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Phase I Study of Sorafenib and Whole-liver Radiation Therapy (WLRT) or Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases
Volume 84 Number 3S Supplement 2012 Purpose/Objective(s): To determine the maximally tolerated dose of sorafenib, a tyrosine kinase inhibitor with antiangiogenic properties, delivered pre-, during, and post-SBRT in hepatocellular carcinoma (HCC). Materials/Methods: Eligible patients had advanced HCC not suitable for standard local or regional therapies, with Child-Pugh A liver function. SBRT was delivered in 2 strata: (1) low effective liver volume irradiated (Veff) (<30%, dose range: 39-54 Gy in 6 fractions (fr) over 2 weeks) and (2) High Veff (30%-60%, dose range: 39-54 Gy in 6 fr). Maximal permitted dose to luminal tissue was 31-34 Gy. Study sorafenib was delivered 1 week prior to, during and 4 weeks post SBRT, at which point escalation to full dose sorafenib was permitted. The study sorafenib dose was planned to be escalated in each strata from 400 mg (200 mg po bid) to 600 mg (400 mg po q am and 200 mg po q pm) to 800 mg (400 mg po bid) in a phase I trial design. Dose limiting toxicity (DLT) was defined as grade 4 or 5 related toxicity. Evaluable patients had to receive at least 3 weeks of study dose sorafenib and SBRT and be followed for at least 3 months (mos) without liver PD. Results: Twenty-four patients consented to this study. Eight were screened ineligible, leaving 16 eligible HCC patients who initiated study therapy (4 Low Veff, median dose 51 Gy; 12 High Veff, median dose 33 Gy). Seventy-five percent of patients were BCLC stage C. The majority had main branch portal vein tumor thrombosis. In the low Veff strata, none of 3 evaluable patients treated with SBRT combined with sorafenib 400 mg developed DLT. A fourth patient was not evaluable due to discontinuation of sorafenib after 11 days due to grade 3 thrombocytopenia. The sorafenib dose level was not escalated in this strata due to poor accrual. In the high Veff strata, 2 of 3 evaluable patients treated with sorafenib 400 mg po daily developed DLT (1 grade 3 large bowel bleed 3.5 mo post-SBRT and 1 grade 3 bowel obstruction 3 mos post-SBRT). Two other patients were taken off study prior to SBRT due to liver enzyme increase and tumor rupture after 7 and 3 days of sorafenib respectively. Thus, sorafenib was de-escalated to 200 mg po daily. One of 6 evaluable patients at this dose level developed DLT (tumor rupture, after 5 weeks of sorafenib and SBRT, with death at 8 weeks). Another patient developed grade 3 liver enzymes after 7 days of sorafenib, and was taken off study. Median survival of the 12 evaluable patients in both strata, including those with DLT, was 8.4 mos (range, 2-12.3 mos). Follow-up is ongoing. Conclusions: Low liver Veff (<30%) HCC SBRT delivered concurrently with sorafenib 400 mg po daily appears tolerable. However, in high liver Veff (30-60%) HCC SBRT, 400 mg was not tolerable due to luminal GI toxicity, and sorafenib 200 mg po daily was the maximally tolerated dose. Strategies to reduce toxicity from SBRT and sorafenib are needed. Sequential SBRT followed by sorafenib, rather than a concurrent approach, is recommended. Author Disclosure: L.A. Dawson: E. Research Grant; Bayer. O. Patent/ License Fee/Copyright; Raysearch. A. Brade: E. Research Grant; Bayer. C. Cho: None. J. Kim: None. J. Brierley: None. R. Dinniwell: None. R. Wong: None. J. Ringash: None. B. Cummings: None. J. Knox: None.
