Locally Advanced Non-small Cell Lung Cancer Patients Research Articles

Pneumonectomy after induction chemoradiotherapy for locally advanced non-small cell lung cancer: should curative intent pulmonary resection be avoided?

We conducted a retrospective analysis to assess the practicality of pneumonectomy, especially after concurrent induction chemoradiotherapy (i-CRT), for locally advanced non-small cell lung cancer (LA-NSCLC). The operative risks vs. the survival benefit of this procedure for such patients is a subject of controversy. The subjects of this retrospective study were 71 consecutive LA-NSCLC patients with cStage IIIA-C NSCLC, who underwent i-CRT followed by curative intent pulmonary resection between February, 2001 and March, 2013. Thirty-two patients underwent pneumonectomy (group P) and 39 patients underwent lobectomy (group L). In group P, 17 (54.8%) patients underwent right pneumonectomy. There was no 30-day postoperative mortality in either group and no significant difference in 90-day postoperative mortality between the groups (3.1% vs. 2.6% in groups P and L, respectively). The 5-year overall survival (OS) rate was 58.7% (95% CI: 41.5-75.9%) in group P and 57.3% (95% CI 41.2-73.4%) in group L, without a significant difference between the groups. Our findings suggest that i-CRT followed by pneumonectomy is feasible, with a similar survival benefit to lobectomy. Thus, pneumonectomy after i-CRT should not be avoided as it is a potentially curative intent strategy for carefully selected patients.

Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer

PurposeStudies have associated increased radiation therapy (RT) heart dose with cardiac toxicity. Others have correlated RT-related immunosuppression with worsened survival. Given the large vascular volumes irradiated during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized an association between increased heart dose and immunosuppression. MethodsWe identified 400 LA-NSCLC patients treated with definitive RT ± chemotherapy between 2001 and 2016. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil-to-lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and post-RT. Multivariable analysis (MVA) was performed to correlate Clinical factors with both hematologic toxicity and overall survival. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables. ResultsMedian follow up was 17 months (range 0.2–174 months) in all patients and 46 months (range 0.2–161 months) in survivors. A total of 94% of patients had stage III disease and 77% received concurrent chemo radiation. Two-year overall survival (OS), freedom from local recurrence (FFLR), and freedom from distant metastases (FFDM) was 42%, 60% and 45%, respectively. Median survival was 18 months. On MVA for OS (n = 207), male gender (Hazard Ratio [HR] 1.7; 95% CI 1.2–2.3), RT alone (HR 2.1; 95% CI 1.9–4.0), the percentage of heart receiving ≥50 Gy (V50) (HR 1.02; 95% CI 1.01–1.03), and higher NLR at 4 months (HR 1.02, 95% CI 1.01–1.03) were associated with reduced OS. ALC nadir was not associated with treatment outcomes. NLR >10.5 was associated with decreased OS (p < 0.001) and decreased FFDM (p = 0.04). On MVA evaluating factors associated with hematological toxicity (n = 247), adjuvant chemotherapy (HR 2.6; 95% CI 1.3–5.0; p = 0.006), RT alone (HR 3.6; 95% CI 1.1–12; p = 0.04), and heart V50 >25% (HR 2.0; 95% CI 1.1–3.5; p = 0.02) were associated with a NLR >10.5 4 months post-RT. ConclusionRT related immunosuppression is associated with worse patient outcomes, and may represent a source of increased mortality beyond cardiac toxicity alone.

(P37) Radiation-Induced Immunosuppression in Locally Advanced Non-Small Cell Lung Cancer: Another Cardiac Toxicity?

