Limited-stage Small-cell Lung Cancer Patients Research Articles

Determination of Risk Factors Related to Supraclavicular Recurrence for Limited-Stage Small Cell Lung Cancer (SCLC) Patients.

BackgroundThis research aimed to determine high-risk factors of supraclavicular recurrence for limited-stage small cell lung cancer (LS-SCLC) patients to discover a potential subpopulation that can benefit from prophylactic supraclavicular irradiation (PSCI).Material/MethodsBetween July 2006 and July 2011, LS-SCLC patients without supraclavicular lymph node (SCLN) involvement consecutively treated with concurrent chemo-radiation but without PSCI in the Radiotherapy Department of the Cancer Institute and Hospital of Tianjin Medical University, were retrospectively analyzed. SCLN recurrence rate, overall survival (OS), and distant metastasis-free survival (DMFS) were assessed. Binary logistic regression analysis was conducted to discover the high-risk factors related to the SCLN recurrence. The receiver operating characteristic (ROC) curves were drawn to evaluate logistic regression model prediction performance.ResultsEighty-eight LS-SCLC patients were analyzed in this study. During 99 months (ranging from 72 months to 124 months) for survivors, 28 (31.8%) had SCLN recurrence. There were significant differences for median DMFS and OS between LS-SCLC patients with and without SCLN recurrence. The logistic regression model revealed that lymphadenopathy at mediastinal level 2 and level 3 prior to chemotherapy were significantly associated with SCLN recurrence, which was validated by ROC.ConclusionsLymphadenopathy at mediastinal level 2 and level 3 prior to chemotherapy were the high-risk factors associated with SCLN recurrence for patients with LS-SCLC. Further work is needed to determine whether patients with these factors can benefit from PSCI.

Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary?

PurposeProphylactic cranial irradiation (PCI) reduces the incidence of brain metastases in patients with limited stage small cell lung cancer (LS-SCLC). However, PCI is associated with neurotoxicity. Previous studies have not consistently used pretreatment magnetic resonance imaging. Modern imaging improvements continue to enhance early metastasis detection, potentially decreasing the utility of PCI. We sought to determine whether PCI was associated with improved outcomes in LS-SCLC patients with modern imaging. Methods and MaterialsWe identified LS-SCLC patients with no intracranial disease who were treated between 2007 and 2018. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated and multivariate Cox proportional hazards models were generated. The cumulative incidence of brain metastases was estimated using competing risks methodology. ResultsNinety-two patients were identified without intracranial disease at initial staging, 39 of whom received PCI. Median follow-up was 56.7 months. The median OS for the cohort was 35.5 months (95% CI, 25.8-49.3), and median PFS was 19.1 months (95% CI, 12.3-30.5). Median OS with PCI versus observation was 37.9 months (95% CI, 31.8-not reached) versus 30.5 months (95% CI, 14.6-56.1; P = .07), whereas median PFS was 26.3 months (95% CI 19.1-not reached) versus 12.3 months (95% CI, 8.5-30.5; P = .02), respectively. Overall, at 2 years, the cumulative incidence of brain metastases was 10% with PCI and 29% without; this increased to 32% and 29% by 4 years (P = .66). In those patients who had negative magnetic resonance imaging of the brain after completing initial treatment, the 1-year cumulative incidence of brain metastasis was not significantly different at 8% versus 11% (P = .46) respectively. Both PCI and treatment response were independent predictors for PFS on multivariate analysis. Stratified by disease response, patients with a complete response did not benefit from PCI (P = .50), whereas those with partial response or stable disease experienced improved PFS (P = .01). ConclusionsOverall, PCI was associated with improved PFS and reduced early incidence of brain metastases. Patients achieving a complete response to initial therapy did not experience a PFS benefit with PCI. This may indicate that subsets of LS-SCLC patients can potentially be spared from PCI in the era of modern imaging.

Clinical Outcomes and Prognostic Factors in Limited-Stage Small Cell Lung Cancer Patients Treated with Intensive Modified Radiation Therapy

