Chemoradiotherapy For Lung Cancer Research Articles

Model development of dose and volume predictors for esophagitis induced during chemoradiotherapy for lung cancer as a step towards radiobiological treatment planning

BackgroundCurrently, radiation therapy treatment planning system intends biological optimization that relies heavily upon plan metrics from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. Implementation and expansion of TCP and NTCP models with alternative data is an important step towards reliable radiobiological treatment planning. In this retrospective single institution study, the treatment charts of 139 lung cancer patients treated with chemo-radiotherapy were reviewed and correlated dosimetric predictors with the incidence of esophagitis and established NTCP model of esophagitis grade 1 and 2 for lung cancer patients.MethodsEsophagus is an organ at risk (OAR) in lung cancer radiotherapy (RT). Esophagitis is a common toxicity induced by RT. In this study, dose volume parameters Vx (Vx: percentage esophageal volume receiving ≥ x Gy) and mean esophagus dose (MED) as quantitative dose-volume metrics, the esophagitis grade 1 and 2 as endpoints, were reviewed and derived from the treatment planning system and the electronic medical record system. Statistical analysis of binary logistic regression and probit were performed to have correlated the probability of grade 1 and 2 esophagitis to MED and Vx. IBM SPSS software version 24 at 5% significant level (α = 0.05) was used in the statistical analysis.ResultsThe probabilities of incidence of grade 1 and 2 esophagitis proportionally increased with increasing the values of Vx and MED. V20, V30, V40, V50 and MED are statistically significant good dosimetric predictors of esophagitis grade 1. 50% incidence probability (TD50) of MED for grade 1 and 2 esophagitis were determined. Lyman Kutcher Burman model parameters, such as, n, m and TD50, were fitted and compared with other published findings. Furthermore, the sigmoid shaped dose responding curve between probability of esophagitis grade 1 and MED were generated respecting to races, gender, age and smoking status.ConclusionsV20, V30, V40 and V50 were added onto Quantitative Analysis of Normal Tissue Effects in the clinic, or QUANTEC group’s dose constrains of V35, V50, V70 and MED. Our findings may be useful as both validation of 3-Dimensional planning era models and also additional clinical guidelines in treatment planning and plan evaluation using radiobiology optimization.

Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation

O-linked β-N-acetyl glucosamine (O-GlcNAc) is at the crossroads of cellular metabolism, including glucose and glutamine; its dysregulation leads to molecular and pathological alterations that cause diseases. Here we report that O-GlcNAc directly regulates de novo nucleotide synthesis and nicotinamide adenine dinucleotide (NAD) production upon abnormal metabolic states. Phosphoribosyl pyrophosphate synthetase 1 (PRPS1), the key enzyme of the de novo nucleotide synthesis pathway, is O-GlcNAcylated by O-GlcNAc transferase (OGT), which triggers PRPS1 hexamer formation and relieves nucleotide product-mediated feedback inhibition, thereby boosting PRPS1 activity. PRPS1 O-GlcNAcylation blocked AMPK binding and inhibited AMPK-mediated PRPS1 phosphorylation. OGT still regulates PRPS1 activity in AMPK-deficient cells. Elevated PRPS1 O-GlcNAcylation promotes tumorigenesis and confers resistance to chemoradiotherapy in lung cancer. Furthermore, Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity. Together, our findings establish a direct connection among O-GlcNAc signals, de novo nucleotide synthesis and human diseases, including cancer and Arts syndrome.

Preclinical evaluation of PEGylated liposomal doxorubicin as an effective radiosensitizer in chemoradiotherapy for lung cancer.

Development of asafe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains amajor goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexinV staining. Aradiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase‑3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in adose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin‑V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as aradiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed alonger half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as aradiosensitizer, supporting its potential clinical development as acomponent of chemoradiotherapy.

OC-0527 Tumour Repopulation Varies Between Sequential vs. Concurrent Chemoradiation in Lung Cancer

OC-0527 Tumour Repopulation Varies Between Sequential vs. Concurrent Chemoradiation in Lung Cancer

Improved adaptive radiotherapy to adjust for anatomical alterations during curative treatment for locally advanced lung cancer.