Recent reports have associated increased radiation therapy (RT) dose to the heart with higher rates of cardiac toxicity. Other reports have correlated RT-related immunosuppression with worsened survival in patients with solid malignancies. Given the large vascularized volumes exposed to RT during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized that there is an association between increased heart dose and immunosuppression. A total of 400 LA-NSCLC patients with follow up laboratory values treated at a single institution with definitive intent RT +/- chemotherapy between 2001-2016 were identified. Organs at risk were reviewed and re-contoured according to the RTOG 0617 cardiac secondary analysis atlas. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil to lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and at 2 and 4 months post-RT start. Patient, tumor, treatment, and dosimetric factors were correlated with hematologic toxicity and treatment outcomes. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables and identify cutpoints for hematologic values as a predictor of mortality. The median follow up was 17 (range 0.2-174) months in all patients and 46 (range 0.2-161) months in survivors. Patients received a median dose of 66 Gy (range 50-75.25 Gy) in median 2 Gy (range 1.8-2.5 Gy) fractions delivered with IMRT in 41% of patients. The estimated median overall survival (OS) was 17.9 months and progression free survival (PFS) 12.8 months. The estimated 5 year freedom from local recurrence (FFLR) and freedom from distant metastasis (FFDM) were 49% and 34%, respectively. There were 331/363 (91%) cases of ≥ grade 3 lymphopenia and 129/362 (36%) ≥ grade 4 lymphopenia at the nadir. At 4 months after RT start (290 patients), the median ALC, ANC, and NLR were 600 cells/mm3 (range: 100-4600), 4700 cells/mm3 (range: 300-113,600), and 7.2 (range: 0.60-259), respectively. On multivariable analysis, male gender (Hazard Ration [HR] 1.66; 95% CI 1.20-2.29; p=0.02), RT alone (HR 2.08; 95% CI 1.9-3.96; p=0.026), heart V50 (HR 1.02; 95% CI 1.01-1.03; p<0.001), and higher NLR at 4 months (HR 1.015, 95% CI 1.005-1.025; p=0.002) were significantly associated with worse OS. An upper tertile cutpoint of NLR > 10.5 at 4 months post RT, was associated with decreased OS (p<0.001) and decreased FFDM (p=0.04). The median OS stratified by NLR > 10.5 and NLR ≤ 10.5 was 11 months and 24 months, respectively (p < 0.001). NLR > 10.5 was associated with worse FFDM (p=0.04) and was borderline for PFS (p=0.08). On multivariable analysis, CRT with adjuvant chemotherapy (HR 2.55; 95% CI 1.30-4.98; p=0.006), RT alone (HR 3.56; 95% CI 1.07-11.88; P=0.039), and heart V50 > 25% (HR 1.98; 95% CI 1.11-3.54; p=0.021) were associated with an NLR>10.5 at 4 months post-RT. Higher RT dose to the heart is associated with increased immunosuppression and worse tumor control, and may represent an additional actionable cause of increased mortality beyond cardiac toxicity alone.

(P39) Novel Use of Machine Learning for Predicting Radiation Pneumonitis in Locally Advanced Stage II-III Non-Small Cell Lung Cancer

Radiation pneumonitis (RP) is a common and radiotherapy dose-limiting toxicity for locally-advanced non-small cell lung cancer (LA-NSCLC). Prior studies have proposed relevant dosimetric constraints in order to limit this toxicity. We incorporate machine learning techniques in order to perform additional in-depth analyses of contributing factors to the development of RP in order to uncover previously unidentified criteria, establish more discrete and robust dosimetric criteria, and the elucidate the relative importance of individual factors. Utilizing a cohort of 203 consecutive stage II-III LA-NSCLC patients treated with definitive chemoradiation at our institution from 2008-2016, we evaluated 32 continuous and categorical features per patient grouped into risk factors, comorbidities, pretreatment imaging, stage, histology, radiation treatment, chemotherapy, and dosimetry utilizing a novel machine learning algorithm to identify predictive features for the development of RP. Univariate analysis was performed using optimally trained decision stumps to determine statistically significant features and their corresponding RP thresholds. Multivariate analysis was carried out using Mediboost for feature selection. MediBoost is a novel patient stratification tool that builds decision trees with optimal accuracy comparable to less-interpretable ensemble methods commonly used in the literature. Patients were treated to a median dose of 66.6 Gy in 1.8 Gy fractions. 17.7% patients developed grade ≥3 RP. On univariate analysis, lung dosimetric factors of lung mean, lung V10, and lung V20 were found to be the significant RP predictors with the greatest balance of specificity and sensitivity. On multivariate analysis, using the MediBoost algorithm, esophagus max (61.5%) and lung V20 (30.5%) were the two most common primary differentiators of RP, with lung mean and esophagus mean important secondary RP differentiators. We highlight the utility of a novel machine learning algorithm and demonstrate its ability to both identify known and novel predictors for the development of symptomatic RP. We provide interpretable decision trees using MediBoost that can aid clinicians in decision optimization regarding mitigation of RP and demonstrate the potential utility of our machine learning techniques for future studies.

Exploring Radiotherapy Targeting Strategy and Dose: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for StageIIINSCLC.

