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Postinduction Inflammatory Status Predicts Complete Pathologic Response in Non-Small Cell Lung Cancer Patients Undergoing Induction Chemoradiation Therapy
Poster Viewing Abstracts S665
Volume 90 Number 1S Supplement 2014
3151 Autoantibodies Against p16 Protein-Derived Peptides Predict Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy W. Wang,1 J. Wei,2 and W. Zhong1; 1Department of Radiation Oncology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China, 2Department of Diabetes & Cardiovascular Science, University of the Highlands & Islands, Centre for Health Science, Inverness, United Kingdom Purpose/Objective(s): The p16 protein, a cyclin-dependent kinase inhibitor, has been found to be significantly increased in patients with nonsmall cell lung cancer (NSCLC). Our previous study demonstrated that circulating autoantibody to p16 protein-derived peptides (anti-p16) may be a useful biomarker with prognostic values for NSCLC. Variations of humoral immune response to tumor related antigen can partly explain that normal tissue tolerance to radiation therapy varies by individual. This study aimed to examine the association between the levels of circulating anti-p16 and radiation pneumonitis (RP) in patients with NSCLC treated with radiation therapy (RT). Materials/Methods: Patients with stage I-III NSCLC who received definitive chemo-RT were eligible to this prospective study. Patients were seen weekly during-RT, and then 1, 3, 6, 12 and 24 months after RT. RP grading was based on CTC AE3.0 criteria of pneumonitis. The primary endpoint was defined as RP grade 2 related to radiation therapy. Plasma samples for testing were extracted from whole blood which was collected before commencement of treatment. The bioinformatics database and software were used to analyze p16 protein structures and characters. Based on in silico mapping of MHC restricted epitopes derived from these proteins, linear antigen fragments were then designed; the linear peptide antigens were synthesized with a chemical method and an ELISA test was then developed in-house to detect circulating anti-p16. All samples were tested in duplicate and quality control was performed with pooled plasma samples collected from >200 healthy blood donors. The association between the levels of anti-p16 and RP were assessed by Cox proportional hazards model. Kaplan-Meier was used to evaluate the effect of anti-p16 on RP. Results: 86 consecutive patients were enrolled in this study. 8 patients were excluded from final analysis due to palliative RT dose (<60 Gy). 78.2% patients underwent concurrent or sequential platinum-based chemotherapy. The minimum follow-up duration was 12 months for surviving patients and the median follow-up time was 13.2 (7.8-16.5) months. All the ELISA assay reproducibility met the criteria of quality control. Among clinical factors analyzed, mean lung dose (MLD) (p Z 0.016) was significant independent factors predicting RP. Association analysis showed that higher levels of anti-p16 were significantly associated with lower risk of RP (hazard ratio, 0.64, 95% confidence interval, 0.11-0.86, p Z 0.033), adjusted for age, gender, smoking, V20, MLD, and chemotherapy. Conclusions: This study suggests that anti-p16 can have a potential in serving as a biomarker for RP of patients with NSCLC treated with radiation therapy. Larger sample size studies are needed to confirm our findings. Author Disclosure: W. Wang: None. J. Wei: None. W. Zhong: None.
3152 Postinduction Inflammatory Status Predicts Complete Pathologic Response in Non-Small Cell Lung Cancer Patients Undergoing Induction Chemoradiation Therapy Y. Chen, E. Ziel, P. Bonomi, M. Batus, M. Fidler, M. Liptay, W. Warren, G. Chmielewski, and D. Sher; Rush University Medical Center, Chicago, IL Purpose/Objective(s): Preoperative chemoradiation (CRT) followed by surgical resection may improve loco-regional control and progression free survival in non-small cell lung cancer (NSCLC) patients. We investigated prognostic factors in patients treated with tri-modality therapy.