Anatomical changes during chemoradiation for lung cancer may decrease dose to the target or increase dose to organs at risk. To assess our ability to identify clinically significant anatomical alterations, we followed 67 lung cancer patients by daily cone-beam CT scans to ensure correct patient positioning and observe anatomical alterations. We also re-calculated the original dose distribution on a planned control CT scan obtained halfway during the treatment course to identify anatomical changes that potentially affected doses to the target or organs at risk. Of 66 patients who completed the treatment, 12 patients needed adaptation, two patients were adapted twice. We conclude that daily cone-beam CT and routines at the treatment machine discover relevant anatomical changes during curative radiotherapy for patients with lung cancer without additional imaging.

Phase II Trial of Flaxseed to Prevent Acute Complications after Chemoradiation for Lung Cancer

Background: Thoracic radiotherapy is complicated by acute radiation-induced adverse events such as radiation pneumonitis (RP) and radiation esophagitis (RE). Based on preclinical work and a randomi...

Correlation of Pathological Complete Response With Tumor Volume Reduction During Neoadjuvant Chemoradiotherapy in Lung Cancer.

We retrospectively investigated the relationship between pathological complete response (pCR) and tumor volume (TV) reduction during neoadjuvant chemoradiation therapy (NACRT) in non-small cell lung cancer (NSCLC). We evaluated patients who received NACRT (50 Gy/25 fractions with platinum-doublet) plus surgery for NSCLC. TVs before and during NACRT (TVbefore and TVduring, respectively) were measured based on the sums of the volumes of primary tumors and clinically positive lymph nodes. Relative change in TV was computed as % (TVduring - TVbefore)/TVbefore Results: In total, 31 patients were analyzed. The median of the relative change in TV was - 49% and ranged from -83 to -10%. Postoperatively, pCR was achieved in 11 patients (35%). In multivariate analysis, the relative change in TV was found to be an independent predictor of pCR (p=0.003). TV reduction during NACRT appears to be associated with pCR in NSCLC.

Total proctocolectomy with end ileostomy for acute onset of ulcerative colitis during chemoradiotherapy for lung adenocarcinoma (successfully treated by surgery): a case report

BackgroundUlcerative colitis (UC) developing during chemotherapy is very rare. Here, we describe a case of acute onset during chemoradiotherapy for lung adenocarcinoma, requiring a total proctocolectomy.Case presentationA 52-year-old man was admitted to the hospital for chemoradiotherapy of lung cancer. He had no obvious history of gastrointestinal diseases, and concurrent chemoradiotherapy was initiated. Thirteen days after 2 cycles of cisplatin and vinorelbine, he experienced persistent hematochezia. Findings of the colonoscopy revealed edematous thickening from the rectum to the transverse colon, suggesting UC, drug-induced colitis, or infectious colitis. Results from bacterial culture were negative for Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA). Immunohistological staining for cytomegalovirus was also negative. Although he was clinically diagnosed with UC and treated with intravenous glucocorticoid, his symptoms gradually worsened and an abdominal X-ray revealed megacolon. Thirty-five days after conservative therapy, a total proctocolectomy with end permanent ileostomy was performed. Based on pathological findings and clinical course, he was diagnosed with UC.ConclusionAlthough the pathogenesis of UC during chemotherapy has been unknown, chemotherapy could be one of the causes of UC in this case. UC should be included in the differential diagnosis in patients with progressive colitis during chemotherapy.

Effects of Intravenous GC4419 on the Incidence and Severity of Esophagitis Due to Chemoradiotherapy for Lung Cancer

Effects of Intravenous GC4419 on the Incidence and Severity of Esophagitis Due to Chemoradiotherapy for Lung Cancer

Chemoradiation in Lung Cancer: Effect on Levels of NGAL and Vitamin D in Serum.

Mortality due to lung cancer is one of the growing concerns worldwide. Accurate and timely diagnosis is the key to treatment of this disease. Neutrophil gelatinase associated lipocalin (NGAL) and vitamin D have been found to be associated with cancer and may have potential to act as biomarkers for lung cancer. Serum levels of NGAL and 25 hydroxy vitamin D (25OH vitamin D) were estimated in 25 patients with lung cancer before (Group I) and 4 weeks after standard treatment (Group II) by chemoradiation. The levels were also analyzed in 25 apparently healthy controls and data was compared among different groups using appropriate statistical analysis. NGAL was estimated by enzyme linked immunosorbent assay (ELISA) and 25OH vitamin D by radioimmunoassay (RIA) in the serum samples. Serum NGAL levels were found to be increased significantly in patients before treatment as compared to healthy controls (p < 0.001) while the levels decreased significantly after treatment (p < 0.01). The levels of vitamin D were found to be decreased in lung cancer patients as compared to healthy controls (p < 0.05) while after treatment the levels of vitamin D were found to be significantly increased (p < 0.001). The correlation was not statistically significant between the levels of vitamin D and NGAL in Group I (r = 0.12, p = 0.57), Group IIa (r = 0.037, p = 0.86), and Group IIb (r = 0.091, p = 0.66). Serum NGAL and vitamin D bear the potential to act as biomarkers in patients with lung cancer.