Concurrent chemoradiotherapy (CRT) is standard therapy for locally advanced NSCLC (LA-NSCLC) patients. This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on patient survival. We collected individual patient data from 3600LA-NSCLC patients participating in 16 cooperative group trials of concurrent CRT. The primary TRT parameters examined included field design strategy (elective nodal irradiation [ENI] compared to involved-field TRT (IF-TRT)), total dose, and biologically effective dose (BED). Hazard ratios (HRs) for overall survival were calculated with univariable and multivariable Cox models. TRT doses ranged from 60 Gy to 74 Gy with most treatments administered once-daily. ENI was associated with poorer survival than IF-TRT (univariable HR= 1.37, 95% confidence interval [CI]: 1.24-1.51, p < 0.0001; multivariable HR= 1.31, 95% CI: 1.08-1.59, p= 0.002). The median survival times of the IF and ENI patients were 24 months and 16 months, respectively. Patients were divided into three dose groups: low total dose (60 Gy), medium total dose (>60 Gy to 66 Gy), and high total dose (>66 Gy to 74 Gy). With reference to the low-dose group, the multivariable HRs were 1.08 for themedium-dose group (95% CI: 0.93-1.25) and 1.12 for the high-dose group (95% CI: 0.97-1.30).The univariate p= 0.054 and multivariable p= 0.17. BED was grouped as follows: low (<55.5 Gy10), medium (55.5 Gy10), or high (>55.5 Gy10). With reference to the low-BED group, the HR was 1.00 (95% CI: 0.85-1.18) for the medium-BEDgroup and 1.10 (95% CI: 0.93-1.31) for the high-BEDgroup. The univariable p= 0.076 and multivariable p= 0.16. For LA-NSCLC patients treated with concurrent CRT, IF-TRT was associated with significantly better survival than ENI-TRT. TRT total and BED dose levels were not significantly associated with patient survival. Future progress will require research focusing on better systemic therapy and TRT.

Is Surgery after Chemoradiotherapy Feasible in Lung Cancer Patients with Superior Vena Cava Invasion?

Purpose: The purpose of this study is to explore the possibility of surgery after chemoradiotherapy (CRT) for locally advanced-non-small-cell lung cancer (LA-NSCLC) with superior vena cava (SVC) resection in terms of prognosis and early and late postoperative course.Methods: The medical records of NSCLC patients who underwent surgery after CRT at our institution between January 2001 and March 2016 were reviewed. We evaluated the feasibility of surgery with SVC resection after CRT.Results: A total of 8 LA-NSCLC patients were enrolled in this study. The SVC management included a graft replacement in two patients, pericardial patch repair in two, and direct suture closure in four. A complete resection was achieved in seven of the eight patients (87.5%). Postoperative early and late complication rate (Clavien-Dindo classification ≥ grade III) was 25%. All the complications were manageable, and no treatment-related deaths occurred in this series. Although seven out of eight patients showed good patency of reconstructed SVC, one patient exhibited the SVC occlusion during long-term follow-up period. Regarding the prognosis, the 5-year overall survival (OS) rate was 60.0%, and the 2-year recurrence-free survival (RFS) rate was 75.0%.Conclusion: Our results suggest that surgery with SVC resection after CRT is a feasible procedure in terms of clinical outcomes and postoperative course.

P1.14-012 Hypofractionated Simultaneous Integrated Boost IMRT Concurrent with Chemotherapy Improved Loco-Regional Control in Locally Advanced NSCLC

This study investigated the loco-regional control (LRC) and toxicity of hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) for locally advanced non-small-cell lung cancer (LANSCLC) in the setting of concurrent chemotherapy. One hundred and ten LANSCLC patients treated with SIB-IMRT and concurrent chemotherapy were retrospectively analyzed. Radical-intent radiotherapy was delivered at a fraction dose of 2.0∼2.2, 2.4∼2.6, and 2.9∼3.1Gy respectively. Factors potentially predictive of LRC (age, sex, tumor stage, tumor volume, biological effective dose (BED), dose per fraction, overall radiation time (ORT) and concurrent chemotherapy) were assessed in the univariate analysis and Cox multivariate model. Toxicity data was collected and analyzed. With a median follow-up of 24.4 months, the median duration of LRC was 21.4 months. LRC was 71.9% at 1 year, 45.9% at 2 years, and 41.8% at 3 years. In univariate analysis, BED (p=0.007), dose per fraction (p=0.002) and ORT (p=0.029) were associated significantly with LRC. In multivariate analysis, RT dose per fraction was independently prognostic of LRC (HR, 0.597; CI, 0.362∼0.986). Grade ≥3 pneumonitis, pulmonary fibrosis and esophagitis were observed in 6 (5.5%), 2 (1.8%) and 19 (17.3%) of patients, respectively. There was no significant difference in toxicity among different doses per fraction. Our study showed that LRC was improved by the dose per fraction escalation in the setting of concurrent chemotherapy. Hypofractionated SIB-IMRT could be a feasible and effective approach for dose intensification, while maintaining tolerable toxicities.

