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A Phase 1 Trial of Concurrent Sorafenib and Stereotactic Radiosurgery for Patients With 1-4 Brain Metastases
Poster Viewing Abstracts S271
Volume 87 Number 2S Supplement 2013 of rCBV, rCBF, and rK2trans identified cut-off values with optimal sensitivity and specificity for outcome. Results: rK2trans distinguished PD from response (p Z 0.03). The optimal threshold value, sensitivity, specificity and AUC were 12.8, 69.2%, 63.6% and 67.4%, respectively. rCBF and rCBV at one month discriminated PD from non-PD (p < 0.05 each) with optimal threshold values, sensitivity, specificity and AUC of 2.09, 87.5%, 66.7%, 74.2% and 3.08, 82.8%, 81.8%, 84.3%, respectively. Logistic regression identified decreased rK2trans, absence of prior radiation and steroid administration at one week as early predictors of tumor response (complete or partial response). At one month, only a decrease in rCBV was predictive OF PD. Conclusions: Early changes in rK2trans and rCBV are biomarkers of therapeutic response for brain metastases following radiation. Author Disclosure: A. Sahgal: None. R. Jakubovic: None. R. Milwid: None. A. Eilaghi: None. H. Soliman: None. R.I. Aviv: None.
2175 A Phase 1 Trial of Concurrent Sorafenib and Stereotactic Radiosurgery for Patients With 1-4 Brain Metastases K. Arneson,1 J. Mondshein,2 A.J. Cmelak,1 K. Niermann,1 L. Horn,1 I. Puzanov,1 F. Xia,3 and A. Chakravarthy1; 1Vanderbilt University Medical Center, Nashville, TN, 2University of Pennsylvania, Philadelphia, PA, 3 Ohio State University, Columbus, OH Purpose/Objective(s): Stereotactic radiosurgery (SRS) has been shown to provide high rates of local control for patients with limited brain metastases. However, patients remain at risk for developing new metastases at other brain sites. Preclinical studies suggest that combining angiogenic blockade with radiation may result in increased DNA damage. Sorafenib is an oral multi-kinase inhibitor which targets both tumor proliferation and tumor angiogenesis. We hypothesized that sorafenib when used in combination with SRS will improve target lesion control and intracranial control by treating subclinical disease in the brain. This Phase I study assesses the safety and tolerability of sorafenib (BAY 43-9006) when administered in combination with SRS in the treatment of patients with up to 4 brain metastases. Materials/Methods: Patients 18 years old with histologically confirmed solid tumors and 1-4 brain metastases, ECOG performance status 0-1 with adequate metabolic function were eligible. Exclusion criteria included concurrent chemotherapy, grade 3 hemorrhage within 4 weeks, uncontrolled hypertension, heart failure > NYHA class II, or angina. SRS doses were determined by the number, location, and size of the target lesions. Sorafenib was started 5-7 days prior to SRS and continued for 14 days after SRS. Dose escalation of sorafenib was conducted via a “3 + 3” dose escalation design. A dose limiting toxicity (DLT) was defined as grade 3 neurologic toxicities which are attributable to the combination of sorafenib and SRS. Patients were followed for 1 month after SRS to assess for DLTs. Patients had brain MRIs at 2, 6, and 12 months after SRS to assess for local and regional tumor control. Results: To date, six patients have enrolled. One has completed the entire 1 year study, one died 10 months after enrollment from progressive systemic disease, and four continue to be followed. There were no DLTs at dose level 1 (400 mg per day) nor dose level 2 (400 mg twice a day). There were two grade 3 toxicities (hypertension) and one grade 3 toxicity (rash) both which are known side effects of sorafenib alone. One patient at dose level 2 mistakenly took an inappropriate lower dose of sorafenib and therefore will not be included in the final analysis. Data on radiographic response continues to be collected. Conclusions: The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at doses as high as 400 mg twice a day. No DLTs were encountered. Grade 3 toxicities of rash and hypertension are known systemic side effects of sorafenib and were unrelated to the concurrent use of SRS. Enrollment continues and this study lays the foundation to potentially expand into a Phase II trial to allow formal assessment of intracranial disease response to SRS combined with sorafenib.