Salvage surgery after definitive chemo-radiotherapy for patients with Non-Small Cell Lung Cancer

IntroductionDespite all treatment advances, lung cancer is still the main cause of death worldwide. Treatment for resectable stage IIIA remains controversial including definitive chemoradiotherapy and induction treatment followed by surgery. After definitive chemoradiation up to 35% of patients will relapse locally. Experience with salvage resection after definitive chemoradiotherapy in lung cancer is limited. We present our experience in 27 patients who underwent surgical resection after definitive treatment. Patients and methodsBetween January 2007 and December 2016, 27 patients were evaluated in our department for surgical resection after receiving definitive chemoradiation treatment in different institutions. We conducted a retrospective study gathering the following data: age, gender, clinical and pathologic stage, histology, chemotherapy treatment regimen, radiotherapy dosage, surgical procedure and complications. Time between surgical resection and last follow-up was used to calculate Overall Survival (OS). Disease-Free Survival (DFS) was calculated from surgical resection to diagnosis of relapse. ResultsMost of the patients were men with a median age of 56.09 years. Median follow-up time was 46.94 months. All patients received platinum-based chemotherapy regimen and high-dose radiotherapy, except for one patient who received 45 Gy. Lobectomy and bilobectomy was performed in 7 patients each, and pneumonectomy in 13. Complications appeared in 5 patients. Bronchopleural fistula appeared in two patients, and only one death in the early postoperative period. The analysis showed an OS of 75.56 months, with 1-year, 3-year and 5-year survival of 74.1%, 57.8% and 53.3% respectively. ConclusionSalvage surgery in selected patients is technically feasible, with low morbidity and mortality rates and good long-term outcomes.

Prediction of 90 Day and Overall Survival after Chemoradiotherapy for Lung Cancer: Role of Performance Status and Body Composition

AimsIf appropriate patients are to be selected for lung cancer treatment, an understanding of who is most at risk of adverse outcomes after treatment is needed. The aim of the present study was to identify predictive factors for 30 and 90 day mortality after chemoradiotherapy (CRT), and factors that were prognostic for overall survival. Materials and methodsA retrospective cohort study of 194 patients with lung cancer who had undergone CRT in South East Scotland from 2008 to 2010 was undertaken. Gender, age, cancer characteristics, weight loss, body mass index (BMI), performance status (Eastern Cooperative Oncology Group; ECOG) and computed tomography-derived body composition variables were examined for prognostic significance using Cox's proportional hazards model and logistic regression. ResultsThe median overall survival was 19 months (95% confidence interval 16.3, 21.7). Four of 194 patients died within 30 days of treatment completion, for which there were no independent predictive variables; 22/194 (11%) died within 90 days of treatment completion. BMI < 20 and ECOG performance status ≥2 were independent predictors of death within 90 days of treatment completion (P = 0.001 and P = 0.004, respectively). Patients with either BMI < 20 or ECOG performance status ≥ 2 had an odds ratio of death within 90 days of 5.97 (95% confidence interval 2.20, 16.19), rising to an odds ratio of 13.27 (1.70, 103.47) for patients with both BMI < 20 and ECOG performance status ≥ 2. Patients with low muscle attenuation had significantly reduced overall survival (P = 0.004); individuals with low muscle attenuation had a median survival of 15.2 months (95% confidence interval 12.7, 17.7) compared with 23.0 months (95% confidence interval 18.3, 27.8) for those with high muscle attenuation, equating to a hazard ratio of death of 1.62 (95% confidence interval 1.17, 2.23, P = 0.003). ConclusionPoor performance status, low BMI and low muscle attenuation identify patients at increased risk of premature death after CRT. Risk factors for adverse outcomes should inform personalised discussions with patients about the potential harms as well as the intended benefits of treatment.