Radiotherapy Dosing for Locally Advanced Non-Small Cell Lung Carcinoma: "MTD" or "ALARA"?

Locally advanced non-small cell lung cancer (LA-NSCLC) is typically treated with thoracic radiotherapy, often in combination with cytotoxic chemotherapy. Despite tremendous advances in the evaluation, treatment techniques, and supportive care measures provided to LA-NSCLC patients, local disease progression and distant metastases frequently develop following definitive therapy. A recent landmark randomized trial demonstrated that radiotherapy dose escalation may reduce survival rates, highlighting our poor understanding of the effects of thoracic radiotherapy for LA-NSCLC. Here, we present rationale for further studies of radiotherapy dose escalation as well as arguments for exploring relatively low radiotherapy doses for LA-NSCLC.

Heart dose associated with overall survival in locally advanced NSCLC patients treated with hypofractionated chemoradiotherapy

Association of heart dose and overall survival was investigated in a cohort including 469 locally-advanced NSCLC patients receiving daily low-dose hypofractionated chemo-radiotherapy. Significant associations were found over a range of dose parameters. Multivariate analysis showed significant associations of heart_V2Gy:HR=1.007%−1 (95% CI:1.002–1.013; p=0.006), age:HR=1.026year−1 (1.011–1.042; p=0.001) and GTV volume:HR=1.001cc−1 (1.000–1.002; p=0.006) with overall survival.

Induction chemoradiotherapy using docetaxel and cisplatin with definitive-dose radiation followed by surgery for locally advanced non-small cell lung cancer.

Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (LA-NSCLC). Typically, around 40-50 Gy of radiation is applied as the induction-dose; however, a definitive-dose (DD) of radiation (60 Gy or higher) is occasionally applied to increase local control. We investigated the impact of induction CRT with DD radiation in LA-NSCLC patients treated with a single regimen of docetaxel and cisplatin. We reviewed 110 patients with LA-NSCLC who underwent induction CRT followed by surgery using a single regimen (docetaxel and cisplatin) between January 1999 and December 2014 at our hospital. The clinical outcomes of a DD group (60 Gy or higher, n=11) and a non-DD group (less than 60 Gy, n=99) were investigated using a propensity score (PS)-matched analysis. An advanced clinical stage was significantly more common in the DD group than in the non-DD group (P=0.033). Before and after the PS-matching based on seven factors including clinical stage, there was no significant difference in the rates of postoperative (PO) complication, mortality, 5-year overall survival (OS), or 5-year recurrence-free survival (RFS) between the two groups. After the PS-matching, the pathological complete response (CR) rate was significantly higher in the DD group than in the non-DD group [50% (n=5/10) vs. 0% (n=0/10), P=0.033]. Induction CRT followed by surgery using docetaxel and cisplatin with DD radiation can be performed safely and is associated with a higher pathological CR rate than that attained using non-DD radiation in LA-NSCLC patients.

Neutrophil-Lymphocyte Ratio Is a Prognostic Marker in Patients with Locally Advanced (Stage IIIA and IIIB) Non-Small Cell Lung Cancer Treated with Combined Modality Therapy.

Neutrophil-lymphocyte ratio (NLR) is a measure of systemic inflammation that appears prognostic in localized and advanced non-small cell lung cancer (NSCLC). Increased systemic inflammation portends a poorer prognosis in cancer patients. We hypothesized that low NLR at diagnosis is associated with improved overall survival (OS) in locally advanced NSCLC (LANSCLC) patients. Records from 276 patients with stage IIIA and IIIB NSCLC treated with definitive chemoradiation with or without surgery between 2000 and 2010 with adequate data were retrospectively reviewed. Baseline demographic data and pretreatment peripheral blood absolute neutrophil and lymphocyte counts were collected. Patients were grouped into quartiles based on NLR. OS was estimated using the Kaplan-Meier method. The log-rank test was used to compare mortality between groups. A linear test-for-trend was used for the NLR quartile groups. The Cox proportional hazards model was used for multivariable analysis. The NLR was prognostic for OS (p < .0001). Median survival in months (95% confidence interval) for the first, second, third, and fourth quartile groups of the population distribution of NLR were 27 (19-36), 28 (22-34), 22 (12-31), and 10 (8-12), respectively. NLR remained prognostic for OS after adjusting for race, sex, stage, performance status, and chemoradiotherapy approach (p = .004). To our knowledge, our series is the largest to demonstrate that baseline NLR is a significant prognostic indicator in LANSCLC patients who received definitive chemoradiation with or without surgery. As an indicator of inflammatory response, it should be explored as a potential predictive marker in the context of immunotherapy and radiation therapy. Neutrophil-lymphocyte ratio measured at the time of diagnosis was associated with improved overall survival in 276 patients with stage IIIA and IIIB non-small cell lung cancer (NSCLC) treated with definitive chemoradiation with or without surgery. To our knowledge, our series is the largest to demonstrate that baseline neutrophil-lymphocyte ratio is a significant prognostic indicator in locally advanced NSCLC patients who received definitive chemoradiation with or without surgery. Neutrophil-lymphocyte ratio is an inexpensive biomarker that may be easily utilized by clinicians at the time of locally advanced NSCLC diagnosis to help predict life expectancy.

