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Phase I Trial of Radiation Dose Escalation in Patients with Locally Advanced Hepatocellular Carcinoma: an Interim Report
Proceedings of the 50th Annual ASTRO Meeting
31
Validation of Randomization Based on Patient Genotype Results from RTOG 9704 Trial in Pancreatic Cancer and Implications for Future Trial Design
J. J. Farrell1, K. Bae2, M. Fromm3, W. Regine4, R. Abrams5, H. Safran6, J. P. Hoffman7, A. P. Dicker8, H. Elsaleh9 1
Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, 2Department of Statistics, Radiation Therapy Oncology Group, Philadelphia, PA, 3University of Utah, Salt Lake City, UT, 4University of Maryland, Baltimore, MD, 5Rush University, Chicago, IL, 6Brown University, Providence, RI, 7Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA, 8Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 9Australian National University, Canberra, Australia Purpose/Objective(s): In a prospective randomized trial effective randomization of patients, using baseline clinical and demographic features is an essential factor in assessing trial efficacy and reducing bias in treatment outcomes. Single nucleotide polymorphisms (SNPs) reflect inter-individual variation in patient genotype and have been associated with differences in treatment response and toxicity. We sought to determine if differences in patient genotypes between treatment arms in RTOG 9704 might reveal potential study biases. Materials/Methods: RTOG 9704 randomized 538 patients after pancreatic resection to receive 5FU based chemoradiation preceded and followed by either gemcitabine or 5-FU chemotherapy. The addition of gemcitabine to adjuvant chemoradiation was associated with a non-significant survival benefit and increased, but clinically unimportant, toxicity. 800 SNP genotypes from 120 genes important in pancreatic cancer pathogenesis, prognosis and therapy were determined. SNPs with minor allele frequencies (MAF) \0.05 and patients with more than 30% missing genotype were excluded. The Hardy Weinberg Equilibrium assumption was checked by Fisher’s exact test. We adjusted p value cutoffs to address multiple testing problems. Logistic regression was used for testing the genotype difference for each SNP between the two arms with and without adjusting other covariates. The likelihood-ratio test statistic was used to test null hypothesis of no association between a SNP genotype and treatment arms. All testing was two-sided and was done at a significance level of 0.05. Results: 800 SNPs from 229 RTOG 9704 were determined. There were no significant differences in clinical baseline demographic clinical, pathologic features or outcome between patients with SNP genotype data and those without. There were 359 SNPs whose MAF were less than 0.05 and excluded, leaving 441 SNPs for analysis. 12 SNPs deviated from HWE in the combined treatment arms. Four hundred twenty nine SNPs that meet HWE were analyzed separately. For all 429 SNPs, there is no difference with respect to the distribution of the genotypes of any SNP and the assigned treatment arm. Conclusions: To our knowledge this is the first analysis in a randomized prospective clinical trial to demonstrate effective randomization of patients between treatment arms based on patient genotypes. It is unlikely that the trend towards improved survival or the increased toxicity in the gemcitabine treatment arm in this study can be accounted for by differences in the patient genotype. It is possible that patient genotype could be used as a method to quantify statistical power and confirm effective randomization in future prospective randomized studies. Author Disclosure: J.J. Farrell, None; K. Bae, None; M. Fromm, None; W. Regine, None; R. Abrams, None; H. Safran, None; J.P. Hoffman, None; A.P. Dicker, None; H. Elsaleh, None.