P3.06-004 A Systematic Review of Outcome Reporting in Studies of Radical Radiotherapy and Chemoradiotherapy in Lung Cancer: Topic: Clinical Studies

Clinical decision making in lung oncology is informed by evidence about the risks and benefits of proposed treatments, alongside other important factors including clinician experience and patient preference. There is no consensus about which outcome measures are most meaningful to patients or informative for clinicians. Measures relating to disease response and survival are common, but it is not known which specific measures are most favored, how consistently they are defined, and how frequently domains such as quality of life are represented. A systematic review of EMBASE, COCHRANE and MEDLINE was conducted. Prospective studies of radical radiotherapy or chemoradiotherapy for lung cancer published during 2013-2016 were included, where clinically-relevant outcomes (including patient-reported outcomes) were reported. Individual outcomes were recorded and categorized. Frequency of outcomes, reported definitions and consistency of reporting both within and between studies were examined. Study quality was assessed against UK national standards. 29 papers met the full inclusion criteria. 124 separate outcome measures were reported, within which, 68 distinct outcomes were identified. 47/124 outcome measures were defined or referenced. None were defined consistently between studies. 3 papers described an outcome measure in their Methods but did not report it in their Results. 24/29 papers reported outcomes not introduced in their Methods. One paper included patient-reported outcome measures. No short-term outcome measures (such as 30 or 90 day mortality) were reported. This systematic review has highlighted significant variation in practice in outcome measure reporting in studies of radical lung cancer treatments. A large number of different outcome measures were reported, the majority of which weren’t defined. Where apparently identical outcome measures were reported in more than one study, definitions were inconsistent. Outcome measures relating to short-term survival were not reported at all, despite the fact that long-term survival in this patient population was uncommon. Only one study included patient-reported outcome measures. If lung cancer research is to optimally inform clinical decision making, study endpoints should reflect outcomes that are most meaningful to patients and their clinicians. Variation in outcome-reporting practice, particularly where definitions are lacking and inconsistent, is a significant concern. It threatens the ability of clinicians to assimilate the findings from multiple studies and limits the extent to which the true benefits and burdens of proposed treatments can be understood. Consideration should be given as to whether a core outcome set, incorporating clinically meaningful and patient-reported outcomes, might be warranted in lung cancer. Further research is needed.

Prospective Assessment of Demographic Characteristics Associated With Worse Health-Related Quality of Life Measures Following Definitive Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer

Background The purpose of this study was to evaluate baseline demographic characteristics which may be associated with worse health related quality of life (HRQOL) for patients with locally advanced non-small cell lung cancer (NSCLC) receiving definitive chemoradiation (CRT). Materials Patients with NSCLC were prospectively enrolled on an Institutional Review Board-approved clinical trial between 2009 and 2012. HRQOL assessments were collected pre-radiation therapy (RT), during RT, and within 3 months post-RT using Euroqol (EQ-5D), MD Anderson Symptom Inventory (MDASI), and Functional Assessment of Cancer Therapy General (FACT-G). HRQOL correlation was assessed with categorical variables by Wilcoxon rank sum tests and with continuous variables by Pearson correlation. P<0.05 was defined as statistically significant. Results Forty-three consecutive patients received definitive concurrent CRT and completed assessments at one or more time-points. Patients most commonly had stage IIIB disease (72%), were married or with a partner (70%) and Caucasian (91%). Median patient age was 65 (range: 39-79) years and Charlson comorbidity index (CCI) was 0 (range: 0-5). Female gender, African-American ethnicity, age, chemotherapy type, baseline hemoglobin, and CCI were associated with worse post-treatment HRQOL measures. Conclusions We have identified novel characteristics associated with worse quality of life following definitive CRT for lung cancer. Patients at risk for worse post-treatment quality of life may benefit from earlier follow-up and greater supportive measures following treatment.

Increased Posttreatment Neutrophil-to-Lymphocyte Ratio Is an Independent Prognostic Marker for Worse Overall Survival in Patients Receiving Concurrent Chemoradiation for Lung Cancer

Increased Posttreatment Neutrophil-to-Lymphocyte Ratio Is an Independent Prognostic Marker for Worse Overall Survival in Patients Receiving Concurrent Chemoradiation for Lung Cancer

Increased Pretreatment Neutrophil-to-Lymphocyte Ratios and Platelet-to-Lymphocyte Ratios are Independent Prognostic Markers for Worse Overall Survival in Patients Receiving Concurrent Chemoradiation for Lung Cancer

Increased Pretreatment Neutrophil-to-Lymphocyte Ratios and Platelet-to-Lymphocyte Ratios are Independent Prognostic Markers for Worse Overall Survival in Patients Receiving Concurrent Chemoradiation for Lung Cancer