25 Outcomes of Stereotactic Radiation Therapy (SRT) for Primary and Metastatic Liver Tumors with 3-D CT and Single Photon Emission Computed Tomography (3D-CT/SPECT) Treatment Planning A.V. Kirichenko, N. Thai, E. Lappinen, O. Gayou, K. Kotinsley, E. Day, and S. Gott; Allegheny General Hospital, Pittsburgh, PA Purpose/Objective(s): SPECT provides functional imaging of the liver parenchyma through the uptake of radioactive colloid by Kupffer cells in proportion to vascular perfusion. We report on outcomes and toxicity of liver SRT/SBRT based on 3D-CT/SPECT treatment planning with conformal avoidance of well-perfused functional normal liver volumes (FNLV). Materials/Methods: Fifty-one patients with unresectable metastatic (36) or primary (15) hepatic tumors (65 target lesions) completed SRT. FNLVs were estimated from 99mTc sulfur colloid SPECT fused with 3D-CT. 4DCT was used to define internal target volume (ITV). Various degrees of FNLV retraction were observed as a result of hepatic cirrhosis, systemic, or intrahepatic chemotherapy. To maximize conformal avoidance of the residual FNLV, total dose and fractionation were adapted to FNLV
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constraints. Dose of 45 Gy (35-60 Gy) was prescribed to the periphery of PTV derived from ITV with 0-10 mm added margins (mean 202 cm3, range 10-2220 cm3) with a mean dose per fraction 6.4 Gy (2.5-12 Gy). When fraction dose was <5 Gy, patients received chronomodulated capecitabine. The influence of the SPECT information on FNLV avoidance was analyzed. Treatment outcomes and toxicity were calculated with a medium follow-up of 14.5 months (3-36 months). Results: SPECT-defined FNLV (20 min acquisition) correlated well with 4D-NLV (p < 0.05) but not with 3D-NLV, reflecting the effect of liver respiratory motion. Overall FNLVs were significantly reduced compared to 4D-CT NLV (p < 0.01) with marked volume contraction observed in patients with Child-Pugh B cirrhosis, those who completed hepatic resections or TACE within 2 months prior to SRT. Treatment planning with incorporated liver SPECT allows significant reduction of FNLVs receiving doses above prescription in patients with HCC compared to 4D-CT volumes receiving doses above prescription (p < 0.01). The effect was not statistically significant for non-HCC patients. The in-field local control rate was 95%, hepatic failure-free survival was 88%, hepatic progression-free survival was 78%, and overall survival was 70%. Twenty-five percent patients with pretreatment normal or abnormal liver function developed grade 2 elevation of liver enzymes with no incidence of “classic” radiation-induced liver disease. None of the patients with hepatic cirrhosis had Child-Pugh score progression. The most common toxicity was grade 2 fatigue. Conclusions: Three-dimensional-SPECT/CT treatment planning allows identification and conformal avoidance of FNLV from high radiation doses facilitating safety of liver SRT in patients with pre-existing liver disease. Outcomes for this selective group are favorable. A prospective phase III trial is required to validate this technique. Author Disclosure: A.V. Kirichenko: None. N. Thai: None. E. Lappinen: None. O. Gayou: None. K. Kotinsley: None. E. Day: None. S. Gott: None.
