- Email: [email protected]
RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for Centrally Located Non-Small Cell Lung Cancer (NSCLC)
Volume 94 Number 1 2016
5
Late-Breaking Abstract Special Session
LBA 9 NRG Oncology/RTOG 0937: Randomized Phase 2 Study Comparing Prophylactic Cranial Irradiation (PCI) Alone to PCI and Consolidative Extracranial Irradiation for Extensive Disease Small Cell Lung Cancer (ED-SCLC) E.M. Gore,1 C. Hu,2 A. Sun,3 D. Grimm,1 S. Ramalingam,4 N.E. Dunlap,5 K.A. Higgins,4 M. Werner-Wasik,6 A.M. Allen,7 P. Iyengar,8 G.M. Videtic,9 R.K. Hales,10 R.C. McGarry,11 J.J. Urbanic,12 A.T. Pu,13 C. Johnstone,1 J.N. Atkins,14 and J.D. Bradley15; 1Medical College of Wisconsin, Milwaukee, WI, 2NRG Oncology, Philadelphia, PA, 3Princess Margaret Hospital, Toronto, ON, Canada, 4Emory University, Atlanta, GA, United States, 5University of Louisville, Louisville, KY, 6Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, 7Rabin Medical Center, Petah Tikva, Israel, 8University of Texas Southwestern Medical Center, DALLAS, TX, 9Cleveland Clinic, Cleveland, OH, 10Johns Hopkins University, Baltimore, MD, United States, 11University of Kentucky, Lexington, KY, 12University of California, San Diego, La Jolla, CA, 13Sutter Medical Group - Radiological Associates of Sacramento, Sacramento, CA, 14Southeast Cancer Consortium-Upstate NCORP, Goldsboro, NC, 15Washington University School of Medicine, St. Louis, MO Purpose/Objective(s): The primary objective of Radiation Therapy Oncology Group (RTOG) 0937 was to evaluate the survival benefit of PCI plus consolidative radiation therapy to intrathoracic disease and extracranial metastases in patients with ED-SCLC. Materials/Methods: This was a randomized phase 2 trial. Patients with 1 to 4 metastatic lesions and no brain metastases at diagnosis were eligible after CR or PR to 4 to 6 cycles of platinum-based chemotherapy. Randomization was to PCI only or PCI and consolidative radiation to the thorax and original sites of metastatic disease (PCI+RT). Original stratification included PR versus CR after chemotherapy and 1 versus 2 to 4 metastatic lesions; age <65 versus >65 years was added after an imbalance was observed. PCI dose was 25 Gy in 10 fractions for all patients. The recommended dose for chest and metastatic lesions was 45 Gy in 15 fractions. A dose of 30 to 40 Gy in 10 fractions was allowed if necessary to meet normal tissue dose constraints. The primary endpoint was 1-year overall survival (OS). In order to detect an improvement from 30% to 45% with a 34% hazard reduction (HRZ0.66) under a 0.1 type 1 error (1-sided) and 80% power, 154 patients were required. Results: Ninety-seven patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (9 PCI, 2 PCI+RT), leaving 42 patients in the PCI arm and 44 in the PCI+RT arm. A planned interim analysis indicated that the study crossed the futility boundary for the primary endpoint and the study was closed prior to meeting the accrual target. Median follow-up was 9 months. Sixty-nine percent of patients received >45 Gy to the thorax in the PCI+RT arm, and 94.2% of all patients received 25 Gy PCI. More patients assigned to PCI+RT were >65 years of age (28.6% vs 54.5%, P<.05). The 1-year OS was not significantly different between the groups: 60.1% (95% CI: 41.2%-74.7%) for PCI and 50.8% (95% CI: 34.0%-65.3%) for PCI+RT (PZ.21). The 3- and 12-month rates of any progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+RT, respectively. Time to any progression favored PCI+RT with a hazard ratio of 0.53 (PZ.01). One patient in each arm had grade 4 toxicity at least possibly attributed to therapy. One patient had grade 5 respiratory failure in the PCI+RT group attributed to therapy. This patient’s V20 and mean lung dose exceeded dose constraints required by the study.