PO-0675: Early detection of normal tissue complications using FDG PET/CT during lung cancer chemoradiotherapy

PO-0675: Early detection of normal tissue complications using FDG PET/CT during lung cancer chemoradiotherapy

Low Elderly Participation in Non-Small Cell Lung Cancer Clinical Trials

Background: Lung cancer, with a median age at diagnosis of 70 years, is the current leading cause of cancer mortality in the United States. A lack of elderly enrollment in lung cancer clinical trials, however, has led to difficulty establishing elderly guidelines for treatment and has been highlighted by the Institute of Medicine and the American Society of Clinical Oncology as a key area for improvement. While there have been few elderly-specific clinical trials investigating chemoradiotherapy in lung cancer, there have been no elderly-specific trials investigating targeted therapy or immunotherapy and little is known about elderly outcomes with these agents. Methods: PubMed was queried for phase I clinical trials involving non-small cell lung cancer (NSCLC) in English in the past five years. Of these 192 studies, 49 investigated targeted therapy and/or immunotherapy without protocolized chemoradiotherapy. These articles were reviewed and assessed based on age demographics and outcomes. Results: Twelve percent of studies had a mean/median age of 65-69 years; no studies had a mean/median age of 70 years or greater. Of the seven studies with published information on age distribution, only four had information regarding the percentage of participants 70 years or older, which ranged from 8-33% and was limited by a total sample size of 15-26. The few studies that published information on age-specific outcomes suggested that targeted therapy and immunotherapy in the elderly may be as well tolerated and have similar treatment outcomes, but were limited by the small number of elderly participants in these trials. Conclusion: Additional research involving elderly enrollment and outcomes in NSCLC clinical trials is warranted. Increased recruitment of the elderly in clinical trials and publication of elderly-specific outcomes in lung cancer research is key to improving treatment guidelines in this field.

A Retrospective Study of Risk Factors for Radiation Pneumonitis of Definitive Chemoradiotherapy for the Treatment of Locally Advanced Lung Cancer By Emphysema Quantification

ABSTRACT Aim: Radiation pneumonitis (RP) is one of the most crucial adverse events of definitive chemoradiotherapy for the treatment of locally advanced lung cancer. Although chronic obstructive pulmonary disease (COPD) is considered as one of the risk factors of RP, the relationship between RP and pulmonary emphysema (PE) that is a subtype of COPD is not clear. We examined the clinical backgrounds of patients experiencing RP due to concurrent chemodadiotherapy for the treatment of locally advanced lung cancer and evaluated risk factors. Methods: We retrospectively examined patients with locally advanced lung cancer who underwent definitive chemoradiotherapy between Janary 2010 and December 2012. For quantitative assessments of PE, percentage of low attenuation volumes (%LAV) and mean density (MD) were computationally calculated by using AZE Virtual place Fujin (Tokyo). Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 was used to evaluate RP. We evaluated the relationship between clinical backgrounds, the degree of emphysema (%LAV, MD), radiation dose (the percentage of pulmonary volume irradiated to >20Gy (V20), mean lung dose (MLD)) and RP. Results: 33 patients were analyzed, of which 19 (58%) had symptomatic RP (>= Grade2) and 14 (42%) had asymptomatic RP (=Grade1). Age, sex, pathology and stage in patients were similar between both groups. There is no significant difference in forced expiratory volume in 1 second (FEV1) between the symptomatic group and the asymptomatic group (2.23 + -0.60L vs 2.35 + -0.50L, P = 0.296). The symtomatic group had significantly more severe PE (LAV% 10.9 + -8.7% MD -880 ± 21HU) than the asymptomatic group (LAV% 4.4 + -4.0% (P = 0.025), MD -856 + -24 HU (P = 0.002)), respectively. Radiation dose was significantly higher in the symptomatic group (V20 24.6 + -5.1%, MLD 12.9 + -3.4Gy) than the asymptomatic group ((V20 19.9 + -3.3% (P = 0.005), MLD 9.1 + -3.2Gy (P = 0.002)). Conclusions: Severity of emphysma appears to be a factor that can be used to predict RP after concurrent chemoradiotherapy for lung cancer. Disclosure: All authors have declared no conflicts of interest.

142 Concurrent chemoradiation for lung cancer in a North of England population – are we managing toxicities appropriately?

142 Concurrent chemoradiation for lung cancer in a North of England population – are we managing toxicities appropriately?