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Phase 1 Trial of Icotinib Combined With Whole-Brain Radiation Therapy for EGFR-Mutated Non-Small Cell Lung Cancer Patients With Brain Metastases: Updated Results
S608
International Journal of Radiation Oncology Biology Physics
p Z 0.0002). A drop in SUV >3 was noted in 81% for primary (p Z NS) and 35% for LN (60% with DE-RT, 18% only with SD-RT, p Z 0.009). Correlation between % drop in SUV for primary and LN (50% drop, 75% drop, at 3 cutoff) was same in the two dose groups. Median survival was 50 months for the entire cohort, with a 2- & 5- year survival of 88%, 65%. DE-RT pts have not yet achieved median survival. The 2-year DFS was 70% (37 mo median DFS). None of the factors including RT dose, T down staging, MNC, different cut off points for SUV drop were significant for outcomes on DFS, OS. At last follow up, 17 pts (46%) were free of disease and 14 alive (38%). Conclusions: RT dose escalation resulted in improvement in MNC and correlated with the PET response in our series. Lon-term follow-up and larger pt numbers are needed for the DE-RT pts to prove the concept. PET response can be utilized as predictor of outcomes in operable NSCLC pts. Author Disclosure: A. Turaka: None. S. Hasan: None. T. Li: None. R. Mehra: None. W.J. Scott: None. J.Q. Yu: None.
of icotinib, and there were the highest CSF concentration and penetration rate at dose of 375 mg tid. Within 20 weeks of treatment, there was no neurocognitive function deterioration observed in this trail. Author Disclosure: L. Zhou: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc. J. He: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc. W. Xiong: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc. Q. Yu: None. J. Xiang: None. M. Liang: None. J. Xue: None. Y. Liu: None. Z. Ding: None. Y. Gong: None. M. Huang: None. J. Zhu: None. L. Li: None. Y. Wang: None. M. Hou: None. L. Ren: None. Y. Lu: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc.
3009 Phase 1 Trial of Icotinib Combined With Whole-Brain Radiation Therapy for EGFR-Mutated Non-Small Cell Lung Cancer Patients With Brain Metastases: Updated Results L. Zhou,1 J. He,1 W. Xiong,1 Q. Yu,2 J. Xiang,2 M. Liang,2 J. Xue,1 Y. Liu,1 Z. Ding,1 Y. Gong,1 M. Huang,1 J. Zhu,1 L. Li,1 Y. Wang,1 M. Hou,1 L. Ren,1 and Y. Lu3; 1Department of Thoracic Cancer, Cancer Center, West China Hospital, Sichuan University, Chengdu, China, 2State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, 3Department of Thoracic Cancer, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China Purpose/Objective(s): Icotinib has been demonstrated to provide similar efficacy to gefitinib in non-small cell lung cancer (NSCLC) patients. This phase 1 trial (NCT01516983) evaluated the dose-escalation toxicities of icotinib combined with whole brain radiation therapy (WBRT) in EGFRmutated NSCLC patients with brain metastases, and cerebrospinal fluid (CSF) penetration rates of icotinib were assessed in the dose-escalation. Materials/Methods: The cohorts were constructed with a 3 + 3 design, and the dose-escalation schedule of icotinib was set as 125 mg tid, 250 mg tid, 375 mg tid, 500 mg tid, and 625 mg tid. Icotinib was started 7 days before and continued during WBRT (37.5 Gy/15 f/21 d), and maintained until disease progression or intolerable toxicities occurred. The blood and CSF samples were obtained on day 7 (before WBRT), day 29 (after WBRT) and day 57 of therapy. Neurocognitive function (NCF) was assessed with MiniMental Status Examination. Results: Fifteen patients were enrolled in this trial. The most frequent treatment-related toxicities were grade 1-2 alopecia (15/15), acne-like rash (14/15) and nausea (11/15). At dose level of 500 mg tid, 3 out of 6 patients experienced dose-limiting toxicity including 1 grade 3 alanine aminotransferase elevation and 2 grade 3 nausea. The mean CSF penetration rate of icotinib was 4.04% (range: 1.23%-9.71%), and there was a good correlation between plasma and CSF concentrations (R2 Z 0.577, P<0.001). There were no statistical differences in plasma concentrations, CSF concentrations, and penetration rates of icotinib between day 7, day 29, and day 57. However, CSF concentration (154.09 ng/mL, P<0.001) and penetration rate (7.06%, P<0.001) of icotinib were much higher at dose of 375 mg tid. After the median follow-up time of 56 weeks, the overall response rate (ORR), disease control rate (DCR) and median progress free survival (PFS) were 80%, 100% and 46 weeks (95% CI: 43-49 weeks), corresponding to 80%, 100% and 78 weeks (95% CI: 20.4-123.6 weeks) of intracranial lesions. There were no statistical differences in NCF of patients in low-dose group (125 mg tid-250 mg tid) and high-dose group (375 mg tid-500 mg tid) within 20 weeks of treatment. Moreover, compared to baseline, there were no significant differences in NCF of patients within 20 weeks either. Conclusions: WBRT with concurrent and maintenance icotinib (125 mg tid-375 mg tid) were tolerable and efficient in EGFR-mutated NSCLC patients with brain metastases. WBRT might not increase penetration rate