To investigate the clinical effect of combined modality treatment and examine the prognostic factors for overall survival (OS) in limited-stage small cell lung cancer (LS-SCLC) on the base of intensive modified radiotherapy (IMRT). A retrospective analysis was performed on the clinical data of 484 LS-SCLC patients treated with chemotherapy and IMRT in our centre from August 2006 to May 2014. All patients were primarily managed with concurrent or sequential chemoradiotherapy, followed by prophylactic cranial irradiation (PCI) in patients with complete or partial response. IMRT was adopted in all patients with a median radiation dose 60Gy (2Gy once daily over 6 weeks). Kaplan-Meier method was used for survival analysis, and Log-rank test and Cox regression were used for univariate and multivariate analysis of prognostic factors. Follow-up rate was 93%. The median survival time(MST) was 23.8 months (95%CI 20.3-27.4), and the 2-,3-, and 5-year OS were 48.7%,39.8%, and 28.6%, respectively. The median progression-free survival time(PFS) was 14.1 months (95%CI 12.6-15.5), and the 2-,3-, and 5-year PFS were 34.4%, 30.5%, and 28.3%, respectively. The acute toxicity after chemotherapy and thoracic IMRT was tolerable. The acute toxicities included grade ≥3 hematological toxicity, grade ≥2 radiation esophagitis and grade ≥2 pneumonitis, which occurred in 26.9%, 24.8%, and 18.4% of all patients. The rates of CR, PR, SD, PD after thoracic radiation were 15.5%, 69.0%, 5.6%, 7.0%, respectively. Response information of 14 patients were lost and objective response rate was 84.5%. The univariate analysis showed that age, smoking history, TNM stage, PCI and the number of induction chemotherapy cycles were significant prognostic factors for OS of LS-SCLC (P=0.006, 0.001, 0.047, <0.001,0.046). The multivariate analysis showed that smoking history and PCI were independent factors affecting the prognosis for the LS-SCLC patients (P=0.001, <0.001). Combined chemotherapy and thoracic IMRT achieved satisfactory clinical outcomes and mild toxicity in LS-SCLC. Smoking history and PCI are independent prognostic factors for OS of LS-SCLC.

Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer Patients: Secondary Findings From the Prospective Randomized Phase 3 CONVERT Trial

IntroductionThe impact of the dose and fractionation of thoracic radiotherapy on the risk of developing brain metastasis (BM) has not been evaluated prospectively in limited stage SCLC patients receiving prophylactic cerebral irradiation (PCI). MethodsData from patients treated with PCI from the CONVERT trial were analyzed. ResultsFour hundred forty-nine of 547 patients (82%) received PCI after completion of chemoradiotherapy. Baseline brain imaging consisted of computed tomographic scans in 356 of 449 patients (79%) and magnetic resonance imaging in 83 of 449 (18%) patients. PCI was delivered to 220 of 273 participants (81%) in the twice-daily (BD) group and 229 of 270 in the once-daily (OD) group (85%; p = 0.49). Total median PCI dose was 25 Gy in both the BD and OD groups (p = 0.74). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, gross tumor volume (GTV) was associated with an increased risk of BM (p = 0.007) or other radiological progression events (p = 0.006), whereas in a multivariate analysis both thoracic GTV (tGTV) and ECOG performance score were associated with either progression type. The median overall survival (OS) of patients treated with PCI was 29 months. In the univariate analysis of OS, PCI timing from end of chemotherapy, weight loss of more than 10%, and tGTV were prognostic factors associated with OS. In the multivariate analysis, only tGTV was associated with OS. Delay between end of chemotherapy and PCI was not associated with OS. ConclusionsPatients receiving OD or BD thoracic radiotherapy have the same risk of developing BM. Larger tumors are associated with a higher risk of BM.

P2.12-15 Prognostic and Predictive Covariates in Limited-Stage Small-Cell Lung Cancer: Analysis of the Phase 3 CONVERT Trial

The majority of patients with limited-stage small cell lung cancer (LS-SCLC) progress after concurrent chemo-radiotherapy (cCTRT). Data from the CONVERT trial was analysed to investigate prognostic and predictive covariates in LS-SCLC patients. CONVERT is an international multi-centre phase III trial that randomly assigned fit patients to receive either twice-daily (45Gy in 30 fractions) or once-daily (66Gy in 33 fractions) radiotherapy starting on day 22 of chemotherapy cycle 1 (ClinicalTrials.gov NCT00433563). Chemotherapy consisted of 4 or 6 cycles (centres choice) of cisplatin and etoposide. Prophylactic cranial irradiation was offered, if indicated. The following covariates were investigated for prognostic and predictive significance (benefit from twice-daily radiotherapy and completion of cCTRT): clinical (age, performance score, TNM staging, smoking status, weight loss >10% and lung function), laboratory (alkaline phosphatase, sodium and lactate dehydrogenase) and dosimetric (gross tumour volume (GTV), heart and lung dose). Completion of chemotherapy was defined as delivery of all planned cycles while completion of radiotherapy was defined as delivery of all fractions. Results of the multivariate regression analysis of overall survival (OS) and progression-free survival (PFS) were reported after correcting for multiple comparisons. Of 547 patients recruited to CONVERT, 449 with complete covariate and outcome data were eligible for this analysis. GTV was the strongest prognostic covariate of OS (hazard ratio (HR) 1.37 (95% confidence interval (CI) 1.21-1.56); p<0.001). The addition of weight loss and performance score modestly improved the concordance probability (0.59 to 0.61) of this model. The HR for OS between high and low risk groups using this model was 2.72 (95% CI 1.94-3.81), median OS: 21 months (95% CI 19-26) vs 44 months (95% CI 36-not reached), respectively. For PFS, the HR between high and low risk groups was 2.55 (95% CI 1.86-3.5), median PFS: 13 months (95% CI 12-15) vs 26 months (95% CI 18-48), respectively. None of the tested covariates predicted patient benefit from twice-daily radiotherapy. Increase in patient age (continuous variable) predicted non-completion of planned chemotherapy (p=0.002). Due to the high completion of radiotherapy (86% in twice-daily and 80% in once-daily group), a multivariate analysis to predict radiotherapy completion was not performed. We report a clinical prognostic model in LS-SCLC, providing information that clinicians can relay to their patients to aid clinical decisions. The addition of biological covariates could help refine these prognostic models in the future.