26 Phase I Study of Sorafenib and Whole-liver Radiation Therapy (WLRT) or Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases A.M. Brade,1 J. Kim,1 J. Brierley,1 R. Dinniwell,1 R. Wong,1 C. Cho,2 Z. Kassam,3 A. Joshua,1 J. Knox,1 and L. Dawson1; 1Princess Margaret Hospital, Toronto, ON, Canada, 2Southlake Cancer Centre, Newmarket, ON, Canada, 3Southlake Cancer Centre, Newmarket, ON, Canada Purpose/Objective(s): SBRT has efficacy in selected patients with liver metastases but out-of-field progression is common despite local control. WLRT can palliate symptoms from diffuse liver metastases, but durable responses are rare. Sorafenib is a tyrosine kinase inhibitor that targets a number of kinases involved in angiogenesis including VEGFR-2/3 and PDGF-b. Preclinical data has suggested improved efficacy of RT in combination with VEGF axis inhibition. Thus, a phase I study evaluating sorafenib combined with SBRT and WLRT in patients with liver metastases was conducted. Materials/Methods: Eligible patients had metastases from solid cancers not suitable for standard local and systemic therapies, Child-Pugh A status, liver enzymes <5x normal, platelets >100,000. RT was delivered in 2 strata: (1) focal SBRT (with doses from 30 to 60 Gy in 6 fractions) and (2) diffuse WLRT (21.6 Gy in 6 fractions). Maximal permitted dose to luminal GI tract was 33 Gy. Sorafenib was dose escalated in each strata from 400 mg (200 mg po bid, level 1) to 600 mg (400 mg po q am and 200 mg po q pm, level 2) to 800 mg (400 mg po bid, level 3) over 4 weeks (pre-, during, and post-RT). Dose limiting toxicity (DLT) was defined as grade 3, 4, or 5 classic or nonclassic radiation induced liver disease (RILD) or any grade 4 or 5 RT-related toxicity. Evaluable patients received at least 75% of the study treatment and were followed for at least 3 months without liver PD. Results: Fifty-three patients consented to participate in this study. Nineteen patients were screened ineligible, and 1 did not initiate therapy, leaving 33 eligible patients who initiated therapy (18 partial liver, 15 whole liver) with the most common diagnoses colon (10) and melanoma (7). In the partial liver SBRT cohort (doses 30 to 54 in 6 fractions, med dose: 42 Gy), no DLT was seen in 15 evaluable patients treated at level 1 (3), level 2 (6), and level 3 (6). One additional patient in level 2 was not evaluable due
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to discontinuation of sorafenib prior to RT due to sorafenib toxicity. Two other patients (1-level 2, 1-level 3) had sorafenib dose reductions to 200 mg daily due to sorafenib toxicity, without DLT. Three patients developed transient grade 3 chest wall pain (1-level 1, 2-level 2). Median survival was 14.0 months. In the WLRT strata, 2 grade 5 liver DLTs were seen: 1 of 6 evaluable patients at level 1, and 1 of 5 evaluable patients at level 2 (2 patients at 2-month follow-up). One grade 3 pneumonitis (level 2) and 1 chest wall pain (level 2) were also seen. Four additional WLRT patients died of other causes during RT (urosepsis, level 1) and at 3-3.5 months from progressive disease. Median survival of WLRT patients was 5.8 months. Conclusions: Full dose sorafenib can be combined safely with SBRT, although chest wall toxicity is increased. Serious toxicity was seen following low dose sorafenib combined with whole liver RT at 21.6 Gy. Author Disclosure: A.M. Brade: None. J. Kim: None. J. Brierley: None. R. Dinniwell: None. R. Wong: None. C. Cho: None. Z. Kassam: None. A. Joshua: None. J. Knox: None. L. Dawson: None.
cholangiocarcinoma harbor unresectable disease. The role of conventional radiation therapy and systemic chemotherapy alone, or in combination, for these patients is limited by poor overall outcomes. We investigated the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in these patients. Materials/Methods: Patients with unresectable, nonmetastatic intrahepatic or hilar cholangiocarcinoma were included in this retrospective study. A multidisciplinary team of Surgeons, and Medical and Radiation oncologists evaluated all patients. Most patients received gemcitabine and cisplatin chemotherapy. Patients received hypofractionated SBRT to their tumor. Three fractions of 8-15 Gy per fraction were delivered in 3 consecutive working days. The doses were determined based on the extent of the tumor and liver tolerance. Patients were followed 1 month after treatment and every 3-4 months thereafter with clinical examination, liver function tests and CT scans. Results: Twenty patients (11 male and 9 female) with 25 lesions were included in this analysis. Of those patients, 10 received prior systemic therapy and 1 had R2 resection. The mean SBRT dose was 30 Gy in 3 fractions. At a median 26 months follow-up one local failure occurred. Overall response consisted of stable disease (SD) in 13 patients, partial response (PR; any decrease in size) in 5 patients and complete response (CR) in 1 patient. Local control (SD, PR or CR) was achieved in 19 of 20 patients with a 93% local control rate. The median overall survival was 17 months. Nine patients failed within the liver but outside of the treatment area, or systemically. The median progression free survival rate was 13 months and the median liver progression free survival was 16 months. Four patients had grade 3 toxicity consisting of duodenal ulceration in 2 patients, cholangitis in 1 patient and a liver abscess in 1 patient. Conclusions: The median survival for advanced intrahepatic and hilar cholangiocarcinoma using current therapies is 6-12 months with most patients who develop liver or systemic failure succumbing to their disease. SBRT offers a short, 3-day treatment that does not interfere with systemic therapy. Our results suggest SBRT may be effective and potentially offer local control which in combination with adequate systemic therapy may lead to improved survival. Author Disclosure: A. Mahadevan: None.