Conclusion: Observed overall survival exceeded predicted OS for both arms. Consolidative radiation therapy to the thorax and extracranial metastases delayed progression of disease but did not improve 1-year OS. Acknowledgment(s): This project was supported by grants U10CA21661 (RTOG-Ops-Stat), U10CA180868 (NRG Oncology Operations), and U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI). Clinical trial: NCT01055197.
LBA 10 Primary Study Endpoint Analysis for NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for Centrally Located Non-Small Cell Lung Cancer (NSCLC) A. Bezjak,1 R. Paulus,2 L.E. Gaspar,3 R.D. Timmerman,4 W.L. Straube,5 W.F. Ryan,6 Y. Garces,7 A.T. Pu,8 A.K. Singh,9 G.M. Videtic,10 R.C. McGarry,11 P. Iyengar,12 J.R. Pantarotto,13 J.J. Urbanic,14 A. Sun,15 M.E. Daly,16 I.S. Grills,17 D.P. Normolle,18 J.D. Bradley,5 and H. Choy19; 1 Princess Margaret Cancer Centre, Toronto, ON, Canada, 2NRG Oncology, Philadelphia, PA, 3University of Colorado Denver, Aurora, CO, 4 The University of Texas Southwestern School of Medicine, Dallas, TX, 5 Washington University, St. Louis, MO, 6Pocono Cancer Center, East Stroudsburg, PA, 7Mayo Clinic, Rochester, MN, 8Sutter Medical Group Radiological Associates of Sacramento, Sacramento, CA, 9Roswell Park Cancer Institute, Buffalo, NY, United States, 10Cleveland Clinic, Cleveland, OH, 11University of Maryland Medical Systems, Baltimore, MD, 12University of Texas Southwestern Medical Center, DALLAS, TX, 13 University of Ottawa, Ottawa, ON, Canada, 14University of California, San Diego, La Jolla, CA, 15Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada, 16University of California, Davis, Sacramento, CA, 17Beaumont Health System, Royal Oak, MI, 18University of Pittsburgh, Pittsburgh, PA, United States, 19 University of Texas Southwestern Medical Center, Dallas, TX Purpose/Objective(s): NRG/Radiation Therapy Oncology Group (RTOG) 0813 is a phase 1/2 study designed to determine the maximal tolerated dose (MTD) and efficacy of SBRT for NSCLC with centrally located tumors. We hereby report the primary endpoint of the phase 1 portion of the study. Materials/Methods Medically inoperable patients (pts) with biopsy-proven, positron emission tomographyestaged T1-2 (<5 cm) N0M0 NSCLC and centrally located tumors (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura) were successively accrued onto a dose-escalating 5-fraction SBRT schedule ranging from 10 to 12 Gy/fraction delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any grade 3 or worse toxicity (per Common Terminology Criteria for Adverse Events version 4) occurring within the first year, possibly, probably, or definitely related to treatment from a prespecified list of disorders. Any potential DLT within the initial year post-SBRT could have led to dose reduction for subsequent patients accrued, using time-toevent continual reassessment method statistical design. MTD was defined as SBRT dose associated with a 20% probability of DLT. Results: One hundred twenty pts were accrued February 2009 to September 2013 from 43 participating centers. Numbers (n) accrued into each cohort, n eligible for analysis (20 pts excluded as did not receive protocol treatment [12] or were ineligible [8]), and n evaluable for DLT analyses (11 not evaluable, 10 of whom died in the first year without a DLT) are shown in the table. Pts were elderly (median age 72 years), there were slightly more females (57%), and the majority had performance
Late Breaking Abstract #10 Worst treatment-related AE at any time Dose level
Pts accrued (n)
Pts eligible (n)
Pts evaluable for DLT (n)
10 Gy/fr 10.5 Gy/fr 11.0 Gy/fr 11.5 Gy/fr 12.0 Gy/fr
8 8 18 43 43
8 7 14 38 33
8 6 13 32 30
Number and type of DLT 1 1 2 1
0 (death) (bradycardia) (hypoxia) (pneumonitis)
Grade 3 (n)
Grade 4 (n)
Grade 5 (n)
0 0 1 4 5
0 0 0 0 1
0 1 0 2 1
6
International Journal of Radiation Oncology Biology Physics
status 0 to 1 (84%). Most cancers were T1 (65%) and squamous cell (45%). Median follow-up was 26.6 months. There were 5 DLTs seen; the table details the protocol prespecified DLTs and the worst treatmentrelated adverse events. MTD is 12.0 Gy/fr; DLT on this arm was 7.2% (95% CI 2.8%-14.4%). Conclusion: The novel statistical design used in RTOG 0813 allowed for seamless uninterrupted accrual of pts onto successive dose-escalated cohorts, with a large number of pts contributing to DLT data. The rates of toxicity prespecified as DLT were relatively low. The highest dose level allowed by the protocol was associated with a 7.2% rate of DLT; however, there still is considerable toxicity associated with this level. A decision regarding the optimal dose to be used for centrally located cancers needs to await the efficacy analysis of the phase 2 portion of this study.