Risk factors for brain metastasis in patients with small cell lung cancer without prophylactic cranial irradiation.

This study aimed to determine the risk factors for brain metastasis (BM) and the prognostic factors for overall survival (OS) in patients with small cell lung cancer without prophylactic cranial irradiation (PCI). Limited stage small cell lung cancer (LS-SCLC) patients achieving acomplete response (CR) or partial response (PR) were enrolled into this study between January 2010 and December 2016. We retrospectively evaluated the influencing factors for time to BM and overall survival (OS). Atotal of 153patients were enrolled into this study. Sixty-eight developed BM during the follow-up period. For the whole cohort, the 1‑ and 2‑year BM rates were 29.4 and 41.2%, respectively. Multivariate analysis showed that Tstage (hazard ratio [HR] = 2.27, P = 0.024), neutrophil-to-lymphocyte ratio (NLR; HR = 2.07, P = 0.029), time to thoracic radiotherapy (HR = 0.34, P = 0.002) and chemotherapy cycles (HR = 0.49, P = 0.036) were the independent influencing factors of time to BM. Only NLR (HR = 2.11, P = 0.005) and time to thoracic radiotherapy (HR = 1.95, P = 0.011) were independent prognostic factors of OS. Of the 68 patients developing BM, those with BM occurring as the first relapse (42/68) had better OS than the others (39.5months vs 23.0months, P = 0.016). LS-SCLC patients without PCI had ahigh risk of BM. High Tstage, high NLR, early thoracic radiotherapy and fewer chemotherapy cycles were the risk factors of BM. Further research is needed to confirm the results.

Application of prophylactic cranial irradiation in limited-stage small-cell lung cancer: which patients could benefit?

To analyze the role of prophylactic cranial irradiation (PCI) on the survival for patients with limited-stage small-cell lung cancer (LS-SCLC). We screened patients from SEER database. Kaplan-Meier analysis and Cox proportional hazard model were used to evaluate factors influencing survival. LS-SCLC patients who receiving PCI were associated with better overall survival (OS; p <0.001) and cancer-specific survival (CSS; p <0.001). Multivariable Cox analysis revealed PCI was an independent prognostic factor for OS (p<0.001) and CSS (p<0.001). In subgroup analysis, there were no OS and CSS differences between PCI and no PCI groups in black patients and patient with a tumor size <5cm (all p >0.05). PCI remains an effective method for most LS-SCLC patients. However, caution should be taken in recommending PCI for black patients and patients with a tumor size <5cm. Further clinical trials are necessary to validate our results and identify the most suitable patients for PCI in the modern era.

Effects of thoracic radiotherapy timing and duration on progression-free survival in limited-stage small cell lung cancer.