27 Stereotactic Body Radiation Therapy With Ablative Dose on Liver Metastases: Radiation-induced Liver Disease (RILD) and Toxicity Assessment S. Castiglioni,1 A. Tozzi,1 S. Arcangeli,1 P. Mancosu,1 G. Reggiori,1 P. Navarria,1 E. Clerici,1 A. Fogliata,2 L. Cozzi,2 and M. Scorsetti1; 1 Istituto Clinico Humanitas, Rozzano - Milan, Italy, 2Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland Purpose/Objective(s): To assess the safety of high-dose stereotactic body radiation therapy (SBRT) with volumetric modulated arc therapy (VMAT) technique for the treatment of patients with unresectable liver metastases from solid tumors, with special regard on liver function. Materials/Methods: Patients with 1 to 3 unresectable liver metastases with maximum individual tumor diameters less than 6 cm, a Karnofsky Performance Status of at least 70 and life expectancy more than 6 months were enrolled and treated by SBRT on a phase II clinical trial. Dose prescription to mean clinical target volume (CTV) was 75 Gy in 3 consecutive days, with planning target volume (PTV) covered by at least the isodose of 67%, and where possible, this limit on PTV was increased up to 95% of the prescription. When the dose constraints for normal tissues could not be fulfilled, dose reduction up to 30% was allowed. SBRT was administered using VMAT technique by RapidArc, with a flattening filterfree photon beam 10 MV (FFF) and maximum dose rate of 2400 MU/min. Results: Between February 2010 and August 2011, 57 patients with 77 lesions were enrolled in this trial. Among them, 21% had extrahepatic disease at the time of SBRT. Primary tumor sites were colon in 24, breast in 19, bilio-pancreatic in 6, uterus in 5, and others in the remaining 17. Seventyfour (74%) of patients had 1 lesion, 19% and 7% of patients had 2 and 3 lesions, respectively. Sixty-three lesions (82%) were treated with a full dose of 75 Gy. Dose reduction was provided in only 14 lesions to respect the dose constraints. Mean beam-on time was 2.9 1.5 min (range, 1.9-6.2 min). None of the patients experienced grade 3 or higher acute toxicity. Grade 2 acute toxicity, mainly gastrointestinal, occurred in 7 patients (14%). No radiation-induced liver disease (RILD) was detected. Given the short length of follow-up, no data on late toxicity are currently available. Conclusions: Findings suggest that SBRT for unresectable liver metastases is associated with a low incidence of acute toxicity, and can be considered as a safe and noninvasive therapeutic option in this setting. Author Disclosure: S. Castiglioni: None. A. Tozzi: None. S. Arcangeli: None. P. Mancosu: None. G. Reggiori: None. P. Navarria: None. E. Clerici: None. A. Fogliata: None. L. Cozzi: None. M. Scorsetti: None.