Author Disclosure: K. Arneson: None. J. Mondshein: None. A.J. Cmelak: None. K. Niermann: None. L. Horn: None. I. Puzanov: None. F. Xia: None. A. Chakravarthy: None.
2176 Whole Brain Radiation Therapy With Local Simultaneous Integrated Boost Conformal Radiation Therapy in the Treatment for Patients With 1-3 Brain Metastases X. Qiao, Z. Wang, Y. Song, J. Li, X. Zhang, C. Zhen, and Y. Yue; Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, China Purpose/Objective(s): To evaluate the feasibility whole brain radiation therapy (WBRT) with local simultaneous integrated boost conformal radiation therapy (SIB-CR) in the patients with one to three brain metastases. Materials/Methods: Twenty-one patients with one to three brain metastases confirmed by enhanced MRI/CT were prospectively collected and treated by whole brain radiation therapy with local SIB-CR. The prescribed dose of whole brain was 40 Gy/22 fractions and GTV to 55 Gy/ 22 fractions simultaneously in about 4.5 weeks. The acute radiation toxicities were recorded from the start of treatment to four weeks after the end of treatment. The late toxicities were evaluated. The tumor response was evaluated at 4 weeks after the end of radiation therapy. The overall survival (OS) and intracranial progression-free survival (PFS) time were calculated from the day of treatment until death, intracranial progression or the last follow-up date. Results: There were 11 male and 10 female patients in this group. The median age was 52 years (range, 39-72 years). Fourteen patients received radiation therapy alone while 7 cases received chemoradiation therapy. There were 2 patients with complete response, 16 patients with partial response and 3 patients with stable disease. The overall tumor response rate was 85.7% (18/21). The median follow-up time was 7 months (range, 1-12.5 months). To the follow-up cut-off time, five patients were dead, including 3 cases died of intracranial lesions and 2 of unknown causes. The rate of overall brain control was 85.7% (18/21), the local control rate 90.5% (19/21). The overall median survival time was 7 months. The 6month OS and intracranial PFS rates were 76.6% and 61.3%, respectively. The 1-year OS and intracranial PFS rates were 61.3% and 65.6%, respectively. The 1-year survival rate of patients treated with radiation therapy alone and chemoradiation therapy was 69.3% and 85.7%, respectively (p Z 0.253). Multivariate analysis showed that the RPA classification was correlated with survival. Survival rates among the patients with different RPA scores showed that the median survival period of RPA 1, 2 and 3 level were 9, 8 and 5 months, respectively (p Z 0.021). Conclusions: Whole brain irradiation with SIB-CR technique is effective in patients with one to three brain metastases with a higher tumor response and shorter radiation therapy duration and is well tolerated. SIB-CR technique is an effective option for these patients. Author Disclosure: X. Qiao: None. Z. Wang: None. Y. Song: None. J. Li: None. X. Zhang: None. C. Zhen: None. Y. Yue: None.
2177 Phase 1 Dose Escalation/De-escalation Study of Preoperative Stereotactic Radiosurgery for Brain Metastases: Preliminary Acute Toxicity and Dosimetric Analysis G.M. Clark,1 J.G. Stewart,1 B.L. Guthrie,2 J.M. Markert,2 S.A. Spencer,1 K.O. Riley,2 R. Meredith,1 X. Wu,1 R.A. Popple,1 and J.B. Fiveash1; 1 University of Alabama at Birmingham Radiation Oncology, Birmingham, AL, 2University of Alabama at Birmingham Neurosurgery, Birmingham, AL Purpose/Objective(s): To determine the acute toxicity and dosimetric parameters associated with patients enrolled on a phase I pre-operative radiosurgery trial for management of brain metastases.
