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2 Patterns of failure following 3-D conformal dose escalation radiotherapy for high grade astrocytomas — A quantitative dosimetric study
Proceedings
ABSTRACTS
of the 38th
Annual
OF SCIENTIFIC
ASTRO
159
Meeting
PAPERS TO BE PRESENTED
1 SURVIVAL BENEFIT OF HYPERTHERMIA IN A PROSPECTIVE HYPERTHERMIA FOR GLIOBLASTOMA MULTIFORME
RANDOMIZED
TRIAL
OF
Penny K. Sneed, Paul R. Stauffer, Chris J. Diederich, Michael W. McDermott, Kathleen R. Lamborn, Prados, Susan Chang, Mary K. Malec, Laura Spry, Sharon A. Lamb, Brigid Voss, William M. Wara, Phillips, Philip H. Gutin Departments Puroose: undergoing
of Radiation
Oncology
and Neurological
Surgery,
University
To determine if adjuvant interstitial hyperthermia (HT) brain brachytherapy boost after conventional radiotherapy.
of California,
significantly
BRACHYTHERAPY
BOOST
+
Keith A. Weaver, Michael David A. Larson, Theodore
D. L.
San Francisco
improves
survival
of patients
with
glioblastoma
Materials 8 Methods: Adults with newly-diagnosed, unifocal, circumscribed, supratentorial glioblastoma < 5 cm in diameter were registered postoperatively on a Phase ll/lll prospective randomized trial (BTRC 66-90-2) and treated with partial brain radiotherapy at 1.8 Gy per daily fraction to 59.4 Gy with oral hydroxyurea. If the tumor was still deemed to be implantable on the post-teletherapy imaging study, the patient was randomized to brachytherapy boost alone or brachytherapy boost + HT (high-activity iodine-125 temporary implants giving 60 Gy at 0.40-0.60 Gy/h f helical coil microwave antenna interstitial HT for 30 min immediately before and after brachytherapy). Survival from diagnosis was estimated using the Kaplan-Meier method. Survival curves were compared with the log rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards method. Results: From August 1990 through August 1995, a total of 118 patients were entered on the trial, of which III were eligible. Patient age ranged from 21-75 years (median, 55 years) and KPS ranged from 70-100 (median, 90). Forty patients were randomized to brachytherapy (arm A) and 40 to brachytherapy + HT (arm B). Chiefly due to tumor progression, 31 patients never reached randomization. Thirty-three of 40 arm A patients and 35 of 40 arm B patients were evaluable and actually underwent brachytherapy boost and 31 evaluable arm B patients actually received HT. The median steady-state T90 was 42.1% and the median T90 thermal dose was about I2 CEM 43OT90. Survival analyzed by intent to treat was significantly longer for arm B than for arm A (median survival 89 vs. 76 weeks; p = 0.055 by the log rank test). Analyzing only implanted patients, the median survival was 91 weeks for 35 arm B patients vs. 76 weeks for 33 arm A patients (p = 0.014). Factors associated with improved survival in the multivariate analysis of all 80 randomized patients included lower age (p = 0.001). higher KPS (p = 0.022) and randomization to arm B as opposed to arm A (p = 0.014). Thermal parameters were not associated with survival. There were 2 Grade 4 toxicities (meningitis) and 3 Grade 3 toxicities (I infection, I case of increased hemiparesis, and I case of liver toxicity from hydroxyurea) on arm B, representing a 12.5% (5/40) incidence of serious toxicity. There were no grade 3, 4. or grade 5 toxicities on arm A. Conclusion: Adjuvant interstitial brain hyperthermia given for 30 minutes before and after brain brachytherapy boost after conventional external beam radiotherapy significantly improves survival of patients with focal glioblastoma multiforme, with acceptable toxicity. This represents the first positive randomized North American hyperthermia trial. We feel that our study benefited from the precise image-based treatment planning and catheter placement inherent in stereotactic technique and the lack of pain sensation within brain parenchyma, allowing good quality hyperthermia.