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Phase I Trial of Radiation Dose Escalation in Patients with Locally Advanced Hepatocellular Carcinoma: an Interim Report
J. Zhao, Z. Ren, G. Jiang Fudan University Cancer Hospital, Shanghai, China Purpose/Objective(s): To determine the maximum tolerated dose (MTD) of 3-dimensional conformal radiation therapy (3-DCRT)/intensity modulated radiation therapy (IMRT) for locally advanced hepatocellular carcinoma (HCC). Materials/Methods: Patient eligibility for the study was: HCC confirmed by cytology or histology, solitary intrahepatic lesion, medical inoperable or technical unresectable, hepatic function of Child-Pugh A, and tolerable to active breath coordinator (ABC). The patients were divided into 2 subgroups: tumor diameter more than 5 cm and less than 10 cm (Group 1) and larger than 10 cm (Group 2). The starting radiation doses were the total tumor doses of 42 Gy and 40 Gy in 2 Gy per fractions for Group 1 and 2, respectively. Escalation was achieved by increasing the tumor dose of each cohort in increments of 4.0 Gy. Subsequent cohorts received higher doses up to a chosen maximum of 62 Gy for group 1 and 52 Gy for group 2. Dose constrains were: (1) Liver: Mean dose to normal liver was limited to 23 Gy or less, and the dose volume histogram (DVH) of the normal liver was in the tolerable area: V5 of\86%, V10 of\68%, V15 of \59%, V20 of\49%, V25 of\35%, V30 of\28%, V35 of\25%, and V40 of\20%; (2) Stomach and duodenum: point dose was limited to \50 Gy; (3) Spinal cord: point dose was \50Gy. Dose-limiting toxicity (DLT) was defined as acute Grade $3 liver or gastrointestinal toxicity, or late complication of radiation-induced liver disease (RILD), which would occur in 4 months after irradiation. There would be 4 patients in each dose level. The next dose level would not be started until 4 patients in the previous dose level were demonstrated no DLT. If one patient experienced DLT, an extra 4 patients would be added to that dose level. Once $2 patients developed DLT (2/8), the dose escalation was terminated. Results: From April 2005 to February 2008, 32 patients had been enrolled (28 male, 4 female): median age, 52 years (range, 33-68 years). No patient experienced any DLT, and doses were escalated to 58 Gy for Group 1 and 48 Gy for Group 2. The maximum dose level cohort of both groups is accruing the patients. Conclusions: The radiation dose was safely escalated in HCC patients by using 3D-CRT/IMRT and ABC to 58 Gy for patients with tumor diameter less than 10 cm and 48 Gy for tumor diameter equal or more than 10 cm under strict normal liver DVH constraints. MTD has not been reached yet. Author Disclosure: J. Zhao, None; Z. Ren, None; G. Jiang, None.
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Final Results of a Phase I Whole-Liver Radiation Dose Escalation Trial using Amifostine as a Radioprotector
C. C. Pan, W. D. Ensminger, S. C. Walker, L. D. Olson, D. P. Normolle, E. Ben-Josef, T. S. Lawrence University of Michigan Health Systems, Ann Arbor, MI Purpose/Objective(s): We have previously shown, in a series of phase I/II studies, that high-dose radiation therapy is effective for focal liver involvement. However, normal liver tolerance limits effective irradiation of the whole liver. Amifostine is a prodrug
S15
31
Validation of Randomization Based on Patient Genotype Results from RTOG 9704 Trial in Pancreatic Cancer and Implications for Future Trial Design
J. J. Farrell1, K. Bae2, M. Fromm3, W. Regine4, R. Abrams5, H. Safran6, J. P. Hoffman7, A. P. Dicker8, H. Elsaleh9 1
Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, 2Department of Statistics, Radiation Therapy Oncology Group, Philadelphia, PA, 3University of Utah, Salt Lake City, UT, 4University of Maryland, Baltimore, MD, 5Rush University, Chicago, IL, 6Brown University, Providence, RI, 7Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA, 8Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 9Australian National University, Canberra, Australia Purpose/Objective(s): In a prospective randomized trial effective randomization of patients, using baseline clinical and demographic features is an essential factor in assessing trial efficacy and reducing bias in treatment outcomes. Single nucleotide polymorphisms (SNPs) reflect inter-individual variation in patient genotype and have been associated with differences in treatment response and toxicity. We sought to determine if differences in patient genotypes between treatment arms in RTOG 9704 might reveal potential study biases. Materials/Methods: RTOG 9704 randomized 538 patients after pancreatic resection to receive 5FU based chemoradiation preceded and followed by either gemcitabine or 5-FU chemotherapy. The addition of gemcitabine to adjuvant chemoradiation was associated with a non-significant survival benefit and increased, but clinically unimportant, toxicity. 800 SNP genotypes from 120 genes important in pancreatic cancer pathogenesis, prognosis and therapy were determined. SNPs with minor allele frequencies (MAF) \0.05 and patients with more than 30% missing genotype were excluded. The Hardy Weinberg Equilibrium assumption was checked by Fisher’s exact test. We adjusted p value cutoffs to address multiple testing problems. Logistic regression was used for testing the genotype difference for each SNP between the two arms with and without adjusting other covariates. The likelihood-ratio test statistic was used to test null hypothesis of no association between a SNP genotype and treatment arms. All testing was two-sided and was done at a significance level of 0.05. Results: 800 SNPs from 229 RTOG 9704 were determined. There were no significant differences in clinical baseline demographic clinical, pathologic features or outcome between patients with SNP genotype data and those without. There were 359 SNPs whose MAF were less than 0.05 and excluded, leaving 441 SNPs for analysis. 12 SNPs deviated from HWE in the combined treatment arms. Four hundred twenty nine SNPs that meet HWE were analyzed separately. For all 429 SNPs, there is no difference with respect to the distribution of the genotypes of any SNP and the assigned treatment arm. Conclusions: To our knowledge this is the first analysis in a randomized prospective clinical trial to demonstrate effective randomization of patients between treatment arms based on patient genotypes. It is unlikely that the trend towards improved survival or the increased toxicity in the gemcitabine treatment arm in this study can be accounted for by differences in the patient genotype. It is possible that patient genotype could be used as a method to quantify statistical power and confirm effective randomization in future prospective randomized studies. Author Disclosure: J.J. Farrell, None; K. Bae, None; M. Fromm, None; W. Regine, None; R. Abrams, None; H. Safran, None; J.P. Hoffman, None; A.P. Dicker, None; H. Elsaleh, None.