(RTOG Specimen Bank), U24CA196067 (NRG Specimen Bank), R01CA108633 (to AC), 1R01CA169368 (to AC), 1RC2CA148190 (to AC), U10CA180850-01 (to AC) from the National Cancer Institute (NCI), Brain Tumor Funders Collaborative Grant (to AC), The Ohio State University Comprehensive Cancer Center (to AC), and the Merck & Co. Trial Information: NCT00003375 (9802); NCT00004259 (9813).
LBA 11 Treatment Responses and Survival in IDH1-Mutant Grade II and III Gliomas in NRG Oncology/RTOG 9802 and 9813 E.H. Bell,1 P. Zhang,2 J.C. Buckner,3 S.M. Chang,4 A.L. Salavaggione,1 D. Brachman,5 R.J. Lee,6 A.D. Murtha,7 P.D. Brown,8 C.J. Schultz,9 S. Malone,10 M.P. Mehta,11 S.L. Pugh,2 and A. Chakravarti1; 1The Ohio State University Wexner Medical Center, Columbus, OH, 2NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 3Mayo Clinic, Rochester, MN, 4UCSF Medical Center, San Francisco, CA, 5St. Joseph’s Hospital and Medical Center accruals for Arizona Oncology Services Foundation, Phoenix, AZ, 6Intermountain Medical Center, Murray, UT, 7 Cross Cancer Institute, Edmonton, AB, Canada, 8Mayo Clinic accruals for Rochester Methodist Hospital, Rochester, MN, 9Medical College of Wisconsin, Department of Radiation Oncology, Milwaukee, WI, 10The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, Canada, 11 University of Maryland School of Medicine, Baltimore, MD Purpose/Objective(s): WHO grade II and III gliomas are heterogeneous both genotypically and phenotypically. Patients harboring mutant IDH gliomas have increased survival times, and multiple studies have confirmed the prognostic significance of IDH mutations. However, what has yet to be fully evaluated are the treatment effects of radiation and chemotherapy for both grade II and III gliomas that contain IDH mutations. This study sought to examine the treatment differences between adjuvant radiation therapy (RT) and adjuvant chemoradiation strategies in IDH1-mutant grade II and III gliomas. Materials/Methods: Grade II and III glioma specimens with IDH1 mutations were analyzed from Radiation Therapy Oncology Group (RTOG) 9802, a phase 3 study of RT versus RT+procarbazine, CCNU, and vincristine (PCV) in grade II gliomas and RTOG 9813, a phase 3 study of RT+temozolomide (TMZ) versus RT+nitrosourea (NU) in grade III gliomas. Mutation status was confirmed by immunohistochemistry (IDH1R132H-specific antibody). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Results: Seventy-one and 49 IDH1R132H-mutant patients were analyzed for treatment differences from RTOG 9802 and 9813, respectively. In each study, the 2 treatment arms were balanced on sample size and were similar with respect to patient baseline characteristics. Most patients in both studies were <50 years old, male, with a KPS of 90 to 100, and with minor or no neurologic symptoms. For RTOG 9802, patients treated with RT+PCV demonstrated increased PFS and OS relative to patients treated with RT alone (HRZ0.32, P<.001 [PFS]; HRZ 0.42, PZ.02 [OS]). For RTOG 9813, patients treated with RT+TMZ had increased PFS times and trended toward better OS than patients treated with RT+NU (HRZ0.37, PZ.004 [PFS]; HRZ0.55, PZ.11 [OS]). Conclusion: Taken together, study results highlight the radiation and chemosensitivity of IDH1-mutant grade II and III gliomas and strongly suggests that both adjuvant radiation and chemotherapy prolong survival times in this subpopulation of glioma patients. Further research into treatment effects in molecular subgroups of grade II and III gliomas is warranted. Acknowledgment(s): This project was supported by grants U10CA21661 (RTOG-Ops-Stat), U10CA180868 (NRG Oncology Operations), U10CA 180822 (NRG Oncology SDMC), U10CA37422 (CCOP), U24CA114734