3010 Patterns of Local Recurrence for Mesothelioma Patients Treated With Extrapleural Pneumonectomy and Radiation Therapy Using the Electron-Photon Technique: The Dosimetric Challenges of Electron-Photon Match Lines and Blocks K.S. Mak,1 E.G. Mannarino,2 W.G. Richards,3 R.H. Mak,2 A.B. Chen,2 D.E. Kozono,2 R.R. Gill,3 D.J. Sugarbaker,3 and E.H. Baldini2; 1Harvard Radiation Oncology Program, Boston, MA, 2Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, 3Brigham and Women’s Hospital, Boston, MA Purpose/Objective(s): Hemi-thoracic radiation therapy (RT) after extrapleural pneumonectomy (EPP) appears to reduce local recurrence (LR). The large target volume and proximity of critical organs make RT planning challenging. The electron-photon technique (EPT) developed at Memorial Sloan-Kettering Cancer Center involves photon and electron fields matched in an attempt to deliver uniform dose to areas at risk. Dose inhomogeneities may occur at these electron-photon match lines and under blocks. The purpose of this retrospective study was to describe patterns of LR relative to electron-photon match lines and block placement in patients treated with the EPT. Materials/Methods: From 2003-2009, 34 patients with non-metastatic mesothelioma underwent EPP and adjuvant RT via the EPT. RT consisted of AP-PA photon fields to the hemithorax and mediastinum. Matched electron fields treated the chest wall under blocked abdominal and cardiac regions. Abdominal blocks were added at the start of RT; heart blocks were added for left-sided cases at 19.8 Gy; spinal cord blocks were added at 39.6 Gy. Prescribed dose was 54 Gy. CT scans with LRs were registered with planning CT scans to determine LR locations relative to match lines, blocks, and dosimetry. Results: Twenty-eight patients were male (82%). Median age was 56.5 years. Histology was epithelial for 19 patients (56%) and mixed/biphasic for 15 (44%). Median dose was 54 Gy (range: 45-54). Median follow-up was 24.6 months; median time to LR was 14.8 months. Fifteen patients (44%) had LRs in 38 local sites; ten of these patients (67%) had additional distant failures. The most common LR sites were lateral costophrenic sulcus (53%) and mediastinum (40%). Twenty-one LRs (55%) occurred under a block, six (16%) in the full-dose photon field abutting a block, six (16%) out-of-field, and five (13%) in the full-dose photon field (Table). Twelve LRs (32%) were associated with a match line in areas where the actual dose (median 42.5 Gy) was significantly less than the nominal prescribed dose of 54 Gy (p Z 0.003). LRs under heart or abdominal blocks also occurred in under-dosed locations (median actual dose 45 Gy vs prescribed dose 54 Gy, p Z 0.05). Conclusions: The majority of LRs after hemithoracic RT using EPT occurred at match lines and/or under blocks in under-dosed areas. These limitations of EPT should be considered when selecting the adjuvant RT technique most appropriate for individual patients following EPP. Author Disclosure: K.S. Mak: A. Employee; Brigham and Women’s Hospital. E.G. Mannarino: A. Employee; Brigham and Women’s Hospital. W.G. Richards: A. Employee; Brigham and Women’s Hospital. R.H. Mak: A. Employee; Brigham and Women’s Hospital. G. Consultant; Boehringer Ingelheim, Inc. A.B. Chen: A. Employee; Brigham and Women’s Hospital. D.E. Kozono: A. Employee; Brigham and Women’s
International Journal of Radiation Oncology Biology Physics
p Z 0.0002). A drop in SUV >3 was noted in 81% for primary (p Z NS) and 35% for LN (60% with DE-RT, 18% only with SD-RT, p Z 0.009). Correlation between % drop in SUV for primary and LN (50% drop, 75% drop, at 3 cutoff) was same in the two dose groups. Median survival was 50 months for the entire cohort, with a 2- & 5- year survival of 88%, 65%. DE-RT pts have not yet achieved median survival. The 2-year DFS was 70% (37 mo median DFS). None of the factors including RT dose, T down staging, MNC, different cut off points for SUV drop were significant for outcomes on DFS, OS. At last follow up, 17 pts (46%) were free of disease and 14 alive (38%). Conclusions: RT dose escalation resulted in improvement in MNC and correlated with the PET response in our series. Lon-term follow-up and larger pt numbers are needed for the DE-RT pts to prove the concept. PET response can be utilized as predictor of outcomes in operable NSCLC pts. Author Disclosure: A. Turaka: None. S. Hasan: None. T. Li: None. R. Mehra: None. W.J. Scott: None. J.Q. Yu: None.