Concurrent chemoradiotherapy (CRT) has been recommended and applied widely as the standard treatment for limited‐stage small cell lung cancer (LS‐SCLC). However, controversies remain regarding the optimal timing and treatment duration of thoracic radiotherapy (TRT), and their effects on patient survival. To evaluate prognostic values of TRT timing and duration on progression‐free survival (PFS) in LS‐SCLC and their dependence on TRT fractionation and clinicopathological characteristics, we retrospectively analyzed 197 LS‐SCLC patients receiving CRT from 2000 to 2016 at Sun Yat‐sen University Cancer Center. Based on the optimal cut‐off values of TRT timing and duration generated by Cutoff Finder, patients were divided into early TRT/late TRT group and short TRT/long TRT group respectively. Univariate and multivariate Cox analysis were performed to assess correlations of TRT timing, duration, fractionation, and clinicopathological characteristics with PFS. Univariate analysis revealed that early‐initiated TRT (P = 2.54 × 10−4) and short TRT (P = .001) significantly correlated with longer PFS. Their PFS benefits persisted in patients receiving hyperfractionated TRT and etoposide‐cisplatin (EP) chemotherapy, but were less prominent in those receiving once‐daily TRT and non‐EP chemotherapy. Multivariate analysis further identified early initiated TRT (P = .004) and short TRT (P = .017) as independent prognostic factors for longer PFS in LS‐SCLC. Our study confirmed that early‐initiated TRT and short TRT had positive prognostic roles in LS‐SCLC, especially in patients receiving hyperfractionated TRT and etoposide‐cisplatin chemotherapy. TRT fractionation was not an independent prognostic factor in LS‐SCLC.

Clinical efficacy and prognostic factors of intensity-modulated radiotherapy combined with chemotherapy for limited-stage small cell lung cancer

Objective To investigate the clinical efficacy and prognosis of intensity-modulated radiotherapy (IMRT) combined with chemotherapy for limited-stage small cell lung cancer (LS-SCLC). Methods A retrospective analysis was performed on the clinical data of 484 LS-SCLC patients treated with chemoradiotherapy in our center from 2006 to 2014. The patients with partial or complete response to IMRT received prophylactic cranial irradiation (PCI). The Kaplan-Meier method was used to calculate survival rates, and the log-rank test and Cox regression were used for univariate and multivariate analyses, respectively. Results In all the patients, the follow-up rate was 93%; the median overall survival (OS) time was 23.8 months; the 2-, 3-, and 5-year OS rates were 48.7%, 39.8%, and 28.6%, respectively; the median progression-free survival (PFS) time was 14.1 months; the 2-, 3-, and 5-year PFS rates were 34.4%, 30.5%, and 28.3%, respectively. The incidence rates of grade ≥3 bone marrow suppression, grade ≥2 radiation esophagitis, and grade ≥2 radiation pneumonitis were 26.9%, 24.8%, and 18.4%, respectively, in SCLC patients after IMRT. The objective response rate was 84.5%. The univariate analysis showed that age, smoking history, TNM stage, PCI, and the number of chemotherapy cycles before radiotherapy were prognostic factors for OS (P=0.006, 0.001, 0.047, 0.000, and 0.046). The multivariate analysis showed that smoking history and PCI were independent prognostic factors (P=0.001 and 0.000). Conclusions IMRT combined with chemotherapy achieves satisfactory clinical outcomes in the treatment of LS-SCLC. Smoking history and PCI are independent prognostic factors for OS of LS-SCLC patients. Key words: Carcinoma, small cell lung/intensity modulated radiotherapy; Combined modality therapy; Prognosis

Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer: Survey of US Radiation Oncologists on Current Practice Patterns

PurposeProphylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer (LS-SCLC) is considered the standard of care. Meta-analysis of 7 clinical trials indicates a survival benefit to PCI, but all of these trials were conducted in the pre–magnetic resonance imaging (MRI) era. Therefore, routine brain imaging with MRI before PCI—as recommended by National Comprehensive Cancer Network guidelines—is not directly supported by the evidence. Current US practice patterns for patients with LS-SCLC are unknown. Materials and MethodsWe surveyed practicing US radiation oncologists via an institutional review board–approved online questionnaire. Questions covered demographic information and treatment recommendations for LS-SCLC. ResultsWe received 309 responses from US radiation oncologists. Ninety-eight percent recommended PCI for patients with LS-SCLC, 96% obtained brain MRI before PCI, 33% obtained serial brain imaging with MRI after PCI to detect new metastases, and 35% recommended memantine for patients undergoing PCI. Recommending memantine was associated with fewer years of practice (P < .001), fewer lung cancer patients treated per year (P = .045), and fewer LS-SCLC patients treated per year (P = .024). ConclusionAlmost all responding radiation oncologists recommended PCI and pre-PCI brain MRI for LS-SCLC patients with disease responsive to initial therapy. Only a third of respondents followed these patients with serial brain MRI. Approximately one third provided memantine therapy to try to limit neurocognitive effects of PCI. Further research is warranted to determine the best treatment for patients with LS-SCLC. This survey can inform the development of future trials that depend on participation from radiation oncologists.