The efficacy analysis of simultaneous integrated boost intensity-modulated radiotherapy for locally advanced non-small cell lung cancer

Objective To investigate the clinical efficacy and toxicity in the use of simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) for inoperable locally advanced non-small cell lung cancer (LA-NSCLC). Methods Between February 2012 and July 2015, 58 pathologically diagnosed inoperable LA-NSCLC patients treated with SIB-IMRT were analyzed. A radiation dose of 50-64 Gy was administered in 1.8-2.2 Gy/fraction (26-30 fractions) to the planning target volume (PTV). Simultaneously, 60-70 Gy was administered in 2.0-2.35 Gy/fraction (26-30 fractions) to the planning gross tumor volume (PGTV). Results The median follow-up time was 28.0 months (ranging from 6.0 to 40.0 months). The median overall survival (OS) and progress-free survival (PFS) were 25.0 (95% CI: 23.8-26.2) and 15.0 (95% CI: 11.3-18.7) months, respectively. The 1-, 2-year OS were 91.4% and 51.7%, respectively. The 1-, 2-year PFS were 56.9% and 22.7%, respectively. None of the patients developed grade 4 or 5 pneumonitis and esophagitis. In addition, in the subgroup analysis, the patients with N3 have a higher incident of ≥ grade 2 esophagitis compared with N0-N2, the incident are 29.2% and 20.6%, respectively (P<0.05). Conclusions SIB-IMRT is feasible and well-tolerated for inoperable LA-NSCLC patients. It remains to be further evaluated in a large sample size prospective clinical trial. Key words: Radiotherapy, intensity-modulated; Carcinoma, non-small-cell lung/RT

The predictive value of 18F-FDG PET-CT for assessing the clinical outcomes in locally advanced NSCLC patients after a new induction treatment: low-dose fractionated radiotherapy with concurrent chemotherapy

BackgroundPatients with locally advanced non-small-cell lung cancer (LA-NSCLC) have poor prognosis despite several multimodal approaches. Recently, low-dose fractionated radiotherapy concurrent to the induction chemotherapy (IC-LDRT) has been proposed to further improve the effects of chemotherapy and prognosis. Until now, the predictive value of metabolic response after IC-LDRT has not yet been investigated. Aim: to evaluate whether the early metabolic response, assessed by 18F-fluoro-deoxyglucose positron emission-computed tomography (18F-FDG PET-CT), could predict the prognosis in LA-NSCLC patients treated with a multimodal approach, including IC-LDRT.MethodsForty-four consecutive patients (35males, mean age: 66 ± 7.8 years) with stage IIIA/IIIB NSCLC were retrospectively evaluated. Forty-four patients underwent IC-LDRT (2 cycles of chemotherapy, 40 cGy twice daily), 26/44 neo-adjuvant chemo-radiotherapy (CCRT: 50.4Gy), and 20/44 surgery. 18F-FDG PET-CT was performed before (baseline), after IC-LDRT (early) and after CCRT (final), applying PET response criteria in solid tumours (PERCIST). Patients with complete/partial metabolic response were classified as responders; patients with stable/progressive disease as non-responders. Progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meyer analysis; the relationship between clinical factors and survivals were assessed using uni-multivariate regression analysis.ResultsForty-four out of 44, 42/44 and 23/42 patients underwent baseline, early and final PET-CT, respectively. SULpeak of primary tumour and lymph-node significantly (p = 0.004, p = 0.0002, respectively) decreased after IC-LDRT with a further reduction after CCRT (p = 0.0006, p = 0.02, respectively). At early PET-CT, 20/42 (47.6%) patients were classified as responders, 22/42 (52.3%) as non-responders. At final PET-CT, 19/23 patients were classified as responders (12 responders and 7 non-responders at early PET-CT), and 4/23 as non-responders (all non-responders at early PET-CT). Early responders had better PFS and OS than early non-responders (p ≤ 0.01). Early metabolic response was predictive factor for loco-regional, distant and global PFS (p = 0.02, p = 0.01, p = 0.005, respectively); surgery for loco-regional and global PFS (p = 0.03, p = 0.009, respectively).ConclusionsIn LA-NSCLC patients, 18F-FDG metabolic response assessed after only two cycles of IC-LDRT predicts the prognosis. The early evaluation of metabolic changes could allow to personalize therapy. This multimodality approach, including both low-dose radiotherapy that increases the effects of induction chemotherapy, and surgery that removes the disease, improved clinical outcomes. Further prospective investigation of this new induction approach is warranted.