LBA 12 A Prognostic Analysis on Using the Combination of Tumor Volume and Epstein-Barr Virus DNA in Patients With Nasopharyngeal Carcinoma Treated With IMRT L. Lu,1 J. Li,2 W. Jia,3 C. Zhao,4 and T. Lu5; 1651 Dongfeng road east, Guangzhou, China, 2Sun Yat-sen University, the first affiliated hospital, guangzhou, China, 3Sun Yat-sen University, Cancer Center, Guangzhou, China, 4Sun Yat-Sen University Cancer Center, Guangzhou, China, 5Sun Yat-Sen University Cancer Center, Guang Dong Province, United States Purpose/Objective(s): To evaluate the prognostic effect of combining the assessment of tumor volume with that of Epstein-Barr virus DNA (EBV DNA) level and their impacts in the prognosis analysis in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT). Materials/Methods: A total of 180 consecutive NPC patients who underwent IMRT were enrolled from 2006 to 2010. Pretreatment plasma EBV DNA level was quantified by a polymerase chain reaction assay. The tumor volume was delineated by IMRT planning system. Survival rates of different groups of patients segregated by tumor volume and EBV DNA level alone or by the combination of the tumor volume and EBV DNA level were compared cross-over. Results: Increased tumor volume and elevated EBV DNA levels were significantly correlated with poor disease-free, distant, and overall survival in the patients. The 5-year survival rates in patients with GTVnx (gross tumor volume of the nasopharynx) 20 cm3 and >20 cm3 were 95.1% and 70.6% (PZ.001), while in patients with GTVnd (gross tumor volume of the lymph nodes) 10 cm3 and >10 cm3 were 86.0% and 75.8% (PZ.051), respectively. The same 5-year survival in patients with EBV DNA <10,000 copies/ mL and 10,000 copies/mL were 98.6% and 67.2% (P<.001), respectively. The patients were segregated into 4 groups by combination of tumor volume and pretreatment EBV DNA level. The patients with a lower EBV DNA level showed significantly better prognosis than those with a higher EBV DNA level in same GTVnx or GTVnd groups. The results demonstrate that the accuracy of prognostic evaluation was further improved. Conclusion: Our study has, for the first time in the studies of NPC, implemented a prognostic analysis on NPC patients by using the combined variable of tumor volume and pretreatment plasma EBV DNA concentration. Patients with small tumor volume or a low plasma EBV DNA level demonstrated a better prognosis. The cross-grouping analysis in the combination of 2 factors revealed that the combination of tumor volume and EBV DNA had a better prognosis predictive value for NPC patients. It is recommended that the 2 indicators representing the tumor load can be incorporated into clinical staging of NPC so as to better guide the prognosis of patients. Late Breaking Abstract #12 Overall survival of patient subgroups with combination of tumor volume and pretreatment EBV DNA Level.