2 PATTERNS OF ASTROCYTOMAS Susan W. Leel,
Departments
FAILURE FOLLOWING 3-D CONFORMAL - A QUANTITATIVE DOSIMETRIC STUDY
Katherine
of Radiation
Herbortl,
Mary K. Martell,
Oncology1
and Radiology2,
Lon H. Marshl,
University
DOSE
ESCALATION
Stephen S. Gebarski2,
of Michigan,
RADIOTHERAPY Eric H. Radanyl,
Howard
FOR
HIGH
GRADE
M. Sandlerl
Ann Arbor, MI 48 109
Purpose: It is well known that the predominate pattern of failure of high grade astrocytomas is local recurrence. Using 3-dimensional conformal radiotherapy (3DCRT) high dose radiation can be delivered to a more precisely defined target while sparing normal tissue. However, if smaller target volumes are used to reduce morbidity, the risk for marginal misses may increase. The purpose of this study is to analyze the patterns of failure of high grade astrocytomas following high dose 3DCRT using a novel quantitative technique to calculate the dose received by the radiographically defined recurrence. Materials and Methods: From 4/89 to 10195, 71 patients with supratentorial high grade astrocytomas have ken entered in a dose escalation study. All patients were treated using 3DCRT to 70 - 80 Gy in conventional daily fractionation of 1.8 2.0 Gy. The clinical target volumes (CTV) consisted of successive cone downs with the final CTV defined as the enhancing lesion plus 0.5 cm margin. As of 10/95, 45 patients have radiographic evidence of disease recurrence/progression. This is defined as 25% increase in the sum of products of measurable lesion over the smallest sum observed, reappearance of any lesion which had previously disappeared, or appearance of any new lesion. Of the 45 patients, 28 have recurrent scans (Cf or MRI) that can be entered into our planning system and registered onto the treatment planning scans. Once the recurrent tumors were defined, dose volume histograms (DVHs) of the recurrent tumors were generated so that the dose delivered to the recurrent tumor volume from previous irradiation could be calculated. The recurrences were divided into 3 categories: 1) in-field recurrence, if 595% of the recurrence volume received 295% of the final prescribed dose, 2) marginal recurrence, if 26% - 94% of the recurrence volume received 295% of the final prescribed dose, and 3) distant recurrence, if <25% of the recurrence volume received ?95% of the final prescribed dose. Results: The median age of the 28 patients was 51.5 years (range: 22.5 - 72.8 years). All had grade 4 supratentorial astrocytomas. The median time of disease recurrence/progression of these 28 patients was 4.1 months (range: 1.1 - 15.4 months). In 24 of 28 patients only one lesion was seen on recurrent scan. The remaining 4 patients had more than one lesion seen on recurrent scans. Of the 24 patients who had a single recurrence, 22/24 were in-field recurrence and 2/24 were marginal recurrences. The volumes of marginal recurrences that received 276 Gy (i.e., 295% of the prescribed dose) were 80.5% and 74%. respectively. In the 4 patients who had multiple recurrences, 3 patients had 2 lesions and 1 patient had 3 lesions. Their patterns of failure were as follows: in the first patient, one lesion was an in-field recurrence, but the second lesion was a marginal recurrence with 86% of the volume having received 276 Gy; in the second patient, both lesions were marginal recurrences with 41 - 77% of their volumes having received 276 Gy; in the third patient, both lesions were again marginal recmrences with 35 - 49% of their volumes having received 276 Gy, and in the last patient who had 3 recurrences, 1 lesion was a marginal recurrence with 69% of its volume having received 276 Gy but 2 lesions were distant recurrences with 0% of their volumes having received 276 Gy. Conclusion: This represents the first report which analyzed the patterns of failure of high grade astrocytomas with respect to the actual dose delivered to the volume occupied by the radiographic recurrence. In the current study we found that 23/28 patients failed within the region of previous high dose irradiation (276 Gy). Of the five patients who had marginal recurrence as a component of their failure pattern, the volumes of the marginal recurrences that received 295% of the prescribed dose ranged from 35 - 86% with majority being >70%. No patients had distant recurrence alone. Therefore, despite high dose 3DCRT and the small margin applied to the contrast enhancing lesion for the final cone down, the predominate pattern remains one of local recurrence. Until the local disease can be controlled, further dose escalation using 3DCRT is warranted.