P2.02-020 Pattern of Care of Inoperable Locally Advanced (LA) NSCLC in Elderly Patients: Analysis of the Experience of Two Academic Italian Hospitals

Optimal treatment in LA NSCLC patients is still debated. In fit patients concomitant radio-chemotherapy (RCT) seems to be the best treatment in terms of local control (LC), progression free survival (PFS) and overall survival (OS) while sequential RCT is a good alternative in unfit patients. Moderately hypofractionated radiotherapy improve OS in recent studies. Elderly patients often cannot be offered multimodality treatments. We report our experience with over 70 years old LA NSCLC patients deemed unfit for surgery. Tabled 1Patients' CharacteristicsAgeMedian75Range70-83GenderMale50 (70%)Female21 (30%)Performance Status (ECOG)0129 (41%)36 (51)26 (8%)HistologyAdenocarcinoma31 (44%)Squamous Cell Carcinoma39 (55%)Large Cell Carcinoma1 (1%)StageIIa/IIb12 (17%)IIIa39 (55%)IIIb20 (28%)ChemotherapyConcomitant9 (13%)Sequential62 (87%)Cycles: median4Cycles: range1-8RadiotherapyMedian Dose62,3 GyModerate hypofractionation26 (37%)Conventional fractionation45 (63%) Open table in a new tab Characteristics of patients and treatments are summarized in table 1. All patients were treated with a platinum based doublet of chemotherapy (CT). RT target volumes included the primary lung tumor and involved mediastinal lymphnodes as defined on pre-treatment contrast enhanced CT scan. Elective nodal irradiation was not performed. Acute/late toxicities were reported in accordance to 4.0 CTCAE scale. Clinical response was evaluated according to RECIST criteria. At a median follow up of 10 months clinical response was evaluable in 69/71 patients obtaining a partial response in 35 of them, stable disease in 17, progressive disease in 17 patients. Twenty six patients experienced a local relapse within RT primary tumor volume, while 13 on nodal volume (5 patients both tumor and nodal relapse). 22 patients developed metastatic disease. One and 3-year OS was 62.3% (SE±6.2%) and 24,5% (SE±7.8%) respectively, while 1- and 3 year PFS was 45.1% (SE±6.9%) and 9,7% (SE±5.7%) respectively. At univariate analysis, tumor dimension (p<0,002) was the only prognostic factor statistically significant for OS. G1-G2 acute toxicity was observed in 45 patients: 36/62 in sequential CRT (3/36 developed also chronic toxicities) and 9/9 in concomitant CRT; most events were G1 oesophagitis (27 patients) and G1 cough (17 patients). No G3-4 event was reported. CRT is feasible in elderly patients; multidisciplinary evaluation is needed in order to reserve CRT to very fit patients.

P2.02-012 Long-Term Survival of Phase II of Full-Dose Oral Vinorelbine Combined with Cisplatin &amp; Radiotherapy in Locally Advanced NSCLC