32
Phase I Trial of Radiation Dose Escalation in Patients with Locally Advanced Hepatocellular Carcinoma: an Interim Report
J. Zhao, Z. Ren, G. Jiang Fudan University Cancer Hospital, Shanghai, China Purpose/Objective(s): To determine the maximum tolerated dose (MTD) of 3-dimensional conformal radiation therapy (3-DCRT)/intensity modulated radiation therapy (IMRT) for locally advanced hepatocellular carcinoma (HCC). Materials/Methods: Patient eligibility for the study was: HCC confirmed by cytology or histology, solitary intrahepatic lesion, medical inoperable or technical unresectable, hepatic function of Child-Pugh A, and tolerable to active breath coordinator (ABC). The patients were divided into 2 subgroups: tumor diameter more than 5 cm and less than 10 cm (Group 1) and larger than 10 cm (Group 2). The starting radiation doses were the total tumor doses of 42 Gy and 40 Gy in 2 Gy per fractions for Group 1 and 2, respectively. Escalation was achieved by increasing the tumor dose of each cohort in increments of 4.0 Gy. Subsequent cohorts received higher doses up to a chosen maximum of 62 Gy for group 1 and 52 Gy for group 2. Dose constrains were: (1) Liver: Mean dose to normal liver was limited to 23 Gy or less, and the dose volume histogram (DVH) of the normal liver was in the tolerable area: V5 of\86%, V10 of\68%, V15 of \59%, V20 of\49%, V25 of\35%, V30 of\28%, V35 of\25%, and V40 of\20%; (2) Stomach and duodenum: point dose was limited to \50 Gy; (3) Spinal cord: point dose was \50Gy. Dose-limiting toxicity (DLT) was defined as acute Grade $3 liver or gastrointestinal toxicity, or late complication of radiation-induced liver disease (RILD), which would occur in 4 months after irradiation. There would be 4 patients in each dose level. The next dose level would not be started until 4 patients in the previous dose level were demonstrated no DLT. If one patient experienced DLT, an extra 4 patients would be added to that dose level. Once $2 patients developed DLT (2/8), the dose escalation was terminated. Results: From April 2005 to February 2008, 32 patients had been enrolled (28 male, 4 female): median age, 52 years (range, 33-68 years). No patient experienced any DLT, and doses were escalated to 58 Gy for Group 1 and 48 Gy for Group 2. The maximum dose level cohort of both groups is accruing the patients. Conclusions: The radiation dose was safely escalated in HCC patients by using 3D-CRT/IMRT and ABC to 58 Gy for patients with tumor diameter less than 10 cm and 48 Gy for tumor diameter equal or more than 10 cm under strict normal liver DVH constraints. MTD has not been reached yet. Author Disclosure: J. Zhao, None; Z. Ren, None; G. Jiang, None.
33
Final Results of a Phase I Whole-Liver Radiation Dose Escalation Trial using Amifostine as a Radioprotector
C. C. Pan, W. D. Ensminger, S. C. Walker, L. D. Olson, D. P. Normolle, E. Ben-Josef, T. S. Lawrence University of Michigan Health Systems, Ann Arbor, MI Purpose/Objective(s): We have previously shown, in a series of phase I/II studies, that high-dose radiation therapy is effective for focal liver involvement. However, normal liver tolerance limits effective irradiation of the whole liver. Amifostine is a prodrug
S15