Materials/Methods: The cohort was comprised of all newly-diagnosed patients with non-metastatic, locally advanced NSCLC treated with chemoradiation therapy followed by surgery between 2004 and 2013 with complete blood count data before CRT and/or surgery. Pre-treatment and post-CRT neutrophil-to-lymphocyte ratio (NLR) was calculated and divided into quartiles: the highest quartile was designated as high NLR. The probability of pathologic complete response (PCR) was compared between patients with and without high NLR and compared with Fisher’s exact test. Overall survival was assessed using the logrank test for univariable analysis and Cox regression for multivariable analysis. Results: A total of 87 patients were included in this analysis. With a median follow-up for surviving patients of 43.7 months (interquartile range [IQR] 25.5-59.5 months), the median, 3- and 5-year survival probabilities were 68 months, 59%, and 52%, respectively. Twenty-two patients (26%) developed a PCR. The median (interquartile range, IQR) values for preCRT NLR (preRT-NLR) and pre-surgery NLR (preS-NLR) were 3.07 (2.18-4.57) and 3.52 (2.79-5.44), respectively. There was no association between high preRT-NLR and PCR, but a strong association between high preS-NLR and PCR (32.3% PCR vs 4.8% with lower and high preS-NLR, respectively, p Z 0.01). On multivariable analysis, adenocarcinoma histology, clinical T stage, and either continuous preRT-NLR (hazard ratio [HR] 1.24 per 1 point increase, p Z 0.0018) or preS-NLR (HR 1.08, p Z 0.0081) were significant negative prognostic factors. When dichotomizing as high NLR or not, preRT-NLR was significantly associated with inferior survival (HR 2.12, p Z 0.047) , whereas there was a weak trend for preSNLR (HR 1.86, p Z 0.12). Conclusions: A simple assessment of the systemic inflammatory state may have predictive and prognostic power in patients undergoing trimodality therapy for locally advanced NSCLC. Additional research is necessary to determine whether the NLR reflects tumor-host biology or it is a marker of confounding comorbid conditions. Author Disclosure: Y. Chen: None. E. Ziel: None. P. Bonomi: None. M. Batus: None. M. Fidler: None. M. Liptay: None. W. Warren: None. G. Chmielewski: None. D. Sher: None.
3153 Radiation Dose-Volume Effect in Lung: A Functional SubunitseBased Normal Tissue Complication Probability Model and Its Application to 3DCRT and SBRT Y. Fan; Baystate Health Systems, Inc., Springfield, MA Purpose/Objective(s): To develop a Normal Tissue Complication Probability (NTCP) model to describe the dose-volume effect in radiation treatment of lung which goes beyond the usual DVH reduction parameters such as MLD, V20 and takes into account the whole DVH and related biological equivalent dose distribution. To apply the model to clinical data of radiation pneumonitis (RP) rates in both 3DCRT and SBRT. Materials/Methods: The clinical RP rate data of whole lung irradiation summarized by QUANTEC with correspondent equivalent dose in 2 Gy fractions (EQD2) were used to obtain the parameters of a functional subunits (FSU) based NTCP model. The mean FSU damage was calculated with EQD2 distributions and fractionations in typical 3DCRT and SBRT. The NTCP was obtained through the cumulative binomial probability of the inactivation of certain amount of FSUs within the lung. The calculated NTCPs were compared with the published clinical data of RP rates in 3DCRT and SBRT. Results: The model relates well the calculated NTCP to the clinical data of RP rate of both 3DCRT and SBRT. The FSU damage curve has a damagesensitive dose range of around 20-30 Gy (EQD2). This makes the single dose-volume parameters such as V20, V30 useful for RP estimation in 2 Gy fractionation treatments and causes the hypofractionation (with same EQD2 to tumor) to be less toxic than traditional 2 Gy fractionation for higher prescribed tumor dose because hypofractionation decreases the volume of the lower EQD2 region in the lung. Quantitative results from EQD2 -Volume-Histograms give w15% NTCP for typical 3DCRT with 60 Gy in 30 fractions when V20w30% and w20% NTCP for typical SBRT