Subgroup Combination of GTVnx & EBV DNA GTVnx20 cm3, low EBV DNA GTVnx20 cm3, high EBV DNA GTVnx>20 cm3, low EBV DNA GTVnx>20 cm3, high EBV DNA Combination of GTVnd & EBV DNA GTVnd10 cm3, low EBV DNA GTVnd10 cm3, high EBV DNA GTVnd>10 cm3, low EBV DNA GTVnd>10 cm3, high EBV DNA
5-Year P No. of survival (%) 95% CI (%) value patients <.001 54 29 26 71
97.1 86.1 91.8 61.6
94.2 to 100 79.6 to 92.6 86.2 to 97.4 55.1 to 68.1
65 50 15 50
98.4 68.8 100 66.1
96.8 to 100 61.4 to 76.2 — 58.8 to 73.4
<.001
5
Late-Breaking Abstract Special Session
LBA 9 NRG Oncology/RTOG 0937: Randomized Phase 2 Study Comparing Prophylactic Cranial Irradiation (PCI) Alone to PCI and Consolidative Extracranial Irradiation for Extensive Disease Small Cell Lung Cancer (ED-SCLC) E.M. Gore,1 C. Hu,2 A. Sun,3 D. Grimm,1 S. Ramalingam,4 N.E. Dunlap,5 K.A. Higgins,4 M. Werner-Wasik,6 A.M. Allen,7 P. Iyengar,8 G.M. Videtic,9 R.K. Hales,10 R.C. McGarry,11 J.J. Urbanic,12 A.T. Pu,13 C. Johnstone,1 J.N. Atkins,14 and J.D. Bradley15; 1Medical College of Wisconsin, Milwaukee, WI, 2NRG Oncology, Philadelphia, PA, 3Princess Margaret Hospital, Toronto, ON, Canada, 4Emory University, Atlanta, GA, United States, 5University of Louisville, Louisville, KY, 6Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, 7Rabin Medical Center, Petah Tikva, Israel, 8University of Texas Southwestern Medical Center, DALLAS, TX, 9Cleveland Clinic, Cleveland, OH, 10Johns Hopkins University, Baltimore, MD, United States, 11University of Kentucky, Lexington, KY, 12University of California, San Diego, La Jolla, CA, 13Sutter Medical Group - Radiological Associates of Sacramento, Sacramento, CA, 14Southeast Cancer Consortium-Upstate NCORP, Goldsboro, NC, 15Washington University School of Medicine, St. Louis, MO Purpose/Objective(s): The primary objective of Radiation Therapy Oncology Group (RTOG) 0937 was to evaluate the survival benefit of PCI plus consolidative radiation therapy to intrathoracic disease and extracranial metastases in patients with ED-SCLC. Materials/Methods: This was a randomized phase 2 trial. Patients with 1 to 4 metastatic lesions and no brain metastases at diagnosis were eligible after CR or PR to 4 to 6 cycles of platinum-based chemotherapy. Randomization was to PCI only or PCI and consolidative radiation to the thorax and original sites of metastatic disease (PCI+RT). Original stratification included PR versus CR after chemotherapy and 1 versus 2 to 4 metastatic lesions; age <65 versus >65 years was added after an imbalance was observed. PCI dose was 25 Gy in 10 fractions for all patients. The recommended dose for chest and metastatic lesions was 45 Gy in 15 fractions. A dose of 30 to 40 Gy in 10 fractions was allowed if necessary to meet normal tissue dose constraints. The primary endpoint was 1-year overall survival (OS). In order to detect an improvement from 30% to 45% with a 34% hazard reduction (HRZ0.66) under a 0.1 type 1 error (1-sided) and 80% power, 154 patients were required. Results: Ninety-seven patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (9 PCI, 2 PCI+RT), leaving 42 patients in the PCI arm and 44 in the PCI+RT arm. A planned interim analysis indicated that the study crossed the futility boundary for the primary endpoint and the study was closed prior to meeting the accrual target. Median follow-up was 9 months. Sixty-nine percent of patients received >45 Gy to the thorax in the PCI+RT arm, and 94.2% of all patients received 25 Gy PCI. More patients assigned to PCI+RT were >65 years of age (28.6% vs 54.5%, P<.05). The 1-year OS was not significantly different between the groups: 60.1% (95% CI: 41.2%-74.7%) for PCI and 50.8% (95% CI: 34.0%-65.3%) for PCI+RT (PZ.21). The 3- and 12-month rates of any progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+RT, respectively. Time to any progression favored PCI+RT with a hazard ratio of 0.53 (PZ.01). One patient in each arm had grade 4 toxicity at least possibly attributed to therapy. One patient had grade 5 respiratory failure in the PCI+RT group attributed to therapy. This patient’s V20 and mean lung dose exceeded dose constraints required by the study.