of icotinib, and there were the highest CSF concentration and penetration rate at dose of 375 mg tid. Within 20 weeks of treatment, there was no neurocognitive function deterioration observed in this trail. Author Disclosure: L. Zhou: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc. J. He: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc. W. Xiong: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc. Q. Yu: None. J. Xiang: None. M. Liang: None. J. Xue: None. Y. Liu: None. Z. Ding: None. Y. Gong: None. M. Huang: None. J. Zhu: None. L. Li: None. Y. Wang: None. M. Hou: None. L. Ren: None. Y. Lu: L. Funding Other; Research funding of present study was from Zhejiang Beta Pharma Inc.
3009 Phase 1 Trial of Icotinib Combined With Whole-Brain Radiation Therapy for EGFR-Mutated Non-Small Cell Lung Cancer Patients With Brain Metastases: Updated Results L. Zhou,1 J. He,1 W. Xiong,1 Q. Yu,2 J. Xiang,2 M. Liang,2 J. Xue,1 Y. Liu,1 Z. Ding,1 Y. Gong,1 M. Huang,1 J. Zhu,1 L. Li,1 Y. Wang,1 M. Hou,1 L. Ren,1 and Y. Lu3; 1Department of Thoracic Cancer, Cancer Center, West China Hospital, Sichuan University, Chengdu, China, 2State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, 3Department of Thoracic Cancer, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China Purpose/Objective(s): Icotinib has been demonstrated to provide similar efficacy to gefitinib in non-small cell lung cancer (NSCLC) patients. This phase 1 trial (NCT01516983) evaluated the dose-escalation toxicities of icotinib combined with whole brain radiation therapy (WBRT) in EGFRmutated NSCLC patients with brain metastases, and cerebrospinal fluid (CSF) penetration rates of icotinib were assessed in the dose-escalation. Materials/Methods: The cohorts were constructed with a 3 + 3 design, and the dose-escalation schedule of icotinib was set as 125 mg tid, 250 mg tid, 375 mg tid, 500 mg tid, and 625 mg tid. Icotinib was started 7 days before and continued during WBRT (37.5 Gy/15 f/21 d), and maintained until disease progression or intolerable toxicities occurred. The blood and CSF samples were obtained on day 7 (before WBRT), day 29 (after WBRT) and day 57 of therapy. Neurocognitive function (NCF) was assessed with MiniMental Status Examination. Results: Fifteen patients were enrolled in this trial. The most frequent treatment-related toxicities were grade 1-2 alopecia (15/15), acne-like rash (14/15) and nausea (11/15). At dose level of 500 mg tid, 3 out of 6 patients experienced dose-limiting toxicity including 1 grade 3 alanine aminotransferase elevation and 2 grade 3 nausea. The mean CSF penetration rate of icotinib was 4.04% (range: 1.23%-9.71%), and there was a good correlation between plasma and CSF concentrations (R2 Z 0.577, P<0.001). There were no statistical differences in plasma concentrations, CSF concentrations, and penetration rates of icotinib between day 7, day 29, and day 57. However, CSF concentration (154.09 ng/mL, P<0.001) and penetration rate (7.06%, P<0.001) of icotinib were much higher at dose of 375 mg tid. After the median follow-up time of 56 weeks, the overall response rate (ORR), disease control rate (DCR) and median progress free survival (PFS) were 80%, 100% and 46 weeks (95% CI: 43-49 weeks), corresponding to 80%, 100% and 78 weeks (95% CI: 20.4-123.6 weeks) of intracranial lesions. There were no statistical differences in NCF of patients in low-dose group (125 mg tid-250 mg tid) and high-dose group (375 mg tid-500 mg tid) within 20 weeks of treatment. Moreover, compared to baseline, there were no significant differences in NCF of patients within 20 weeks either. Conclusions: WBRT with concurrent and maintenance icotinib (125 mg tid-375 mg tid) were tolerable and efficient in EGFR-mutated NSCLC patients with brain metastases. WBRT might not increase penetration rate