Volume 87 Number 2S Supplement 2013 of rCBV, rCBF, and rK2trans identified cut-off values with optimal sensitivity and specificity for outcome. Results: rK2trans distinguished PD from response (p Z 0.03). The optimal threshold value, sensitivity, specificity and AUC were 12.8, 69.2%, 63.6% and 67.4%, respectively. rCBF and rCBV at one month discriminated PD from non-PD (p < 0.05 each) with optimal threshold values, sensitivity, specificity and AUC of 2.09, 87.5%, 66.7%, 74.2% and 3.08, 82.8%, 81.8%, 84.3%, respectively. Logistic regression identified decreased rK2trans, absence of prior radiation and steroid administration at one week as early predictors of tumor response (complete or partial response). At one month, only a decrease in rCBV was predictive OF PD. Conclusions: Early changes in rK2trans and rCBV are biomarkers of therapeutic response for brain metastases following radiation. Author Disclosure: A. Sahgal: None. R. Jakubovic: None. R. Milwid: None. A. Eilaghi: None. H. Soliman: None. R.I. Aviv: None.
2175 A Phase 1 Trial of Concurrent Sorafenib and Stereotactic Radiosurgery for Patients With 1-4 Brain Metastases K. Arneson,1 J. Mondshein,2 A.J. Cmelak,1 K. Niermann,1 L. Horn,1 I. Puzanov,1 F. Xia,3 and A. Chakravarthy1; 1Vanderbilt University Medical Center, Nashville, TN, 2University of Pennsylvania, Philadelphia, PA, 3 Ohio State University, Columbus, OH Purpose/Objective(s): Stereotactic radiosurgery (SRS) has been shown to provide high rates of local control for patients with limited brain metastases. However, patients remain at risk for developing new metastases at other brain sites. Preclinical studies suggest that combining angiogenic blockade with radiation may result in increased DNA damage. Sorafenib is an oral multi-kinase inhibitor which targets both tumor proliferation and tumor angiogenesis. We hypothesized that sorafenib when used in combination with SRS will improve target lesion control and intracranial control by treating subclinical disease in the brain. This Phase I study assesses the safety and tolerability of sorafenib (BAY 43-9006) when administered in combination with SRS in the treatment of patients with up to 4 brain metastases. Materials/Methods: Patients 18 years old with histologically confirmed solid tumors and 1-4 brain metastases, ECOG performance status 0-1 with adequate metabolic function were eligible. Exclusion criteria included concurrent chemotherapy, grade 3 hemorrhage within 4 weeks, uncontrolled hypertension, heart failure > NYHA class II, or angina. SRS doses were determined by the number, location, and size of the target lesions. Sorafenib was started 5-7 days prior to SRS and continued for 14 days after SRS. Dose escalation of sorafenib was conducted via a “3 + 3” dose escalation design. A dose limiting toxicity (DLT) was defined as grade 3 neurologic toxicities which are attributable to the combination of sorafenib and SRS. Patients were followed for 1 month after SRS to assess for DLTs. Patients had brain MRIs at 2, 6, and 12 months after SRS to assess for local and regional tumor control. Results: To date, six patients have enrolled. One has completed the entire 1 year study, one died 10 months after enrollment from progressive systemic disease, and four continue to be followed. There were no DLTs at dose level 1 (400 mg per day) nor dose level 2 (400 mg twice a day). There were two grade 3 toxicities (hypertension) and one grade 3 toxicity (rash) both which are known side effects of sorafenib alone. One patient at dose level 2 mistakenly took an inappropriate lower dose of sorafenib and therefore will not be included in the final analysis. Data on radiographic response continues to be collected. Conclusions: The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at doses as high as 400 mg twice a day. No DLTs were encountered. Grade 3 toxicities of rash and hypertension are known systemic side effects of sorafenib and were unrelated to the concurrent use of SRS. Enrollment continues and this study lays the foundation to potentially expand into a Phase II trial to allow formal assessment of intracranial disease response to SRS combined with sorafenib.