The Role of Advanced Imaging in Assessing Response to Definitive Chemoradiation Before Prophylactic Cranial Irradiation in Limited-Stage Small-Cell Lung Cancer

IntroductionProphylactic cranial irradiation (PCI) improves survival for small-cell lung cancer (SCLC). Evidence for PCI in limited-stage SCLC largely derives from studies requiring only chest x-ray (CXR) to determine remission status. We analyzed thoracic chemoradiation therapy (TCRT) outcomes according to imaging modality to determine which patients benefitted most from PCI. Patients and MethodsAll limited-stage SCLC patients who received TCRT as well as PCI at our institution were reviewed. Imaging between TCRT end and PCI start was characterized as complete (CR), partial (PR), or other response. ResultsThirty-eight consecutive patients were assessed for TCRT response before PCI with CXR (n = 21), chest computed tomography (CT; n = 27), and/or positron emission tomography (PET)/CT (n = 11). CR was identified on 71% of CXRs, 41% of CT scans, and 18% of PET/CT scans. Median survival was 28.3 months for the entire cohort and did not differ for patients who had CXR alone versus CT and/or PET/CT for restaging (P = .78) or those with PR using any modality versus CR using all modalities (22.6 months vs. 45.5 months; P = .22). CT CR patients had numerical but not statistically significant improved 2-year (P = .18) and 3-year (P = .13) survival compared with CT PR. ConclusionCXR remains an appropriate modality to assess TCRT response before PCI in limited-stage SCLC. Advanced imaging did not inform the decision to offer PCI in this study. Because of similar excellent survival profiles independent of imaging modality and TCRT response, this analysis suggests limited-stage SCLC patients with PR using any modality should not be denied PCI, akin to standards for extensive-stage SCLC.

A Strategy to Reduce Acute Toxicity from Twice Daily Chemoradiation Therapy for Limited-Stage Small-Cell Lung Cancer

The standard of care for limited stage small cell lung cancer (LS-SCLC), as outlined in the Intergroup 0096 trial, involves twice daily radiation therapy delivered to two out of four fields at a time. This results in high rates of clinically significant acute toxicities, especially esophagitis. This study examines acute esophagitis and treatment breaks in patients treated with radiation therapy as outlined by Intergroup 0096 versus those treated with all four fields treated with each fraction, a minor modification of the Intergroup 0096 technique that we hypothesize will reduce acute esophagitis rates and treatment breaks. We identified SCLC patients who received 45 Gy in 1.5 Gy twice-daily fractions from an institutional database. Treatment break was defined as an interruption of ≥3 total days. Associations were assessed via Chi-squared test. 74 LS-SCLC patients were treated with 3D-conformal radiation therapy from 2004 - 2010. 18 patients did not satisfy criteria described in the Methods and were excluded. 28 patients were treated per Intergroup 0096 with AP/PA fields twice daily for 1 week followed by AP/PA fields in the AM and 2 oblique fields in the PM for 2 weeks. 28 patients were treated with the same approach except all four fields were treated with each fraction. Patient characteristics were well distributed with no differences observed in median age, race, gender, performance status, T and N stage, lung lobe, laterality, Charlson score, and type and timing of chemotherapy (p >0.20 for all). 35% of patients had CTCAE grade 3 esophagitis with the Intergroup 0096 approach vs. 13% in patients treated with an integrated 4-field approach (p = 0.04). Across groups, 32% of grade 3 esophagitis patients had breaks vs. 8% with grade ≤2 esophagitis (p = 0.02). There was no difference in survival (p = 0.37), with 39% survival in both arms at three years. Grade 3 esophagitis and treatment breaks were reduced in patients receiving integrated 4-field treatment. Future investigation is required to determine whether the observed reduction in treatment breaks could translate to a local control or survival benefit if applied to a larger patient sample, or whether IMRT could further benefit this population of patients.

Evaluation of factors associated with platinum-sensitivity status and survival in limited-stage small cell lung cancer patients treated with chemoradiotherapy.

In this retrospective study, we analyzed the association of clinicopathological factors and therapeutic plans with platinum-sensitivity status and survival of limited-stage small cell lung cancer (LS-SCLC) patients. We enrolled 452 LS-SCLC patients with 279 platinum sensitive and 173 platinum refractory patients. The low serum neuro-specific enolase levels (NSE; p = 0.011), neutrophil-to-lymphocyte ratios (NLR; p = 0.013) and higher objective response rates (p = 0.003) were associated with sensitive group but not the refractory group. Multivariate analysis showed that treatment modality (HR = 0.267, p < 0.001), serum lactate dehydrogenase (LDH; HR = 1.894, p = 0.016), NLR (HR = 2.043, p = 0.043) and platinum-sensitivity status (HR = 0.561, p = 0.036) were independent prognostic factors for survival. We further showed that the numbers of chemotherapy cycles and response to first-line therapy were independent prognostic factors for refractory patients only. Our study demonstrates that platinum-sensitivity status is of prognostic importance, as it is strongly associated with survival in LS-SCLC patients.