Conclusion: Observed overall survival exceeded predicted OS for both arms. Consolidative radiation therapy to the thorax and extracranial metastases delayed progression of disease but did not improve 1-year OS. Acknowledgment(s): This project was supported by grants U10CA21661 (RTOG-Ops-Stat), U10CA180868 (NRG Oncology Operations), and U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI). Clinical trial: NCT01055197.
LBA 10 Primary Study Endpoint Analysis for NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for Centrally Located Non-Small Cell Lung Cancer (NSCLC) A. Bezjak,1 R. Paulus,2 L.E. Gaspar,3 R.D. Timmerman,4 W.L. Straube,5 W.F. Ryan,6 Y. Garces,7 A.T. Pu,8 A.K. Singh,9 G.M. Videtic,10 R.C. McGarry,11 P. Iyengar,12 J.R. Pantarotto,13 J.J. Urbanic,14 A. Sun,15 M.E. Daly,16 I.S. Grills,17 D.P. Normolle,18 J.D. Bradley,5 and H. Choy19; 1 Princess Margaret Cancer Centre, Toronto, ON, Canada, 2NRG Oncology, Philadelphia, PA, 3University of Colorado Denver, Aurora, CO, 4 The University of Texas Southwestern School of Medicine, Dallas, TX, 5 Washington University, St. Louis, MO, 6Pocono Cancer Center, East Stroudsburg, PA, 7Mayo Clinic, Rochester, MN, 8Sutter Medical Group Radiological Associates of Sacramento, Sacramento, CA, 9Roswell Park Cancer Institute, Buffalo, NY, United States, 10Cleveland Clinic, Cleveland, OH, 11University of Maryland Medical Systems, Baltimore, MD, 12University of Texas Southwestern Medical Center, DALLAS, TX, 13 University of Ottawa, Ottawa, ON, Canada, 14University of California, San Diego, La Jolla, CA, 15Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada, 16University of California, Davis, Sacramento, CA, 17Beaumont Health System, Royal Oak, MI, 18University of Pittsburgh, Pittsburgh, PA, United States, 19 University of Texas Southwestern Medical Center, Dallas, TX Purpose/Objective(s): NRG/Radiation Therapy Oncology Group (RTOG) 0813 is a phase 1/2 study designed to determine the maximal tolerated dose (MTD) and efficacy of SBRT for NSCLC with centrally located tumors. We hereby report the primary endpoint of the phase 1 portion of the study. Materials/Methods Medically inoperable patients (pts) with biopsy-proven, positron emission tomographyestaged T1-2 (<5 cm) N0M0 NSCLC and centrally located tumors (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura) were successively accrued onto a dose-escalating 5-fraction SBRT schedule ranging from 10 to 12 Gy/fraction delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any grade 3 or worse toxicity (per Common Terminology Criteria for Adverse Events version 4) occurring within the first year, possibly, probably, or definitely related to treatment from a prespecified list of disorders. Any potential DLT within the initial year post-SBRT could have led to dose reduction for subsequent patients accrued, using time-toevent continual reassessment method statistical design. MTD was defined as SBRT dose associated with a 20% probability of DLT. Results: One hundred twenty pts were accrued February 2009 to September 2013 from 43 participating centers. Numbers (n) accrued into each cohort, n eligible for analysis (20 pts excluded as did not receive protocol treatment [12] or were ineligible [8]), and n evaluable for DLT analyses (11 not evaluable, 10 of whom died in the first year without a DLT) are shown in the table. Pts were elderly (median age 72 years), there were slightly more females (57%), and the majority had performance
Late Breaking Abstract #10 Worst treatment-related AE at any time Dose level
Pts accrued (n)
Pts eligible (n)
Pts evaluable for DLT (n)
10 Gy/fr 10.5 Gy/fr 11.0 Gy/fr 11.5 Gy/fr 12.0 Gy/fr
8 8 18 43 43
8 7 14 38 33
8 6 13 32 30
Number and type of DLT 1 1 2 1
0 (death) (bradycardia) (hypoxia) (pneumonitis)
Grade 3 (n)
Grade 4 (n)
Grade 5 (n)
0 0 1 4 5
0 0 0 0 1
0 1 0 2 1
6
International Journal of Radiation Oncology Biology Physics
status 0 to 1 (84%). Most cancers were T1 (65%) and squamous cell (45%). Median follow-up was 26.6 months. There were 5 DLTs seen; the table details the protocol prespecified DLTs and the worst treatmentrelated adverse events. MTD is 12.0 Gy/fr; DLT on this arm was 7.2% (95% CI 2.8%-14.4%). Conclusion: The novel statistical design used in RTOG 0813 allowed for seamless uninterrupted accrual of pts onto successive dose-escalated cohorts, with a large number of pts contributing to DLT data. The rates of toxicity prespecified as DLT were relatively low. The highest dose level allowed by the protocol was associated with a 7.2% rate of DLT; however, there still is considerable toxicity associated with this level. A decision regarding the optimal dose to be used for centrally located cancers needs to await the efficacy analysis of the phase 2 portion of this study.