28 Stereotactic Body Radiation Therapy for Unresectable Intrahepatic and Hilar Cholangiocarcinoma A. Mahadevan; Beth Israel Deaconess Medical Center, Boston, MA Purpose/Objective(s): Surgery offers the only curative treatment for cholangiocarcinoma; however, many patients with intrahepatic and hilar
29 Stereotactic Body Radiation Therapy (SBRT) for Borderline Resectable and Locally Advanced Pancreatic Cancer is Effective and Well Tolerated M.D. Chuong, C.K. Park, E. Mellon, J.M. Weber, G.M. Springett, P.J. Hodul, M.P. Malafa, S.E. Hoffe, and R. Shridhar; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Purpose/Objective(s): Local control data supports the effectiveness of stereotactic body radiation therapy (SBRT) with minimal toxicity in the setting of locally advanced (LA) pancreatic cancer. This technique can be expanded to include other patient groups, such as those with borderline resectable (BR) with nonmetastatic pancreatic cancer. Materials/Methods: We retrospectively reviewed all nonmetastatic pancreatic cancer patients treated with SBRT delivered in 5 consecutive fractions. Dose painting technique allowed the entire tumor to be treated to a lower dose while simultaneously delivering a higher dose to the region of tumor adjacent to the involved vasculature. Tumor motion resulting from diaphragmatic excursion was accounted for either with abdominal compression or respiratory gating. Patients received chemotherapy prior SBRT, but not concurrently. Those patients who had BR disease were reevaluated for surgical exploration and potential resection. Results: A total of 76 patients were evaluated including 57 with BR (75%) and 17 with LA (22.4%) pancreatic cancer. Two initially resectable patients received SBRT after refusing resection. Most patients (64.5%) received induction GTX (Gemzar, Taxotere, and Xeloda). The median total dose delivered to the region of tumor-vessel abutment was 35 Gy (range, 24-50 Gy) with a median dose per fraction of 7 Gy (range, 5.5-10). Thirtytwo of the BR patients (56.1%) underwent tumor resection after SBRT, with 31 (96.7%) achieving negative surgical margins. Overall median
25 Outcomes of Stereotactic Radiation Therapy (SRT) for Primary and Metastatic Liver Tumors with 3-D CT and Single Photon Emission Computed Tomography (3D-CT/SPECT) Treatment Planning A.V. Kirichenko, N. Thai, E. Lappinen, O. Gayou, K. Kotinsley, E. Day, and S. Gott; Allegheny General Hospital, Pittsburgh, PA Purpose/Objective(s): SPECT provides functional imaging of the liver parenchyma through the uptake of radioactive colloid by Kupffer cells in proportion to vascular perfusion. We report on outcomes and toxicity of liver SRT/SBRT based on 3D-CT/SPECT treatment planning with conformal avoidance of well-perfused functional normal liver volumes (FNLV). Materials/Methods: Fifty-one patients with unresectable metastatic (36) or primary (15) hepatic tumors (65 target lesions) completed SRT. FNLVs were estimated from 99mTc sulfur colloid SPECT fused with 3D-CT. 4DCT was used to define internal target volume (ITV). Various degrees of FNLV retraction were observed as a result of hepatic cirrhosis, systemic, or intrahepatic chemotherapy. To maximize conformal avoidance of the residual FNLV, total dose and fractionation were adapted to FNLV
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constraints. Dose of 45 Gy (35-60 Gy) was prescribed to the periphery of PTV derived from ITV with 0-10 mm added margins (mean 202 cm3, range 10-2220 cm3) with a mean dose per fraction 6.4 Gy (2.5-12 Gy). When fraction dose was <5 Gy, patients received chronomodulated capecitabine. The influence of the SPECT information on FNLV avoidance was analyzed. Treatment outcomes and toxicity were calculated with a medium follow-up of 14.5 months (3-36 months). Results: SPECT-defined FNLV (20 min acquisition) correlated well with 4D-NLV (p < 0.05) but not with 3D-NLV, reflecting the effect of liver respiratory motion. Overall FNLVs were significantly reduced compared to 4D-CT NLV (p < 0.01) with marked volume contraction observed in patients with Child-Pugh B cirrhosis, those who completed hepatic resections or TACE within 2 months prior to SRT. Treatment planning with incorporated liver SPECT allows significant reduction of FNLVs receiving doses above prescription in patients with HCC compared to 4D-CT volumes receiving doses above prescription (p < 0.01). The effect was not statistically significant for non-HCC patients. The in-field local control rate was 95%, hepatic failure-free survival was 88%, hepatic progression-free survival was 78%, and overall survival was 70%. Twenty-five percent patients with pretreatment normal or abnormal liver function developed grade 2 elevation of liver enzymes with no incidence of “classic” radiation-induced liver disease. None of the patients with hepatic cirrhosis had Child-Pugh score progression. The most common toxicity was grade 2 fatigue. Conclusions: Three-dimensional-SPECT/CT treatment planning allows identification and conformal avoidance of FNLV from high radiation doses facilitating safety of liver SRT in patients with pre-existing liver disease. Outcomes for this selective group are favorable. A prospective phase III trial is required to validate this technique. Author Disclosure: A.V. Kirichenko: None. N. Thai: None. E. Lappinen: None. O. Gayou: None. K. Kotinsley: None. E. Day: None. S. Gott: None.