Hypo- or conventionally fractionated radiotherapy combined with chemotherapy in patients with limited stage small cell lung cancer

BackgroundPrevious data from our institution showed that hypofractionated thoracic radiotherapy (HypoTRT) with concurrent etoposide/platinum chemotherapy yielded favorable survival in patients with limited-stage small cell lung cancer (LS-SCLC). The present study retrospectively compared the survival outcomes, failure patterns and toxicities between groups of LS-SCLC patients treated with conventionally fractionated thoracic radiotherapy (ConvTRT) or HypoTRT combined with chemotherapy.MethodsMedical records of LS-SCLC patients between January 2010 and December 2013 at Fudan University Shanghai Cancer Center were retrospectively reviewed. All patients treated with chemotherapy and ConvTRT (2 Gy per fraction daily, DT ≥ 56 Gy) or HypoTRT (2.5 Gy per fraction daily, DT = 55 Gy) were eligible for analysis. Progression-free survival (PFS) and overall survival (OS) were generated for different populations using the Kaplan-Meier method and compared using the log-rank test. Comparisons of failure patterns and toxicity were analyzed using the χ2 test.ResultsA total of 170 patients treated with HypoTRT (n = 69) or ConvTRT (n = 101) were eligible for analysis. The median PFS and OS were 13.7 and 25.3 months, respectively, in the ConvTRT cohort, which was similar to the HypoTRT cohort (PFS 18.2 months, p = 0.991, and OS 27.2 months, p = 0.698), with a median follow-up of 30 months. Multivariate analysis revealed that PCI and TNM stage were prognostic factors for PFS and that PCI was prognostic for OS. The patterns of failure (stratified by local-regional recurrence, distant metastasis or both as first relapse) were similar between the dose cohorts (p = 0.693, p = 0.330, p = 0.572). Distant metastasis remained the main failure pattern. The brain was the most frequent remote failure site, followed by bone, liver and adrenal gland. PCI improved the 2-year survival rate from 46.1% to 70.0% and the 2-year PFS rate from 20.9% to 45.3%, respectively (p < 0.001). Grade ≥3 esophagitis and pneumonitis occurred in 9.9% and 11.9%, respectively, of the patients in the ConvTRT cohort and in 11.6% and 10.0%, respectively, of those in the HypoTRT cohort (p = 0.815).ConclusionThis retrospective analysis demonstrated that HypoTRT or ConvTRT combined with etoposide/platinum chemotherapy yielded statistically similar survival, treatment failure outcomes, and toxicity profiles. PCI correlated with improved PFS and OS.

Neuron-specific enolase and response to initial therapy are important prognostic factors in patients with small cell lung cancer.

The prognostic factors for the survival of small cell lung cancer (SCLC) patients are still widely debated. The aim of this study was to identify the clinical features and prognostic factors in SCLC patients. A retrospective study was conducted on SCLC patients who were treated in our hospital between July 2010 and July 2015. Comparison of overall survival (OS) was performed using the Kaplan-Meier method. Prognostic factors for OS were identified by multivariate Cox regression models. A total of 523 patients with complete data and ECOG 0-2 were enrolled in our study. A total of 383 patients (73.2%) were diagnosed with ES-SCLC (extensive-stage SCLC) and 140 patients (26.8%) were diagnosed with LS-SCLC (limited-stage SCLC). In all patients, early disease stage, good ECOG, normal neuron-specific enolase (NSE), thoracic radiotherapy, ≥4 cycles of chemotherapy, prophylactic cranial irradiation, good response to initial therapy were independent favorable prognostic factors for OS, along with gender, age, CEA and CA125. In LS-SCLC patients, normal NSE, normal CEA, good response to initial therapy and surgery were independent favorable prognostic factors for OS. In ES-SCLC patients, good ECOG, normal NSE, thoracic radiotherapy, ≥4 cycles of chemotherapy, prophylactic cranial irradiation and good response to initial therapy were independent favorable prognostic factors for OS. Remarkably, NSE and response to initial therapy were independent prognostic factors for OS in all SCLC patients, LS-SCLC patients and ES-SCLC patients. The normal NSE and good response to initial therapy predicted a better survival for SCLC patients, regardless of disease stage.