(RTOG Specimen Bank), U24CA196067 (NRG Specimen Bank), R01CA108633 (to AC), 1R01CA169368 (to AC), 1RC2CA148190 (to AC), U10CA180850-01 (to AC) from the National Cancer Institute (NCI), Brain Tumor Funders Collaborative Grant (to AC), The Ohio State University Comprehensive Cancer Center (to AC), and the Merck & Co. Trial Information: NCT00003375 (9802); NCT00004259 (9813).
LBA 11 Treatment Responses and Survival in IDH1-Mutant Grade II and III Gliomas in NRG Oncology/RTOG 9802 and 9813 E.H. Bell,1 P. Zhang,2 J.C. Buckner,3 S.M. Chang,4 A.L. Salavaggione,1 D. Brachman,5 R.J. Lee,6 A.D. Murtha,7 P.D. Brown,8 C.J. Schultz,9 S. Malone,10 M.P. Mehta,11 S.L. Pugh,2 and A. Chakravarti1; 1The Ohio State University Wexner Medical Center, Columbus, OH, 2NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 3Mayo Clinic, Rochester, MN, 4UCSF Medical Center, San Francisco, CA, 5St. Joseph’s Hospital and Medical Center accruals for Arizona Oncology Services Foundation, Phoenix, AZ, 6Intermountain Medical Center, Murray, UT, 7 Cross Cancer Institute, Edmonton, AB, Canada, 8Mayo Clinic accruals for Rochester Methodist Hospital, Rochester, MN, 9Medical College of Wisconsin, Department of Radiation Oncology, Milwaukee, WI, 10The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, Canada, 11 University of Maryland School of Medicine, Baltimore, MD Purpose/Objective(s): WHO grade II and III gliomas are heterogeneous both genotypically and phenotypically. Patients harboring mutant IDH gliomas have increased survival times, and multiple studies have confirmed the prognostic significance of IDH mutations. However, what has yet to be fully evaluated are the treatment effects of radiation and chemotherapy for both grade II and III gliomas that contain IDH mutations. This study sought to examine the treatment differences between adjuvant radiation therapy (RT) and adjuvant chemoradiation strategies in IDH1-mutant grade II and III gliomas. Materials/Methods: Grade II and III glioma specimens with IDH1 mutations were analyzed from Radiation Therapy Oncology Group (RTOG) 9802, a phase 3 study of RT versus RT+procarbazine, CCNU, and vincristine (PCV) in grade II gliomas and RTOG 9813, a phase 3 study of RT+temozolomide (TMZ) versus RT+nitrosourea (NU) in grade III gliomas. Mutation status was confirmed by immunohistochemistry (IDH1R132H-specific antibody). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Results: Seventy-one and 49 IDH1R132H-mutant patients were analyzed for treatment differences from RTOG 9802 and 9813, respectively. In each study, the 2 treatment arms were balanced on sample size and were similar with respect to patient baseline characteristics. Most patients in both studies were <50 years old, male, with a KPS of 90 to 100, and with minor or no neurologic symptoms. For RTOG 9802, patients treated with RT+PCV demonstrated increased PFS and OS relative to patients treated with RT alone (HRZ0.32, P<.001 [PFS]; HRZ 0.42, PZ.02 [OS]). For RTOG 9813, patients treated with RT+TMZ had increased PFS times and trended toward better OS than patients treated with RT+NU (HRZ0.37, PZ.004 [PFS]; HRZ0.55, PZ.11 [OS]). Conclusion: Taken together, study results highlight the radiation and chemosensitivity of IDH1-mutant grade II and III gliomas and strongly suggests that both adjuvant radiation and chemotherapy prolong survival times in this subpopulation of glioma patients. Further research into treatment effects in molecular subgroups of grade II and III gliomas is warranted. Acknowledgment(s): This project was supported by grants U10CA21661 (RTOG-Ops-Stat), U10CA180868 (NRG Oncology Operations), U10CA 180822 (NRG Oncology SDMC), U10CA37422 (CCOP), U24CA114734