26 Phase I Study of Sorafenib and Whole-liver Radiation Therapy (WLRT) or Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases A.M. Brade,1 J. Kim,1 J. Brierley,1 R. Dinniwell,1 R. Wong,1 C. Cho,2 Z. Kassam,3 A. Joshua,1 J. Knox,1 and L. Dawson1; 1Princess Margaret Hospital, Toronto, ON, Canada, 2Southlake Cancer Centre, Newmarket, ON, Canada, 3Southlake Cancer Centre, Newmarket, ON, Canada Purpose/Objective(s): SBRT has efficacy in selected patients with liver metastases but out-of-field progression is common despite local control. WLRT can palliate symptoms from diffuse liver metastases, but durable responses are rare. Sorafenib is a tyrosine kinase inhibitor that targets a number of kinases involved in angiogenesis including VEGFR-2/3 and PDGF-b. Preclinical data has suggested improved efficacy of RT in combination with VEGF axis inhibition. Thus, a phase I study evaluating sorafenib combined with SBRT and WLRT in patients with liver metastases was conducted. Materials/Methods: Eligible patients had metastases from solid cancers not suitable for standard local and systemic therapies, Child-Pugh A status, liver enzymes <5x normal, platelets >100,000. RT was delivered in 2 strata: (1) focal SBRT (with doses from 30 to 60 Gy in 6 fractions) and (2) diffuse WLRT (21.6 Gy in 6 fractions). Maximal permitted dose to luminal GI tract was 33 Gy. Sorafenib was dose escalated in each strata from 400 mg (200 mg po bid, level 1) to 600 mg (400 mg po q am and 200 mg po q pm, level 2) to 800 mg (400 mg po bid, level 3) over 4 weeks (pre-, during, and post-RT). Dose limiting toxicity (DLT) was defined as grade 3, 4, or 5 classic or nonclassic radiation induced liver disease (RILD) or any grade 4 or 5 RT-related toxicity. Evaluable patients received at least 75% of the study treatment and were followed for at least 3 months without liver PD. Results: Fifty-three patients consented to participate in this study. Nineteen patients were screened ineligible, and 1 did not initiate therapy, leaving 33 eligible patients who initiated therapy (18 partial liver, 15 whole liver) with the most common diagnoses colon (10) and melanoma (7). In the partial liver SBRT cohort (doses 30 to 54 in 6 fractions, med dose: 42 Gy), no DLT was seen in 15 evaluable patients treated at level 1 (3), level 2 (6), and level 3 (6). One additional patient in level 2 was not evaluable due
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to discontinuation of sorafenib prior to RT due to sorafenib toxicity. Two other patients (1-level 2, 1-level 3) had sorafenib dose reductions to 200 mg daily due to sorafenib toxicity, without DLT. Three patients developed transient grade 3 chest wall pain (1-level 1, 2-level 2). Median survival was 14.0 months. In the WLRT strata, 2 grade 5 liver DLTs were seen: 1 of 6 evaluable patients at level 1, and 1 of 5 evaluable patients at level 2 (2 patients at 2-month follow-up). One grade 3 pneumonitis (level 2) and 1 chest wall pain (level 2) were also seen. Four additional WLRT patients died of other causes during RT (urosepsis, level 1) and at 3-3.5 months from progressive disease. Median survival of WLRT patients was 5.8 months. Conclusions: Full dose sorafenib can be combined safely with SBRT, although chest wall toxicity is increased. Serious toxicity was seen following low dose sorafenib combined with whole liver RT at 21.6 Gy. Author Disclosure: A.M. Brade: None. J. Kim: None. J. Brierley: None. R. Dinniwell: None. R. Wong: None. C. Cho: None. Z. Kassam: None. A. Joshua: None. J. Knox: None. L. Dawson: None.
