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13 Skull base chordomas: Analysis of dose-response characteristics
Proceedings
of the 39th Annual
ASTRO
Meeting
14
13 SKULL
BASE CHOBDOMAS:
Andrzej Niemierko, Department
ANALYSIS
OF DOSERESPONSE
CHARACTERISTICS
Atsuro Terahara, Michael Goitein
of Radiation Oncology, Massachusetts
Objective: To extract dose-response patients with skull base chordomas.
General Hospital, Boston, MA 02114
characteristics
from dose-volume
histograms and corresponding
actuarial survival
statistics for 115
Materials & Methods: We analyzed data for 115 patients with skull base chordoma treated with combined photon and proton conformal radiotherapy to doses in the range 66.6Gy - 79.2Gy. Data set for each patient included gender, histology, age, tumor volume, prescribed dose, overall treatment time, time to recurrence or time to last observation, target dose-volume histogram, and several dosimetric parameters (minimum/mean/median/ maximum target dose, percent of the target volume receiving the prescribed dose, dose to 90% of the target volume, and the Equivalent Uniform Dose (EUD). Data were analyzed using the Kaplan-Meier survivor function estimate, the proportional hazards (Cox) model, and parametric modeling of the actuarial probability of recurrence. Parameters of dose-response characteristics were obtained using the maximum likelihood method Local failure developed in 42 (36%) of patients, with actuarial local control rates at 5 years of 59.2%. The proportional hazards model revealed significant dependence of gender on the probability of recurrence, with female patients having significantly poorer prognosis (hazard ratio of 2.3 with the p value of 0.008). The Wilcoxon and the log-rank tests of the corresponding Kaplan-Meier recurrence-free survival curves confirmed statistical significance of this effect. The Cox model with stratification by gender showed significance of tumor volume (p=O.Ol), the minimum target dose (p=O.O2), and the EUD (p=O.O2). Other parameters were not significant at the cx level of significance of 0.05, including the prescribed dose (p=O.21). Parametric analysis using a combined model of tumor control probability (to account for non-uniformity of target dose distribution) and the Weibull failure time model (to account for censoring) allowed us to estimate parameters of the timedose-response relationship for the analyzed group of patients. For example, the maximum likelihood estimates of surviving fraction at 2Gy (SF,) are 0.47 with 95% confidence limits of [0.45-0.491 for male and 0.53 [0.51-0.551 for female, with the coefficient of inter-patient variation in SF, of 4.3%. The density of clonogcns was estimated to be 10 *’ clonogens per cubic centimeter. In effect, the slope of the dose-response curve, ym, was estimated to be 2.7 [ 1.9-3.21 for both male and female, and the EDs, doses to be 67Gy and 73Gy respectively. Skull base chordomas of the female patients seemed to be not only more resistant to radiation but also recurring faster than that for male patients (the maximum likelihood estimates of the Weibull shape parameter p are 2.6 for female and 1.7 for male patients). Results:
Conclusions: This analysis revealed several clinically important characteristics of radioresponsiveness of skull base chordomas. The comprehensive patient data obtained using three-dimensional treatment planning system allowed us to demonstrate and quantify the existence of dose-response and dose-volume relationships. In consequence, we are able to estimate prospectively the individual’s probability of staying recurrence-free and her/his overall survival characteristics as a function of the applied three-dimensional dose distribution and time after treatment. Based on the analysis our treatment protocols have been modified to account for differences in radiosensitivity between female and male patients. This work was supported by NIH grants CA 50628 and CA 21239.
