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Pulsed Radiation Therapy Maintains Tumor Oxygenation in a Murine Model of Head and Neck Squamous Cell Carcinoma
International Journal of Radiation Oncology Biology Physics
S194 Digital Poster Abstract 1086; Table Impact of HPV status and pre-RT primary tumor SUVmax ( versus > 14) on FFR Group I II III IV
Description HPV+ Pre-RT HPV+ Pre-RT HPVPre-RT HPVPre-RT
Primary Tumor SUV 14 Primary Tumor SUV > 14 Primary Tumor SUV 14 Primary Tumor SUV > 14
5-year FFR 97% 77% 37% 25%
post-RT P-SUVmax lost significance (HR Z 0.53, 95% CI Z 0.16-1.8, p Z NS). Conclusions: Despite a modest data-set size, this report suggests a dominant prognostic impact of HPV status over PET SUVmax values on overall clinical outcome in patients with SCC-OP. Nevertheless, pre-RT PSUVmax may prove valuable to further stratify HPV+ SCC-OP patients and guide the future design of treatment de-intensification strategies. The interplay of these important prognostic factors will be further defined using large prospective databases. Author Disclosure: P. Mohindra: None. N. Ibrahim: None. S. Barasch: None. H. Geye: None. D.T. Yang: None. S.B. Perlman: None. T.M. McCulloch: None. G.K. Hartig: None. P.M. Harari: None.
1087 Pulsed Radiation Therapy Maintains Tumor Oxygenation in a Murine Model of Head and Neck Squamous Cell Carcinoma J.L. Wobb,1 S.A. Krueger,2 J. Kane,2,3 I.S. Grills,1,3 G. Wilson,2 and B. Marples2; 1Department of Radiation Oncology, Beaumont Health System, Royal Oak, MI, 2Department of Radiation Biology, Beaumont Health System, Royal Oak, MI, 3Oakland University School of Medicine, Rochester, MI Purpose/Objective(s): Despite multimodal therapy, local recurrence for advanced head and neck squamous cell carcinoma (HNSCC) remains high with overall 5-year survival of about 50%. Tumor hypoxia has been identified as a significant source of radioresistance and is associated with poor clinical outcomes. The aim of this study was to determine if tumor response and radiation-induced hypoxia are altered following fractionated standard radiation therapy (SRT) or pulsed radiation therapy (PRT) in murine xenograft model of HNSCC. Materials/Methods: Subcutaneous xenografts were established in female NIH III HO mice using a HNSCC cell line (UT14). Tumors grew to 300500 mm3 before a sub-curative 20 Gy total dose (2 Gy/day) was delivered via SRT or PRT. SRT was continuously-delivered and PRT was given as 10 x 0.2 Gy pulses separated by 3 minutes. 18F-FDG (n Z 68) and 18FFMISO (n Z 42) PET/CT scans were acquired pre-, mid-, and posttreatment using a trimodality system. The tumor maximum standardized uptake value (SUVmax) for each scan was calculated and normalized to pre-treatment values. Sixteen animals were treated and tumors allowed to regrow to 2000 mm3 (n Z 8/RT scheme). Twelve additional animals (n Z 6/RT scheme) were treated with SRT or PRT to 10 Gy or 20 Gy and sacrificed immediately for histological hypoxia analysis. Animal experiments were conducted with the approval and oversight of Institutional IACUC. Results: Analysis of individual tumor regrowth demonstrated that PRT and SRT were equally effective (w31 days growth inhibition for both SRT and PRT). 18FMISO PET imaging indicated a significant increase in the level of hypoxia following SRT treatment when compared to PRT (normalized SUVmax PRT Z 1.55, SRT Z 0.96, p-value Z 0.03). Furthermore, a sizeable increase in hypoxia was noted only in tumors undergoing SRT (pvalue Z 0.04). 18FDG imaging data was less conclusive, although there was a significant increase in FDG tumor SUVmax at 10 Gy in the SRT
group (p-value Z 0.01). Histological analysis of pimonidazole stained tumor samples mimicked 18FMISO imaging data, showing an increase in hypoxia in SRT tumors but not PRT tumors. Ongoing immunohistochemical studies are examining vascular markers to search for the mechanism behind the stabilization of tumor oxygenation levels following PRT. A second study using a more hypoxic HNSCC mouse model (UT15) is currently underway and preliminary data support the conclusions from the UT14 tumors. Conclusions: A significant increase in tumor hypoxia was seen following SRT but not PRT. Overall these data suggest that pulsed radiation therapy may be associated with lower levels of treatment-induced tumor hypoxia, which may translate to better tumor control and improved overall survival in patients given curative treatments. Author Disclosure: J.L. Wobb: None. S.A. Krueger: None. J. Kane: None. I.S. Grills: None. G. Wilson: None. B. Marples: None.