cholangiocarcinoma harbor unresectable disease. The role of conventional radiation therapy and systemic chemotherapy alone, or in combination, for these patients is limited by poor overall outcomes. We investigated the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in these patients. Materials/Methods: Patients with unresectable, nonmetastatic intrahepatic or hilar cholangiocarcinoma were included in this retrospective study. A multidisciplinary team of Surgeons, and Medical and Radiation oncologists evaluated all patients. Most patients received gemcitabine and cisplatin chemotherapy. Patients received hypofractionated SBRT to their tumor. Three fractions of 8-15 Gy per fraction were delivered in 3 consecutive working days. The doses were determined based on the extent of the tumor and liver tolerance. Patients were followed 1 month after treatment and every 3-4 months thereafter with clinical examination, liver function tests and CT scans. Results: Twenty patients (11 male and 9 female) with 25 lesions were included in this analysis. Of those patients, 10 received prior systemic therapy and 1 had R2 resection. The mean SBRT dose was 30 Gy in 3 fractions. At a median 26 months follow-up one local failure occurred. Overall response consisted of stable disease (SD) in 13 patients, partial response (PR; any decrease in size) in 5 patients and complete response (CR) in 1 patient. Local control (SD, PR or CR) was achieved in 19 of 20 patients with a 93% local control rate. The median overall survival was 17 months. Nine patients failed within the liver but outside of the treatment area, or systemically. The median progression free survival rate was 13 months and the median liver progression free survival was 16 months. Four patients had grade 3 toxicity consisting of duodenal ulceration in 2 patients, cholangitis in 1 patient and a liver abscess in 1 patient. Conclusions: The median survival for advanced intrahepatic and hilar cholangiocarcinoma using current therapies is 6-12 months with most patients who develop liver or systemic failure succumbing to their disease. SBRT offers a short, 3-day treatment that does not interfere with systemic therapy. Our results suggest SBRT may be effective and potentially offer local control which in combination with adequate systemic therapy may lead to improved survival. Author Disclosure: A. Mahadevan: None.