14 A MULTI-DISCIPLINARY 8346. S. Donaldson, Pediatric
STUDY INVESTIGATING
M. Torrey,
Oncology
Group
M. Link, A. Glicksman, and Quality
Assurance
RADIOTHERAPY F. Laurie, Review
J. Manning,
IN EWING’S J. Neff,
SARCOMA
E. Thompson,
- A FINAL
REPORT
OF POG
J. Shuster
Center
Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event free (EFS) and overall survival rates from multi-disciplinary therapy in Ewing’s Sarcoma (ES). Materials and Methods: Between 1983 and 1988, 184 children with ES were enrolled onto POG 8346. 178 (97%) met eligibility criteria; 6 had non-ES pathology. Induction treatment of Cyclophosphamide/Adriamycin (C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy (XRT) and C/A, Dactinomycin and Vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. 40 patients were randomized to receive SF, whole bone XRT to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy while 84 were assigned to IF XRT. Results: Of 179 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases. Their 5 yr. EFS was 51% (SE = 5%) and 23% (SE = 7%) respectively. The response rate (RR) to induction chemotherapy was 88% (28% complete, 60% partial), but after XRT the RR increased to 98%. 37 of the localized patients underwent resection of whom 16 (43%) required post-operative XRT with 5 yr. EFS of 80% (SE = 7%). 104 of the localized patients received XRT and had a 5 year EFS of 41% (SE = 5%), with no difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5 year EFS: Distal extremity 65% (SE = 8%), Central - 63% (SE = 9%), Proximal extremity - 46% (SE = 8%), and Pelvis - 24% (SE = 10%). Tumor size did not influence EFS. Patterns of failure among the 141 localized patients were: local only - 18 (13%), local and systemic 14 (IO%), systemic only 28 (20%). There were 4 (11%) local failures among those resected +/- XRT, but 28 (27%) following XRT alone. By protocol, patients suffering a relapse were required to undergo a biopsy of the primary tumor whether the site of relapse was systemic or local. Of 21 irradiated patients with primary site biopsy, 11 had pathologically confirmed local failure; 10 patients were symptomatic and in only 1 patient was it unsuspected. Patients with major radiotherapy protocol deviations in dose or volume had inferior 5 yr. local control than those with no deviations. Adequate treatment volume was most critical with only 45% local control for patients with XRT volume deviations vs. 72% for those treated to the protocol specified volume. Conclusion: As moat failures in ES are systemic, satisfactory EFS requires effective systemic chemotherapy. requires giving full doses and appropriate volumes. Systematic use of MRI and 3-D conformal XRT (which this study) should also improve outcome.
Involved Field XRT were not used in
of the 39th Annual
ASTRO
Meeting
14
13 SKULL
BASE CHOBDOMAS:
Andrzej Niemierko, Department
ANALYSIS
OF DOSERESPONSE
CHARACTERISTICS
Atsuro Terahara, Michael Goitein
of Radiation Oncology, Massachusetts
Objective: To extract dose-response patients with skull base chordomas.
General Hospital, Boston, MA 02114
characteristics
from dose-volume
histograms and corresponding
actuarial survival
statistics for 115
Materials & Methods: We analyzed data for 115 patients with skull base chordoma treated with combined photon and proton conformal radiotherapy to doses in the range 66.6Gy - 79.2Gy. Data set for each patient included gender, histology, age, tumor volume, prescribed dose, overall treatment time, time to recurrence or time to last observation, target dose-volume histogram, and several dosimetric parameters (minimum/mean/median/ maximum target dose, percent of the target volume receiving the prescribed dose, dose to 90% of the target volume, and the Equivalent Uniform Dose (EUD). Data were analyzed using the Kaplan-Meier survivor function estimate, the proportional hazards (Cox) model, and parametric modeling of the actuarial probability of recurrence. Parameters of dose-response characteristics were obtained using the maximum likelihood method Local failure developed in 42 (36%) of patients, with actuarial local control rates at 5 years of 59.2%. The proportional hazards model revealed significant dependence of gender on the probability of recurrence, with female patients having significantly poorer prognosis (hazard ratio of 2.3 with the p value of 0.008). The Wilcoxon and the log-rank tests of the corresponding Kaplan-Meier recurrence-free survival curves confirmed statistical significance of this effect. The Cox model with stratification by gender showed significance of tumor volume (p=O.Ol), the minimum target dose (p=O.O2), and the EUD (p=O.O2). Other parameters were not significant