1088 Validation of a Radiosensitivity Gene Signature in Radiation TherapyeTreated Patients From The Cancer Genome Atlas (TCGA) J. Meng1 and S. Fu2; 1Sixth People’s Hospital of Jiao Tong University Shanghai, China, 2Fudan University Cancer Center, Shanghai, China Purpose/Objective(s): Gene expression signature for predicting radiosensitivity has been developed to subclassify tumor characteristics. Recently, a radiosensitivity gene signature, which includes 31 genes derived by integrating four different microarray experiments, has been found to have a potential for predicting radiosensitivity of cancer cells, but it was seldom validated in clinical cancer samples. In our study, we proposed that the gene signature may serve as a predictive biomarker for estimating the overall survival of radiation-treated patients. The significance of gene signature was tested in independent datasets with The Cancer Genome Atlas (TCGA), which is the most powerful cancer information database in the world. Materials/Methods: We downloaded the mRNA expression profiling of the 16 different cancer types and corresponding clinical information from TCGA. After filtering out cancer types without radiation therapy information or insufficient clinical survival information, the 31 gene signature was applied to three independent datasets: glioblastoma multiforme (GBM), low-grade glioma (LGG), and head and neck squamous cell carcinoma (HNSCC). There were a total of 708 samples treated with radiation therapy, including 465 patients with GBM, 92 patients with HNSCC, and 151 patients with LGG, respectively. The patients were stratified into radiosensitive (RS) and radioresistant (RR) groups according to the abovementioned 31-gene signature. The Kaplan-Meier method was used to estimate survival time and multivariate analysis was carried out using Cox proportional hazard model. Results: All the RT-treated patients were stratified into radiosensitive (RS) and radioresistant (RR) groups according to radiosensitivity gene signature. Patients assigned to RS group had an improved overall survival compared with RR group in GBM (median survival days: RS vs RR, 562 d vs 448 d, p Z 0.001, HR Z 1.568, 95% CI Z 1.207-2.038) and HNSCC (median survival days: RS vs RR, 3314 d vs 2318 d, p Z 0.004, HR Z 3.960, 95% CI Z 1.447-10.833) cohorts. The gene radiosensitivity gene signature has been proved to be an independent predictor, when considering age, KPS, molecular subtype, and additional chemotherapy as covariates for GBM (p Z 0.015), and age and pathologic stage for HNSCC (p Z 0.020). No significant difference of survival time was observed between the predicted RS and RR patients with LGG (p Z 0.128). Conclusions: This is the first study to use a radiosensitivity gene signature model to predict radiation-treated patients’ prognostic in three independent cohorts from TCGA. Although promising, this model needed to be further clinically validated in the routine diagnostic of GBM and HNSCC for an optimal treatment decision. Author Disclosure: J. Meng: None. S. Fu: A. Employee; Fudan University Cancer Center, Shanghai, China. E. Research Grant; (YG2012ZD02, 2JC1407400) from Shanghai Jiaotong University and the Science and
S194 Digital Poster Abstract 1086; Table Impact of HPV status and pre-RT primary tumor SUVmax ( versus > 14) on FFR Group I II III IV
Description HPV+ Pre-RT HPV+ Pre-RT HPVPre-RT HPVPre-RT
Primary Tumor SUV 14 Primary Tumor SUV > 14 Primary Tumor SUV 14 Primary Tumor SUV > 14
5-year FFR 97% 77% 37% 25%
post-RT P-SUVmax lost significance (HR Z 0.53, 95% CI Z 0.16-1.8, p Z NS). Conclusions: Despite a modest data-set size, this report suggests a dominant prognostic impact of HPV status over PET SUVmax values on overall clinical outcome in patients with SCC-OP. Nevertheless, pre-RT PSUVmax may prove valuable to further stratify HPV+ SCC-OP patients and guide the future design of treatment de-intensification strategies. The interplay of these important prognostic factors will be further defined using large prospective databases. Author Disclosure: P. Mohindra: None. N. Ibrahim: None. S. Barasch: None. H. Geye: None. D.T. Yang: None. S.B. Perlman: None. T.M. McCulloch: None. G.K. Hartig: None. P.M. Harari: None.