Chemo-radiotherapy is the standard of care for the treatment of inoperable locally advanced non-small cell lung cancer (LA-NSCLC). Cisplatin (P) plus vinorelbine is one of the chemotherapy (CT) regimens widely used concurrently with radiotherapy (RT). Since oral vinorelbine (oV) has achieved comparable results to the IV formulation, the optimal dose for the oV administration with P and concurrent RT is still being investigated. The aim of this study is to evaluate the efficacy and safety of full-dose oV combined with P and radical RT for LA-NSCLC patients (pts). Untreated pts between 18-70 years (y), with histologically proven inoperable LA-NSCLC (supraclavicular lymph node involvement excluded), V20<30%, adequate bone marrow, respiratory, hepatic and renal function, and ECOG PS0-1; received 4 cycles (cy) of oV 60 mg/m2 D1 & 8 plus P 80 mg/m2 D1, every 3 weeks, plus 2Gy/day of RT started on D1 of 2nd cy (total dose 66Gy). Primary endpoint was overall response rate (ORR) by RECIST 1.1. Secondary endpoints were: progression free survival (PFS), overall survival (OS) & safety profile. To guarantee a type-1 (□) error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint, a sample size of 45 eligible pts was planned. EudraCT 2009-010436-17. Forty-eight pts were included between 02/2010-12/2011. Median age 61y [34-72], male 90%, PS1 58%; smokers 52%; squamous 63%; stage IIIB 54%. Main G3-4 toxicities (% cy) were: neutropenia 33%, febrile neutropenia 14.6%, anemia 12.5%, thrombocytopenia 16.6%, & esophagitis 12.5%. Two treatment-related deaths during the 1st cy. RT was administered to 87.5% of pts; 7.1% received less than 60Gy and 23.8% had delays due to adverse events. The ORR was 77.3% (2 complete responses). With a median follow-up of 28.2 months (m) [0.5-70.6], 33 pts (68.8%) have progressed and 32 (66.7%) have died. Median PFS and OS were 11.8m (CI95% 7.2-16.5) and 29.8m (CI95% 21.4-38.1), respectively. PFS at 1y was 48.8% pts (CI95% 33.9-63.7%). OS at 1 and 2y were 72.7% (CI95% 60-85.4%) and 57.3% (CI95% 43-71.6%), respectively. This long-term analysis confirms the good efficacy results of the administration of full doses of oral vinorelbine combined with cisplatin and concurrent RT in patients with LA-NSCLC.

The effect of consolidation chemotherapy after concurrent chemoradiotherapy on the survival of patients with locally advanced non-small cell lung cancer: a meta-analysis.

Whether consolidation chemotherapy (CCT) after chemoradiotherapy (CRT) helps in the treatment of locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. The aim of this meta-analysis was to evaluate the impact of CCT on overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities in patients with inoperable LA-NSCLC. PubMed, Embase, The Cochrane Library, WanFang, VIP, and CNKI were searched to identify any relevant publications. After screening the literature and completing quality assessment and data extraction, the meta-analysis was performed using RevMan5.3 software. Ultimately, 5 eligible studies with a total of 1036 patients were selected for the present meta-analysis. The results of the analysis indicated that treatment of LA-NSCLC patients with CRT followed by CCT improved OS (pooled HR0.85; 95% CI 0.73-0.99; P=0.03), but did not improve PFS (pooled HR0.78; 95% CI 0.60-1.02; P=0.07) and ORR (P=0.26). Although it could increase the risk of grade ≥3 infection (P=0.04), it may not increase the risk of grade ≥3 radiation pneumonitis (P=0.09) during the CCT period. CCT after concurrent CRT may provide additional benefits in the treatment of LA-NSCLC. Although this therapeutic strategy did not prolong PFS, further assessment is warranted.

Radiologic-pathologic correlation of response to chemoradiation in resectable locally advanced NSCLC

ObjectivesAccurate assessment of tumor response to chemoradiation has the potential to guide clinical decision-making regarding surgical resection and/or dose escalation for patients. Early assessment has implications for Optimal local therapy for operable locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. This study evaluated quantitative CT-based tumor measurements to predict pathologic response. Materials and methodsPatients with operable LA-NSCLC treated with chemoradiation followed by surgical resection were assessed. Tumor diameter and volume were quantified from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. Univariate and multivariate logistic regression were used to determine association with the primary endpoint of pathologic complete response (pCR). Overall survival, locoregional recurrence, and distant metastasis were assessed as secondary endpoints. Results101 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. The median RT dose was 54Gy (range, 46–70) and 98% of patients received concurrent chemoradiation as part of their preoperative treatment. Reduction of CT-defined tumor volume was associated with pCR (OR 1.06 [1.02-1.09], p=0.002) and LRR (HR 1.01 [1.00-1.02], p=0.048). Conventional response assessment determined by RECIST (p=0.213) was not associated with pCR or any secondary endpoints. ConclusionCT-measured reductions in tumor volume after chemoradiation are associated with pCR and provide greater clinical information about tumor response than conventional response assessment (RECIST) or absolute tumor sizes or volumes. This study demonstrates that change in tumor volumes provides better radiologic-pathologic correlation and is thus an additional tool to assess tumor response following chemoradiation.