3010 Patterns of Local Recurrence for Mesothelioma Patients Treated With Extrapleural Pneumonectomy and Radiation Therapy Using the Electron-Photon Technique: The Dosimetric Challenges of Electron-Photon Match Lines and Blocks K.S. Mak,1 E.G. Mannarino,2 W.G. Richards,3 R.H. Mak,2 A.B. Chen,2 D.E. Kozono,2 R.R. Gill,3 D.J. Sugarbaker,3 and E.H. Baldini2; 1Harvard Radiation Oncology Program, Boston, MA, 2Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, 3Brigham and Women’s Hospital, Boston, MA Purpose/Objective(s): Hemi-thoracic radiation therapy (RT) after extrapleural pneumonectomy (EPP) appears to reduce local recurrence (LR). The large target volume and proximity of critical organs make RT planning challenging. The electron-photon technique (EPT) developed at Memorial Sloan-Kettering Cancer Center involves photon and electron fields matched in an attempt to deliver uniform dose to areas at risk. Dose inhomogeneities may occur at these electron-photon match lines and under blocks. The purpose of this retrospective study was to describe patterns of LR relative to electron-photon match lines and block placement in patients treated with the EPT. Materials/Methods: From 2003-2009, 34 patients with non-metastatic mesothelioma underwent EPP and adjuvant RT via the EPT. RT consisted of AP-PA photon fields to the hemithorax and mediastinum. Matched electron fields treated the chest wall under blocked abdominal and cardiac regions. Abdominal blocks were added at the start of RT; heart blocks were added for left-sided cases at 19.8 Gy; spinal cord blocks were added at 39.6 Gy. Prescribed dose was 54 Gy. CT scans with LRs were registered with planning CT scans to determine LR locations relative to match lines, blocks, and dosimetry. Results: Twenty-eight patients were male (82%). Median age was 56.5 years. Histology was epithelial for 19 patients (56%) and mixed/biphasic for 15 (44%). Median dose was 54 Gy (range: 45-54). Median follow-up was 24.6 months; median time to LR was 14.8 months. Fifteen patients (44%) had LRs in 38 local sites; ten of these patients (67%) had additional distant failures. The most common LR sites were lateral costophrenic sulcus (53%) and mediastinum (40%). Twenty-one LRs (55%) occurred under a block, six (16%) in the full-dose photon field abutting a block, six (16%) out-of-field, and five (13%) in the full-dose photon field (Table). Twelve LRs (32%) were associated with a match line in areas where the actual dose (median 42.5 Gy) was significantly less than the nominal prescribed dose of 54 Gy (p Z 0.003). LRs under heart or abdominal blocks also occurred in under-dosed locations (median actual dose 45 Gy vs prescribed dose 54 Gy, p Z 0.05). Conclusions: The majority of LRs after hemithoracic RT using EPT occurred at match lines and/or under blocks in under-dosed areas. These limitations of EPT should be considered when selecting the adjuvant RT technique most appropriate for individual patients following EPP. Author Disclosure: K.S. Mak: A. Employee; Brigham and Women’s Hospital. E.G. Mannarino: A. Employee; Brigham and Women’s Hospital. W.G. Richards: A. Employee; Brigham and Women’s Hospital. R.H. Mak: A. Employee; Brigham and Women’s Hospital. G. Consultant; Boehringer Ingelheim, Inc. A.B. Chen: A. Employee; Brigham and Women’s Hospital. D.E. Kozono: A. Employee; Brigham and Women’s