Volume 90 Number 1S Supplement 2014
3151 Autoantibodies Against p16 Protein-Derived Peptides Predict Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy W. Wang,1 J. Wei,2 and W. Zhong1; 1Department of Radiation Oncology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China, 2Department of Diabetes & Cardiovascular Science, University of the Highlands & Islands, Centre for Health Science, Inverness, United Kingdom Purpose/Objective(s): The p16 protein, a cyclin-dependent kinase inhibitor, has been found to be significantly increased in patients with nonsmall cell lung cancer (NSCLC). Our previous study demonstrated that circulating autoantibody to p16 protein-derived peptides (anti-p16) may be a useful biomarker with prognostic values for NSCLC. Variations of humoral immune response to tumor related antigen can partly explain that normal tissue tolerance to radiation therapy varies by individual. This study aimed to examine the association between the levels of circulating anti-p16 and radiation pneumonitis (RP) in patients with NSCLC treated with radiation therapy (RT). Materials/Methods: Patients with stage I-III NSCLC who received definitive chemo-RT were eligible to this prospective study. Patients were seen weekly during-RT, and then 1, 3, 6, 12 and 24 months after RT. RP grading was based on CTC AE3.0 criteria of pneumonitis. The primary endpoint was defined as RP grade 2 related to radiation therapy. Plasma samples for testing were extracted from whole blood which was collected before commencement of treatment. The bioinformatics database and software were used to analyze p16 protein structures and characters. Based on in silico mapping of MHC restricted epitopes derived from these proteins, linear antigen fragments were then designed; the linear peptide antigens were synthesized with a chemical method and an ELISA test was then developed in-house to detect circulating anti-p16. All samples were tested in duplicate and quality control was performed with pooled plasma samples collected from >200 healthy blood donors. The association between the levels of anti-p16 and RP were assessed by Cox proportional hazards model. Kaplan-Meier was used to evaluate the effect of anti-p16 on RP. Results: 86 consecutive patients were enrolled in this study. 8 patients were excluded from final analysis due to palliative RT dose (<60 Gy). 78.2% patients underwent concurrent or sequential platinum-based chemotherapy. The minimum follow-up duration was 12 months for surviving patients and the median follow-up time was 13.2 (7.8-16.5) months. All the ELISA assay reproducibility met the criteria of quality control. Among clinical factors analyzed, mean lung dose (MLD) (p Z 0.016) was significant independent factors predicting RP. Association analysis showed that higher levels of anti-p16 were significantly associated with lower risk of RP (hazard ratio, 0.64, 95% confidence interval, 0.11-0.86, p Z 0.033), adjusted for age, gender, smoking, V20, MLD, and chemotherapy. Conclusions: This study suggests that anti-p16 can have a potential in serving as a biomarker for RP of patients with NSCLC treated with radiation therapy. Larger sample size studies are needed to confirm our findings. Author Disclosure: W. Wang: None. J. Wei: None. W. Zhong: None.
3152 Postinduction Inflammatory Status Predicts Complete Pathologic Response in Non-Small Cell Lung Cancer Patients Undergoing Induction Chemoradiation Therapy Y. Chen, E. Ziel, P. Bonomi, M. Batus, M. Fidler, M. Liptay, W. Warren, G. Chmielewski, and D. Sher; Rush University Medical Center, Chicago, IL Purpose/Objective(s): Preoperative chemoradiation (CRT) followed by surgical resection may improve loco-regional control and progression free survival in non-small cell lung cancer (NSCLC) patients. We investigated prognostic factors in patients treated with tri-modality therapy.