at the cx level of significance of 0.05, including the prescribed dose (p=O.21). Parametric analysis using a combined model of tumor control probability (to account for non-uniformity of target dose distribution) and the Weibull failure time model (to account for censoring) allowed us to estimate parameters of the timedose-response relationship for the analyzed group of patients. For example, the maximum likelihood estimates of surviving fraction at 2Gy (SF,) are 0.47 with 95% confidence limits of [0.45-0.491 for male and 0.53 [0.51-0.551 for female, with the coefficient of inter-patient variation in SF, of 4.3%. The density of clonogcns was estimated to be 10 *’ clonogens per cubic centimeter. In effect, the slope of the dose-response curve, ym, was estimated to be 2.7 [ 1.9-3.21 for both male and female, and the EDs, doses to be 67Gy and 73Gy respectively. Skull base chordomas of the female patients seemed to be not only more resistant to radiation but also recurring faster than that for male patients (the maximum likelihood estimates of the Weibull shape parameter p are 2.6 for female and 1.7 for male patients). Results:
Conclusions: This analysis revealed several clinically important characteristics of radioresponsiveness of skull base chordomas. The comprehensive patient data obtained using three-dimensional treatment planning system allowed us to demonstrate and quantify the existence of dose-response and dose-volume relationships. In consequence, we are able to estimate prospectively the individual’s probability of staying recurrence-free and her/his overall survival characteristics as a function of the applied three-dimensional dose distribution and time after treatment. Based on the analysis our treatment protocols have been modified to account for differences in radiosensitivity between female and male patients. This work was supported by NIH grants CA 50628 and CA 21239.
14 A MULTI-DISCIPLINARY 8346. S. Donaldson, Pediatric
STUDY INVESTIGATING
M. Torrey,
Oncology
Group
M. Link, A. Glicksman, and Quality
Assurance
RADIOTHERAPY F. Laurie, Review
J. Manning,
IN EWING’S J. Neff,
SARCOMA
E. Thompson,
- A FINAL
REPORT
OF POG
J. Shuster
Center
Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event free (EFS) and overall survival rates from multi-disciplinary therapy in Ewing’s Sarcoma (ES). Materials and Methods: Between 1983 and 1988, 184 children with ES were enrolled onto POG 8346. 178 (97%) met eligibility criteria; 6 had non-ES pathology. Induction treatment of Cyclophosphamide/Adriamycin (C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy (XRT) and C/A, Dactinomycin and Vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. 40 patients were randomized to receive SF, whole bone XRT to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy while 84 were assigned to IF XRT. Results: Of 179 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases. Their 5 yr. EFS was 51% (SE = 5%) and 23% (SE = 7%) respectively. The response rate (RR) to induction chemotherapy was 88% (28% complete, 60% partial), but after XRT the RR increased to 98%. 37 of the localized patients underwent resection of whom 16 (43%) required post-operative XRT with 5 yr. EFS of 80% (SE = 7%). 104 of the localized patients received XRT and had a 5 year EFS of 41% (SE = 5%), with no difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5 year EFS: Distal extremity 65% (SE = 8%), Central - 63% (SE = 9%), Proximal extremity - 46% (SE = 8%), and Pelvis - 24% (SE = 10%). Tumor size did not influence EFS. Patterns of failure among the 141 localized patients were: local only - 18 (13%), local and systemic 14 (IO%), systemic only 28 (20%). There were 4 (11%) local failures among those resected +/- XRT, but 28 (27%) following XRT alone. By protocol, patients suffering a relapse were required to undergo a biopsy of the primary tumor whether the site of relapse was systemic or local. Of 21 irradiated patients with primary site biopsy, 11 had pathologically confirmed local failure; 10 patients were symptomatic and in only 1 patient was it unsuspected. Patients with major radiotherapy protocol deviations in dose or volume had inferior 5 yr. local control than those with no deviations. Adequate treatment volume was most critical with only 45% local control for patients with XRT volume deviations vs. 72% for those treated to the protocol specified volume. Conclusion: As moat failures in ES are systemic, satisfactory EFS requires effective systemic chemotherapy. requires giving full doses and appropriate volumes. Systematic use of MRI and 3-D conformal XRT (which this study) should also improve outcome.
Involved Field XRT were not used in