P2.05-037 Higher Radiation Dose is Still Promising in Patients with Complete Response to 50 Gy of Early Thoracic Radiotherapy with Chemotherapy?: Topic: RT Techniques

For limited stage small cell lung cancer (LSCLC), early thoracic radiotherapy (TRT) with chemotherapy and radiation dose more than 60Gy has been suggested as standard therapy. We aim to evaluate the survival outcomes in LSCLC patients with complete response (CR) to 50 Gy of TRT with chemotherapy. One hundred and fifteen patients with LSCLC who completed the TRT from August 2005 to March 2014 were reviewed retrospectively. We evaluated the age, gender, smoking status, AJCC stage, PET parameters, tumor volume, dose and timing of TRT, duration of treatment, and prophylactic cranial irradiation (PCI) as a prognostic variables. Gross tumor volume (GTV) was defined as the post-chemotherapy tumor volume at the time of the first TRT planning and the pre-chemotherapy involved lymph nodes. Clinical target volume (CTV) was defined as GTV with minimum 7mm margin including the first echelon drainage lymph node station. At the time of 50 Gy of TRT, follow up chest CT was performed to all patient and only patients who showed non-CR received 10 Gy or more radiation. Dose of TRT was median 50 Gy (range, 42 to 65 Gy). Ninety-seven (84.3%) patients received concurrent chemoradiotherapy (CRT) and PCI was performed in all eligible patients. For all patients, median survival was 27.8 months. Two & 3-year OS were 60.7% and 38.58%, respectively. Sixty-five patients (56.5%) showed the complete response (CR) and fifty patients (43.5%) showed non-CR. There was correlation between tumor response to 50Gy of TRT and the ratio of GTV to CTV (p=0.008) or AJCC stage (p=0.036). With univariate analysis, AJCC stage (p<0.001), ratio of GTV to CTV (p = 0.005), tumor response to 50Gy of TRT (p = 0.004), the duration from the start date of induction chemotherapy to the end of TRT (SER, p = 0.003), and PCI (p = 0.035) were statistically significant predictor of OS. Multivariate Cox regression demonstrated that AJCC stage (p<0.001) and SER (p = 0.007) only were significant. In patients with SER <80days & CR to 50Gy TRT, median survival was not yet reached until now. LSCLC patients who showed CR to 50 Gy of TRT and completed TRT within 80days represented the outstanding survival outcomes. Based on these results, we need the further study evaluating whether dose escalation more than 50 Gy is promising for survival improvement in patients with CR at the time of 50 Gy of early TRT and chemotherapy.

Abstract 3371: Genetic, phenotypic and functional characterisation of vasculogenic mimicry in small-cell lung cancer

Abstract Background: Despite a good initial response to chemotherapy, most small cell lung cancer (SCLC) patients relapse with drug resistant disease. Targeting tumor vasculature in SCLC with anti-angiogenic drugs produced disappointing results, therefore angiogenesis-independent tumor vascularisation pathways warrant further investigation. Vasculogenic mimicry (VM) is the ability of tumor cells to mimic endothelial cells by trans-endothelial differentiation, characterised by increased expression of vascular markers including VE-Cadherin. We previously demonstrated that VM correlates with poor Overall Survival in Limited Stage SCLC patients and sought to phenotypically and genetically characterise VM vessels using SCLC Circulating Tumour Cells (CTCs) and CTC-Derived eXplant (CDX) models1 and to explore the functional significance of VE-Cadherin for VM formation in vitro and in vivo.Methods: VM was evaluated using CD31/periodic acid-Schiff (PAS) staining in tumors from 10 CDX models. Laser Capture Microdissection (LCM) and Copy Number Alteration (CNA) analysis was performed on CDX regions with high and low levels of VM. VE-Cadherin expression in SCLC CTCs was evaluated following ISET microfiltration of patients’ blood and Immunofluorescence staining for DAPI, CD45, pan Cytokeratin and VE-Cadherin. VE-Cadherin function was evaluated in vitro by Matrigel network assay using H446 SCLC cells and H446 shRNA VE-Cadherin knockdown (KD) cell lines, and in vivo by growth as xenografts, further treated with Cisplatin. Results: VM was present in CDX models and LCM followed by CNA analysis of VM vessels confirmed their SCLC origin. ISET microfiltration and immunofluorescent staining of CTCs from 37/38 SCLC patients revealed VE-Cadherin as a putative VM biomarker in SCLC CTCs. VE-Cadherin shRNA KD in VM competent H446 SCLC cells abrogated their ability to form VM networks in vitro and in vivo. Cisplatin treatment of mice bearing H446 VE-Cadherin KD tumors resulted in reduced cisplatin binding compared to parental H446 tumors. Conclusions: VM is present in CDX models and co-localises with VE-Cadherin expression. CNA confirms that VM vessels originate from tumour, and these VM-enriched regions bear a unique chromosomal signature compared to the low-VM regions. VE-Cadherin is required for network formation in vitro and VE-Cadherin levels and VM vessel numbers are positively correlated in vivo. Moreover, levels of VM in tumors had significant impact on both tumour growth kinetics and cisplatin delivery which has implications for drug senstivity. Our future research will interrogate the VM signaling pathway in SCLC and its role in chemosensitivity and establish feasibility for therapeutic targeting. Citation Format: Francesca Trapani, Stuart Williamson, Robert L. Metcalf, Hui Sun Leong, Benjamin Abbott, Jenny Antonello, Cassandra Hodgkinson, Lynsey Franklin, Mary J. Hendrix, Richard E b Seftor, Elisabeth Seftor, Dominic Rothwell, Ged Brady, Crispin Miller, Fiona H. Blackhall, Kathryn L. Simpson, Caroline Dive. Genetic, phenotypic and functional characterisation of vasculogenic mimicry in small-cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3371.