ABSTRACTS
of the 38th
Annual
OF SCIENTIFIC
ASTRO
159
Meeting
PAPERS TO BE PRESENTED
1 SURVIVAL BENEFIT OF HYPERTHERMIA IN A PROSPECTIVE HYPERTHERMIA FOR GLIOBLASTOMA MULTIFORME
RANDOMIZED
TRIAL
OF
Penny K. Sneed, Paul R. Stauffer, Chris J. Diederich, Michael W. McDermott, Kathleen R. Lamborn, Prados, Susan Chang, Mary K. Malec, Laura Spry, Sharon A. Lamb, Brigid Voss, William M. Wara, Phillips, Philip H. Gutin Departments Puroose: undergoing
of Radiation
Oncology
and Neurological
Surgery,
University
To determine if adjuvant interstitial hyperthermia (HT) brain brachytherapy boost after conventional radiotherapy.
of California,
significantly
BRACHYTHERAPY
BOOST
+
Keith A. Weaver, Michael David A. Larson, Theodore
D. L.
San Francisco
improves
survival
of patients
with
glioblastoma
Materials 8 Methods: Adults with newly-diagnosed, unifocal, circumscribed, supratentorial glioblastoma < 5 cm in diameter were registered postoperatively on a Phase ll/lll prospective randomized trial (BTRC 66-90-2) and treated with partial brain radiotherapy at 1.8 Gy per daily fraction to 59.4 Gy with oral hydroxyurea. If the tumor was still deemed to be implantable on the post-teletherapy imaging study, the patient was randomized to brachytherapy boost alone or brachytherapy boost + HT (high-activity iodine-125 temporary implants giving 60 Gy at 0.40-0.60 Gy/h f helical coil microwave antenna interstitial HT for 30 min immediately before and after brachytherapy). Survival from diagnosis was estimated using the Kaplan-Meier method. Survival curves were compared with the log rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards method. Results: From August 1990 through August 1995, a total of 118 patients were entered on the trial, of which III were eligible. Patient age ranged from 21-75 years (median, 55 years) and KPS ranged from 70-100 (median, 90). Forty patients were randomized to brachytherapy (arm A) and 40 to brachytherapy + HT (arm B). Chiefly due to tumor progression, 31 patients never reached randomization. Thirty-three of 40 arm A patients and 35 of 40 arm B patients were evaluable and actually underwent brachytherapy boost and 31 evaluable arm B patients actually received HT. The median steady-state T90 was 42.1% and the median T90 thermal dose was about I2 CEM 43OT90. Survival analyzed by intent to treat was significantly longer for arm B than for arm A (median survival 89 vs. 76 weeks; p = 0.055 by the log rank test). Analyzing only implanted patients, the median survival was 91 weeks for 35 arm B patients vs. 76 weeks for 33 arm A patients (p = 0.014). Factors associated with improved survival in the multivariate analysis of all 80 randomized patients included lower age (p = 0.001). higher KPS (p = 0.022) and randomization to arm B as opposed to arm A (p = 0.014). Thermal parameters were not associated with survival. There were 2 Grade 4 toxicities (meningitis) and 3 Grade 3 toxicities (I infection, I case of increased hemiparesis, and I case of liver toxicity from hydroxyurea) on arm B, representing a 12.5% (5/40) incidence of serious toxicity. There were no grade 3, 4. or grade 5 toxicities on arm A. Conclusion: Adjuvant interstitial brain hyperthermia given for 30 minutes before and after brain brachytherapy boost after conventional external beam radiotherapy significantly improves survival of patients with focal glioblastoma multiforme, with acceptable toxicity. This represents the first positive randomized North American hyperthermia trial. We feel that our study benefited from the precise image-based treatment planning and catheter placement inherent in stereotactic technique and the lack of pain sensation within brain parenchyma, allowing good quality hyperthermia.