27 Stereotactic Body Radiation Therapy With Ablative Dose on Liver Metastases: Radiation-induced Liver Disease (RILD) and Toxicity Assessment S. Castiglioni,1 A. Tozzi,1 S. Arcangeli,1 P. Mancosu,1 G. Reggiori,1 P. Navarria,1 E. Clerici,1 A. Fogliata,2 L. Cozzi,2 and M. Scorsetti1; 1 Istituto Clinico Humanitas, Rozzano - Milan, Italy, 2Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland Purpose/Objective(s): To assess the safety of high-dose stereotactic body radiation therapy (SBRT) with volumetric modulated arc therapy (VMAT) technique for the treatment of patients with unresectable liver metastases from solid tumors, with special regard on liver function. Materials/Methods: Patients with 1 to 3 unresectable liver metastases with maximum individual tumor diameters less than 6 cm, a Karnofsky Performance Status of at least 70 and life expectancy more than 6 months were enrolled and treated by SBRT on a phase II clinical trial. Dose prescription to mean clinical target volume (CTV) was 75 Gy in 3 consecutive days, with planning target volume (PTV) covered by at least the isodose of 67%, and where possible, this limit on PTV was increased up to 95% of the prescription. When the dose constraints for normal tissues could not be fulfilled, dose reduction up to 30% was allowed. SBRT was administered using VMAT technique by RapidArc, with a flattening filterfree photon beam 10 MV (FFF) and maximum dose rate of 2400 MU/min. Results: Between February 2010 and August 2011, 57 patients with 77 lesions were enrolled in this trial. Among them, 21% had extrahepatic disease at the time of SBRT. Primary tumor sites were colon in 24, breast in 19, bilio-pancreatic in 6, uterus in 5, and others in the remaining 17. Seventyfour (74%) of patients had 1 lesion, 19% and 7% of patients had 2 and 3 lesions, respectively. Sixty-three lesions (82%) were treated with a full dose of 75 Gy. Dose reduction was provided in only 14 lesions to respect the dose constraints. Mean beam-on time was 2.9 1.5 min (range, 1.9-6.2 min). None of the patients experienced grade 3 or higher acute toxicity. Grade 2 acute toxicity, mainly gastrointestinal, occurred in 7 patients (14%). No radiation-induced liver disease (RILD) was detected. Given the short length of follow-up, no data on late toxicity are currently available. Conclusions: Findings suggest that SBRT for unresectable liver metastases is associated with a low incidence of acute toxicity, and can be considered as a safe and noninvasive therapeutic option in this setting. Author Disclosure: S. Castiglioni: None. A. Tozzi: None. S. Arcangeli: None. P. Mancosu: None. G. Reggiori: None. P. Navarria: None. E. Clerici: None. A. Fogliata: None. L. Cozzi: None. M. Scorsetti: None.
28 Stereotactic Body Radiation Therapy for Unresectable Intrahepatic and Hilar Cholangiocarcinoma A. Mahadevan; Beth Israel Deaconess Medical Center, Boston, MA Purpose/Objective(s): Surgery offers the only curative treatment for cholangiocarcinoma; however, many patients with intrahepatic and hilar
29 Stereotactic Body Radiation Therapy (SBRT) for Borderline Resectable and Locally Advanced Pancreatic Cancer is Effective and Well Tolerated M.D. Chuong, C.K. Park, E. Mellon, J.M. Weber, G.M. Springett, P.J. Hodul, M.P. Malafa, S.E. Hoffe, and R. Shridhar; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Purpose/Objective(s): Local control data supports the effectiveness of stereotactic body radiation therapy (SBRT) with minimal toxicity in the setting of locally advanced (LA) pancreatic cancer. This technique can be expanded to include other patient groups, such as those with borderline resectable (BR) with nonmetastatic pancreatic cancer. Materials/Methods: We retrospectively reviewed all nonmetastatic pancreatic cancer patients treated with SBRT delivered in 5 consecutive fractions. Dose painting technique allowed the entire tumor to be treated to a lower dose while simultaneously delivering a higher dose to the region of tumor adjacent to the involved vasculature. Tumor motion resulting from diaphragmatic excursion was accounted for either with abdominal compression or respiratory gating. Patients received chemotherapy prior SBRT, but not concurrently. Those patients who had BR disease were reevaluated for surgical exploration and potential resection. Results: A total of 76 patients were evaluated including 57 with BR (75%) and 17 with LA (22.4%) pancreatic cancer. Two initially resectable patients received SBRT after refusing resection. Most patients (64.5%) received induction GTX (Gemzar, Taxotere, and Xeloda). The median total dose delivered to the region of tumor-vessel abutment was 35 Gy (range, 24-50 Gy) with a median dose per fraction of 7 Gy (range, 5.5-10). Thirtytwo of the BR patients (56.1%) underwent tumor resection after SBRT, with 31 (96.7%) achieving negative surgical margins. Overall median