1087 Pulsed Radiation Therapy Maintains Tumor Oxygenation in a Murine Model of Head and Neck Squamous Cell Carcinoma J.L. Wobb,1 S.A. Krueger,2 J. Kane,2,3 I.S. Grills,1,3 G. Wilson,2 and B. Marples2; 1Department of Radiation Oncology, Beaumont Health System, Royal Oak, MI, 2Department of Radiation Biology, Beaumont Health System, Royal Oak, MI, 3Oakland University School of Medicine, Rochester, MI Purpose/Objective(s): Despite multimodal therapy, local recurrence for advanced head and neck squamous cell carcinoma (HNSCC) remains high with overall 5-year survival of about 50%. Tumor hypoxia has been identified as a significant source of radioresistance and is associated with poor clinical outcomes. The aim of this study was to determine if tumor response and radiation-induced hypoxia are altered following fractionated standard radiation therapy (SRT) or pulsed radiation therapy (PRT) in murine xenograft model of HNSCC. Materials/Methods: Subcutaneous xenografts were established in female NIH III HO mice using a HNSCC cell line (UT14). Tumors grew to 300500 mm3 before a sub-curative 20 Gy total dose (2 Gy/day) was delivered via SRT or PRT. SRT was continuously-delivered and PRT was given as 10 x 0.2 Gy pulses separated by 3 minutes. 18F-FDG (n Z 68) and 18FFMISO (n Z 42) PET/CT scans were acquired pre-, mid-, and posttreatment using a trimodality system. The tumor maximum standardized uptake value (SUVmax) for each scan was calculated and normalized to pre-treatment values. Sixteen animals were treated and tumors allowed to regrow to 2000 mm3 (n Z 8/RT scheme). Twelve additional animals (n Z 6/RT scheme) were treated with SRT or PRT to 10 Gy or 20 Gy and sacrificed immediately for histological hypoxia analysis. Animal experiments were conducted with the approval and oversight of Institutional IACUC. Results: Analysis of individual tumor regrowth demonstrated that PRT and SRT were equally effective (w31 days growth inhibition for both SRT and PRT). 18FMISO PET imaging indicated a significant increase in the level of hypoxia following SRT treatment when compared to PRT (normalized SUVmax PRT Z 1.55, SRT Z 0.96, p-value Z 0.03). Furthermore, a sizeable increase in hypoxia was noted only in tumors undergoing SRT (pvalue Z 0.04). 18FDG imaging data was less conclusive, although there was a significant increase in FDG tumor SUVmax at 10 Gy in the SRT
group (p-value Z 0.01). Histological analysis of pimonidazole stained tumor samples mimicked 18FMISO imaging data, showing an increase in hypoxia in SRT tumors but not PRT tumors. Ongoing immunohistochemical studies are examining vascular markers to search for the mechanism behind the stabilization of tumor oxygenation levels following PRT. A second study using a more hypoxic HNSCC mouse model (UT15) is currently underway and preliminary data support the conclusions from the UT14 tumors. Conclusions: A significant increase in tumor hypoxia was seen following SRT but not PRT. Overall these data suggest that pulsed radiation therapy may be associated with lower levels of treatment-induced tumor hypoxia, which may translate to better tumor control and improved overall survival in patients given curative treatments. Author Disclosure: J.L. Wobb: None. S.A. Krueger: None. J. Kane: None. I.S. Grills: None. G. Wilson: None. B. Marples: None.
1088 Validation of a Radiosensitivity Gene Signature in Radiation TherapyeTreated Patients From The Cancer Genome Atlas (TCGA) J. Meng1 and S. Fu2; 1Sixth People’s Hospital of Jiao Tong University Shanghai, China, 2Fudan University Cancer Center, Shanghai, China Purpose/Objective(s): Gene expression signature for predicting radiosensitivity has been developed to subclassify tumor characteristics. Recently, a radiosensitivity gene signature, which includes 31 genes derived by integrating four different microarray experiments, has been found to have a potential for predicting radiosensitivity of cancer cells, but it was seldom validated in clinical cancer samples. In our study, we proposed that the gene signature may serve as a predictive biomarker for estimating the overall survival of radiation-treated patients. The significance of gene signature was tested in independent datasets with The Cancer Genome Atlas (TCGA), which is the most powerful cancer information database in the world. Materials/Methods: We downloaded the mRNA expression profiling of the 16 different cancer types and corresponding clinical information from TCGA. After filtering out cancer types without radiation therapy information or insufficient clinical survival information, the 31 gene signature was applied to three independent datasets: glioblastoma multiforme (GBM), low-grade glioma (LGG), and head and neck squamous cell carcinoma (HNSCC). There were a total of 708 samples treated with radiation therapy, including 465 patients with GBM, 92 patients with HNSCC, and 151 patients with LGG, respectively. The patients were stratified into radiosensitive (RS) and radioresistant (RR) groups according to the abovementioned 31-gene signature. The Kaplan-Meier method was used to estimate survival time and multivariate analysis was carried out using Cox proportional hazard model. Results: All the RT-treated patients were stratified into radiosensitive (RS) and radioresistant (RR) groups according to radiosensitivity gene signature. Patients assigned to RS group had an improved overall survival compared with RR group in GBM (median survival days: RS vs RR, 562 d vs 448 d, p Z 0.001, HR Z 1.568, 95% CI Z 1.207-2.038) and HNSCC (median survival days: RS vs RR, 3314 d vs 2318 d, p Z 0.004, HR Z 3.960, 95% CI Z 1.447-10.833) cohorts. The gene radiosensitivity gene signature has been proved to be an independent predictor, when considering age, KPS, molecular subtype, and additional chemotherapy as covariates for GBM (p Z 0.015), and age and pathologic stage for HNSCC (p Z 0.020). No significant difference of survival time was observed between the predicted RS and RR patients with LGG (p Z 0.128). Conclusions: This is the first study to use a radiosensitivity gene signature model to predict radiation-treated patients’ prognostic in three independent cohorts from TCGA. Although promising, this model needed to be further clinically validated in the routine diagnostic of GBM and HNSCC for an optimal treatment decision. Author Disclosure: J. Meng: None. S. Fu: A. Employee; Fudan University Cancer Center, Shanghai, China. E. Research Grant; (YG2012ZD02, 2JC1407400) from Shanghai Jiaotong University and the Science and