidenced by the fact that the highest dose arm was reached, acute drug induced toxicities were minimal. Few limited toxicities were observed during drug administration. Acute IORT-induced toxicities were also minimal with only two patients developing grade 1 toxicities. More severe toxicities were reported during follow-up but all were believed to bc related to surgery and/or radiation, not drug-related. A total of three patients reported grade 3 toxicities 3+ months post treatment, that persist through their last follow-up at 6-8 months post treatment. Three other patients reported grade 4 toxicities. One patient on the 9.0 gm/mzdose arm developed a grade 3 small bowel toxicity at five months that escalated to grade 4 two months later. One patient on the 10.5 gm/m2dose arm experienced simultaneous grade 4 subcutaneous and skin toxicities, related to high dose reirmdiation. and a grade 2 peripheral neuropathy, at 7.6 months post treatment. The third patient was on the 12.0 gm/m2 dose arm and experienced a small bowel fistula which resolved without surgery. Conclusions: IORT is an ideal setting for addressing hypoxic cell radioresistance. ‘I%eserum and tissue concentrations of ETA observed in this trial were substantially higher than expected, and 5-10 times the levels seen with ETA doses given with fractionated external beam RT. With 15 min. infusion duration, IORT should be given 40 min. after the start of the infusion, allowing time for increased intracellular uptake and treatment prior to decline of tissue ETA levels. With a projected sensitizer enhancement ratio of 2.5-3, IORT with ETA is expected to improve local tumor control, thereby improving quality of life and potentially survival in selected patients. A subsequent Phase III trial involving IORT +/- Etanidazole (at 12.0 gm/m2) for patients with locally recurrent rectosigmoid carcinoma is now being planned and will be conducted as a group-wide RTOG trial.