2 PATTERNS OF ASTROCYTOMAS Susan W. Leel,
Departments
FAILURE FOLLOWING 3-D CONFORMAL - A QUANTITATIVE DOSIMETRIC STUDY
Katherine
of Radiation
Herbortl,
Mary K. Martell,
Oncology1
and Radiology2,
Lon H. Marshl,
University
DOSE
ESCALATION
Stephen S. Gebarski2,
of Michigan,
RADIOTHERAPY Eric H. Radanyl,
Howard
FOR
HIGH
GRADE
M. Sandlerl
Ann Arbor, MI 48 109
Purpose: It is well known that the predominate pattern of failure of high grade astrocytomas is local recurrence. Using 3-dimensional conformal radiotherapy (3DCRT) high dose radiation can be delivered to a more precisely defined target while sparing normal tissue. However, if smaller target volumes are used to reduce morbidity, the risk for marginal misses may increase. The purpose of this study is to analyze the patterns of failure of high grade astrocytomas following high dose 3DCRT using a novel quantitative technique to calculate the dose received by the radiographically defined recurrence. Materials and Methods: From 4/89 to 10195, 71 patients with supratentorial high grade astrocytomas have ken entered in a dose escalation study. All patients were treated using 3DCRT to 70 - 80 Gy in conventional daily fractionation of 1.8 2.0 Gy. The clinical target volumes (CTV) consisted of successive cone downs with the final CTV defined as the enhancing lesion plus 0.5 cm margin. As of 10/95, 45 patients have radiographic evidence of disease recurrence/progression. This is defined as 25% increase in the sum of products of measurable lesion over the smallest sum observed, reappearance of any lesion which had previously disappeared, or appearance of any new lesion. Of the 45 patients, 28 have recurrent scans (Cf or MRI) that can be entered into our planning system and registered onto the treatment planning scans. Once the recurrent tumors were defined, dose volume histograms (DVHs) of the recurrent tumors were generated so that the dose delivered to the recurrent tumor volume from previous irradiation could be calculated. The recurrences were divided into 3 categories: 1) in-field recurrence, if 595% of the recurrence volume received 295% of the final prescribed dose, 2) marginal recurrence, if 26% - 94% of the recurrence volume received 295% of the final prescribed dose, and 3) distant recurrence, if <25% of the recurrence volume received ?95% of the final prescribed dose. Results: The median age of the 28 patients was 51.5 years (range: 22.5 - 72.8 years). All had grade 4 supratentorial astrocytomas. The median time of disease recurrence/progression of these 28 patients was 4.1 months (range: 1.1 - 15.4 months). In 24 of 28 patients only one lesion was seen on recurrent scan. The remaining 4 patients had more than one lesion seen on recurrent scans. Of the 24 patients who had a single recurrence, 22/24 were in-field recurrence and 2/24 were marginal recurrences. The volumes of marginal recurrences that received 276 Gy (i.e., 295% of the prescribed dose) were 80.5% and 74%. respectively. In the 4 patients who had multiple recurrences, 3 patients had 2 lesions and 1 patient had 3 lesions. Their patterns of failure were as follows: in the first patient, one lesion was an in-field recurrence, but the second lesion was a marginal recurrence with 86% of the volume having received 276 Gy; in the second patient, both lesions were marginal recurrences with 41 - 77% of their volumes having received 276 Gy; in the third patient, both lesions were again marginal recmrences with 35 - 49% of their volumes having received 276 Gy, and in the last patient who had 3 recurrences, 1 lesion was a marginal recurrence with 69% of its volume having received 276 Gy but 2 lesions were distant recurrences with 0% of their volumes having received 276 Gy. Conclusion: This represents the first report which analyzed the patterns of failure of high grade astrocytomas with respect to the actual dose delivered to the volume occupied by the radiographic recurrence. In the current study we found that 23/28 patients failed within the region of previous high dose irradiation (276 Gy). Of the five patients who had marginal recurrence as a component of their failure pattern, the volumes of the marginal recurrences that received 295% of the prescribed dose ranged from 35 - 86% with majority being >70%. No patients had distant recurrence alone. Therefore, despite high dose 3DCRT and the small margin applied to the contrast enhancing lesion for the final cone down, the predominate pattern remains one of local recurrence. Until the local disease can be controlled, further dose escalation using 3DCRT is warranted.