Author Disclosure: K. Arneson: None. J. Mondshein: None. A.J. Cmelak: None. K. Niermann: None. L. Horn: None. I. Puzanov: None. F. Xia: None. A. Chakravarthy: None.
2176 Whole Brain Radiation Therapy With Local Simultaneous Integrated Boost Conformal Radiation Therapy in the Treatment for Patients With 1-3 Brain Metastases X. Qiao, Z. Wang, Y. Song, J. Li, X. Zhang, C. Zhen, and Y. Yue; Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, China Purpose/Objective(s): To evaluate the feasibility whole brain radiation therapy (WBRT) with local simultaneous integrated boost conformal radiation therapy (SIB-CR) in the patients with one to three brain metastases. Materials/Methods: Twenty-one patients with one to three brain metastases confirmed by enhanced MRI/CT were prospectively collected and treated by whole brain radiation therapy with local SIB-CR. The prescribed dose of whole brain was 40 Gy/22 fractions and GTV to 55 Gy/ 22 fractions simultaneously in about 4.5 weeks. The acute radiation toxicities were recorded from the start of treatment to four weeks after the end of treatment. The late toxicities were evaluated. The tumor response was evaluated at 4 weeks after the end of radiation therapy. The overall survival (OS) and intracranial progression-free survival (PFS) time were calculated from the day of treatment until death, intracranial progression or the last follow-up date. Results: There were 11 male and 10 female patients in this group. The median age was 52 years (range, 39-72 years). Fourteen patients received radiation therapy alone while 7 cases received chemoradiation therapy. There were 2 patients with complete response, 16 patients with partial response and 3 patients with stable disease. The overall tumor response rate was 85.7% (18/21). The median follow-up time was 7 months (range, 1-12.5 months). To the follow-up cut-off time, five patients were dead, including 3 cases died of intracranial lesions and 2 of unknown causes. The rate of overall brain control was 85.7% (18/21), the local control rate 90.5% (19/21). The overall median survival time was 7 months. The 6month OS and intracranial PFS rates were 76.6% and 61.3%, respectively. The 1-year OS and intracranial PFS rates were 61.3% and 65.6%, respectively. The 1-year survival rate of patients treated with radiation therapy alone and chemoradiation therapy was 69.3% and 85.7%, respectively (p Z 0.253). Multivariate analysis showed that the RPA classification was correlated with survival. Survival rates among the patients with different RPA scores showed that the median survival period of RPA 1, 2 and 3 level were 9, 8 and 5 months, respectively (p Z 0.021). Conclusions: Whole brain irradiation with SIB-CR technique is effective in patients with one to three brain metastases with a higher tumor response and shorter radiation therapy duration and is well tolerated. SIB-CR technique is an effective option for these patients. Author Disclosure: X. Qiao: None. Z. Wang: None. Y. Song: None. J. Li: None. X. Zhang: None. C. Zhen: None. Y. Yue: None.
2177 Phase 1 Dose Escalation/De-escalation Study of Preoperative Stereotactic Radiosurgery for Brain Metastases: Preliminary Acute Toxicity and Dosimetric Analysis G.M. Clark,1 J.G. Stewart,1 B.L. Guthrie,2 J.M. Markert,2 S.A. Spencer,1 K.O. Riley,2 R. Meredith,1 X. Wu,1 R.A. Popple,1 and J.B. Fiveash1; 1 University of Alabama at Birmingham Radiation Oncology, Birmingham, AL, 2University of Alabama at Birmingham Neurosurgery, Birmingham, AL Purpose/Objective(s): To determine the acute toxicity and dosimetric parameters associated with patients enrolled on a phase I pre-operative radiosurgery trial for management of brain metastases.