Materials/Methods: The cohort was comprised of all newly-diagnosed patients with non-metastatic, locally advanced NSCLC treated with chemoradiation therapy followed by surgery between 2004 and 2013 with complete blood count data before CRT and/or surgery. Pre-treatment and post-CRT neutrophil-to-lymphocyte ratio (NLR) was calculated and divided into quartiles: the highest quartile was designated as high NLR. The probability of pathologic complete response (PCR) was compared between patients with and without high NLR and compared with Fisher’s exact test. Overall survival was assessed using the logrank test for univariable analysis and Cox regression for multivariable analysis. Results: A total of 87 patients were included in this analysis. With a median follow-up for surviving patients of 43.7 months (interquartile range [IQR] 25.5-59.5 months), the median, 3- and 5-year survival probabilities were 68 months, 59%, and 52%, respectively. Twenty-two patients (26%) developed a PCR. The median (interquartile range, IQR) values for preCRT NLR (preRT-NLR) and pre-surgery NLR (preS-NLR) were 3.07 (2.18-4.57) and 3.52 (2.79-5.44), respectively. There was no association between high preRT-NLR and PCR, but a strong association between high preS-NLR and PCR (32.3% PCR vs 4.8% with lower and high preS-NLR, respectively, p Z 0.01). On multivariable analysis, adenocarcinoma histology, clinical T stage, and either continuous preRT-NLR (hazard ratio [HR] 1.24 per 1 point increase, p Z 0.0018) or preS-NLR (HR 1.08, p Z 0.0081) were significant negative prognostic factors. When dichotomizing as high NLR or not, preRT-NLR was significantly associated with inferior survival (HR 2.12, p Z 0.047) , whereas there was a weak trend for preSNLR (HR 1.86, p Z 0.12). Conclusions: A simple assessment of the systemic inflammatory state may have predictive and prognostic power in patients undergoing trimodality therapy for locally advanced NSCLC. Additional research is necessary to determine whether the NLR reflects tumor-host biology or it is a marker of confounding comorbid conditions. Author Disclosure: Y. Chen: None. E. Ziel: None. P. Bonomi: None. M. Batus: None. M. Fidler: None. M. Liptay: None. W. Warren: None. G. Chmielewski: None. D. Sher: None.
3153 Radiation Dose-Volume Effect in Lung: A Functional SubunitseBased Normal Tissue Complication Probability Model and Its Application to 3DCRT and SBRT Y. Fan; Baystate Health Systems, Inc., Springfield, MA Purpose/Objective(s): To develop a Normal Tissue Complication Probability (NTCP) model to describe the dose-volume effect in radiation treatment of lung which goes beyond the usual DVH reduction parameters such as MLD, V20 and takes into account the whole DVH and related biological equivalent dose distribution. To apply the model to clinical data of radiation pneumonitis (RP) rates in both 3DCRT and SBRT. Materials/Methods: The clinical RP rate data of whole lung irradiation summarized by QUANTEC with correspondent equivalent dose in 2 Gy fractions (EQD2) were used to obtain the parameters of a functional subunits (FSU) based NTCP model. The mean FSU damage was calculated with EQD2 distributions and fractionations in typical 3DCRT and SBRT. The NTCP was obtained through the cumulative binomial probability of the inactivation of certain amount of FSUs within the lung. The calculated NTCPs were compared with the published clinical data of RP rates in 3DCRT and SBRT. Results: The model relates well the calculated NTCP to the clinical data of RP rate of both 3DCRT and SBRT. The FSU damage curve has a damagesensitive dose range of around 20-30 Gy (EQD2). This makes the single dose-volume parameters such as V20, V30 useful for RP estimation in 2 Gy fractionation treatments and causes the hypofractionation (with same EQD2 to tumor) to be less toxic than traditional 2 Gy fractionation for higher prescribed tumor dose because hypofractionation decreases the volume of the lower EQD2 region in the lung. Quantitative results from EQD2 -Volume-Histograms give w15% NTCP for typical 3DCRT with 60 Gy in 30 fractions when V20w30% and w20% NTCP for typical SBRT