Technical advancement improves survival in patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving definitive radiotherapy

This study aimed to evaluate the impact of technical advancement of radiation therapy in patients with LA-NSCLC receiving definitive radiotherapy (RT). Patients treated with definitive RT (≥50 Gy) between 2000 and 2010 were retrospectively reviewed. Overall survival (OS), cancer specific survival (CSS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) were calculated and compared among patients irradiated with different techniques. Radiation-induced lung injury (RILI) and esophageal injury (RIEI) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0 (NCI-CTCAE 3.0). A total of 946 patients were eligible for analysis, including 288 treated with two-dimensional radiotherapy (2D-RT), 209 with three-dimensional conformal radiation therapy (3D-CRT) and 449 with intensity-modulated radiation therapy (IMRT) respectively. The median follow-up time for the whole population was 84.1 months. The median OS of 2D-RT, 3D-CRT and IMRT groups were 15.8, 19.7 and 23.3 months, respectively, with the corresponding 5-year survival rate of 8.7%, 13.0% and 18.8%, respectively (P<0.001). The univariate analysis demonstrated significantly inferior OS, LRPFS, DMFS and PFS of 2D-RT than those provided by 3D-CRT or IMRT. The univariate analysis also revealed that the IMRT group had significantly loger LRPFS and a trend toward better OS and DMFS compared with 3D-CRT. Multivariate analysis showed that TNM stage, RT technique and KPS were independent factors correlated with all survival indexes. Compared with 2D-RT, the utilization of IMRT was associated with significantly improved OS, LRPFS, DMFS as well as PFS. Compared with 3D-CRT, IMRT provided superior DMFS (P=0.035), a trend approaching significance with regard to LRPFS (P=0.073) but no statistically significant improvement on OS, CSS and PFS in multivariate analysis. The incidence rates of RILI were significantly decreased in the IMRT group (29.3% vs. 26.6% vs.14.0%, P<0.001) whereas that of RIET rates were similar (34.7% vs. 29.7% vs. 35.3%, P=0.342) among the three groups. Radiation therapy technique is a factor affecting prognosis of LA-NSCLC patients. Advanced radiation therapy technique is associated with improved tumor control and survival, and decreased radiation-induced lung toxicity.

Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab

Background and purposeRadiation dose escalation using hypofractionation might improve overall survival (OS). We investigated OS in a phase II multicenter study in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypofractionated concurrent chemoradiotherapy. Materials and methodsA 2-armed phase II, multi-center study (NTR2230) was performed with the aim to assess the effect of cetuximab to concurrent chemoradiotherapy in LA-NSCLC patients (stage II/IIIA/B). Arm A received high dose radiotherapy (24×2.75Gy) and concurrent daily low-dose cisplatin (6mg/m2). Arm B received an identical treatment regimen with additional weekly cetuximab. Kaplan–Meier survival curves and 1-, 2- and 5-year OS proportions were calculated. ResultsBetween February 2009 and May 2011, 102 patients were randomly allocated in two arms. Median OS was 31.5months (range 12.8–52.3), not significantly different between arms A and B; 33.0 (range 17.0–57.0) and 30.0 (11.0–52.0) months. 1-, 2- and 5-year OS rates were 74.5%, 59.4% and 37.3%, respectively. In multivariate analyses, worse performance score, V35 of the esophagus and the existence of comorbidities were significantly (P-value<0.05) associated with a shorter OS. DiscussionIn this phase II trial, the median OS for the entire group was remarkably high; 31.5months. Furthermore, 5-year OS was still 37.3%. Hypofractionation might contribute to improved OS in LA-NSCLC patients.

Research progress of prophylactic cranial irradiation for locally advanced non-small cell lung cancer

As multi-modality treatments are now able to ensure better local control and a lower rate of extra-cranial metastasis, brain metastasis has become a major concern in locally advanced non-small cell lung cancer (LA-NSCLC). Prophylactic cranial irradiation (PCI) is now a standard treatment for patients with small cell lung cancer (SCLC), it decreases the incidence of brain metastases and increases the survival rate. Despite the relatively high incidence of brain metastases in LA-NSCLC, the role of PCI in patients treated with radical intent has not been established yet. The objective of this systematic review was to establish whether PCI prevents the development of brain metastasis and increases survival in LA-NSCLC patients, the characteristics of the benefit patients, the tolerance and toxicity, the effective dose and timing of PCI. The main concern in this review is to establish the definitive role of PCI in the treatment of locally advanced NSCLC.