LBA 12 A Prognostic Analysis on Using the Combination of Tumor Volume and Epstein-Barr Virus DNA in Patients With Nasopharyngeal Carcinoma Treated With IMRT L. Lu,1 J. Li,2 W. Jia,3 C. Zhao,4 and T. Lu5; 1651 Dongfeng road east, Guangzhou, China, 2Sun Yat-sen University, the first affiliated hospital, guangzhou, China, 3Sun Yat-sen University, Cancer Center, Guangzhou, China, 4Sun Yat-Sen University Cancer Center, Guangzhou, China, 5Sun Yat-Sen University Cancer Center, Guang Dong Province, United States Purpose/Objective(s): To evaluate the prognostic effect of combining the assessment of tumor volume with that of Epstein-Barr virus DNA (EBV DNA) level and their impacts in the prognosis analysis in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT). Materials/Methods: A total of 180 consecutive NPC patients who underwent IMRT were enrolled from 2006 to 2010. Pretreatment plasma EBV DNA level was quantified by a polymerase chain reaction assay. The tumor volume was delineated by IMRT planning system. Survival rates of different groups of patients segregated by tumor volume and EBV DNA level alone or by the combination of the tumor volume and EBV DNA level were compared cross-over. Results: Increased tumor volume and elevated EBV DNA levels were significantly correlated with poor disease-free, distant, and overall survival in the patients. The 5-year survival rates in patients with GTVnx (gross tumor volume of the nasopharynx) 20 cm3 and >20 cm3 were 95.1% and 70.6% (PZ.001), while in patients with GTVnd (gross tumor volume of the lymph nodes) 10 cm3 and >10 cm3 were 86.0% and 75.8% (PZ.051), respectively. The same 5-year survival in patients with EBV DNA <10,000 copies/ mL and 10,000 copies/mL were 98.6% and 67.2% (P<.001), respectively. The patients were segregated into 4 groups by combination of tumor volume and pretreatment EBV DNA level. The patients with a lower EBV DNA level showed significantly better prognosis than those with a higher EBV DNA level in same GTVnx or GTVnd groups. The results demonstrate that the accuracy of prognostic evaluation was further improved. Conclusion: Our study has, for the first time in the studies of NPC, implemented a prognostic analysis on NPC patients by using the combined variable of tumor volume and pretreatment plasma EBV DNA concentration. Patients with small tumor volume or a low plasma EBV DNA level demonstrated a better prognosis. The cross-grouping analysis in the combination of 2 factors revealed that the combination of tumor volume and EBV DNA had a better prognosis predictive value for NPC patients. It is recommended that the 2 indicators representing the tumor load can be incorporated into clinical staging of NPC so as to better guide the prognosis of patients. Late Breaking Abstract #12 Overall survival of patient subgroups with combination of tumor volume and pretreatment EBV DNA Level.
Subgroup Combination of GTVnx & EBV DNA GTVnx20 cm3, low EBV DNA GTVnx20 cm3, high EBV DNA GTVnx>20 cm3, low EBV DNA GTVnx>20 cm3, high EBV DNA Combination of GTVnd & EBV DNA GTVnd10 cm3, low EBV DNA GTVnd10 cm3, high EBV DNA GTVnd>10 cm3, low EBV DNA GTVnd>10 cm3, high EBV DNA
5-Year P No. of survival (%) 95% CI (%) value patients <.001 54 29 26 71
97.1 86.1 91.8 61.6
94.2 to 100 79.6 to 92.6 86.2 to 97.4 55.1 to 68.1
65 50 15 50
98.4 68.8 100 66.1
96.8 to 100 61.4 to 76.2 — 58.8 to 73.4
<.001