Effect of Accurate Staging Using Positron Emission Tomography on the Outcomes of Prophylactic Cranial Irradiation in Patients With Limited Stage Small-Cell Lung Cancer

BackgroundProphylactic cranial irradiation (PCI) was reported to offer survival benefits in patients with limited stage small-cell lung cancer (LS-SCLC). However, earlier studies did not routinely use positron emission tomography (PET) as part of the initial evaluation, thereby reducing the accuracy of tumor staging. We examined the effect of more accurate staging with PET on the role of PCI in patients with LS-SCLC. Patients and MethodsWe retrospectively collected data from 280 patients with LS-SCLC who had objective responses after combined chemoradiotherapy between 2001 and 2013. The outcomes of PCI were analyzed after stratifying the patients according to whether or not the initial staging included PET imaging. ResultsThe risk of brain metastasis as the first site of relapse was lower in patients who received PCI than in those who did not, only in patients without initial PET imaging (13.3% vs. 37.0%; P = .020), but not in patients with initial PET imaging (34.3% vs. 41.1%; P = .243). There was no survival difference between subgroups who received PCI or not (5-year survival rates, 34.8% vs. 34.1%; P = .938). Patients who had initial staging evaluation with PET achieved long-term survival even without PCI (5-year survival rates, 38.3% with PCI, 38.6% without PCI). ConclusionThe role of PCI needs to be critically reassessed in LS-SCLC patients whose initial staging evaluation included PET because the benefit of PCI was not apparent for them.

The Highest Metabolic Activity on FDG PET Is Associated With Overall Survival in Limited-Stage Small-Cell Lung Cancer.

We evaluated the prognostic value of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) parameters for limited-stage small-cell lung cancer (LS-SCLC).We retrospectively enrolled 59 LS-SCLC patients who underwent pretreatment FDG PET/CT. Various PET parameters were measured in all malignant lesions, and we recorded the highest maximum standardized uptake value (SUVmax), and sum of metabolic tumor volume (MTVsum) and total lesion glycolysis (TLGsum). The relationship between the highest SUVmax and volumetric PET parameters was evaluated. The prognostic significances of PET parameters and clinical variables were assessed using Cox's proportional hazard regression analysis. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan–Meier method.The SUVmax of the highest metabolic lesion had a significant positive correlation with MTVsum and TLGsum (P < 0.001). Upon multivariate analysis, the highest SUVmax was an independent predictor of OS (1 unit increase, hazard ratio [HR]: 1.133, P = 0.003) and MTVsum was a significant prognostic factor of PFS (10-cm3 increase, HR: 1.027, P = 0.034) after adjusting for age, sex, performance status, tumor stage, and treatment modality. The highest SUVmax was a prognostic factor for PFS with marginal significance (1 unit increase, HR: 1.078, P = 0.053). Patients with higher SUVmax (≥11) were also characterized by a significantly shorter median OS (P < 0.001) and PFS (P = 0.002) compared with patients with lower SUVmax.The highest SUVmax is an independent prognostic factor for survival in LS-SCLC patients. Therefore, the highest SUVmax might be a possible imaging biomarker for risk stratification in LS-SCLC. A further study in a large cohort is needed to validate the prognostic significance of the parameter.

Radiation-related lymphopenia as a new prognostic factor in limited-stage small cell lung cancer.

The purpose of this study was to investigate whether the minimum absolute lymphocyte count during radiotherapy (min ALC) and the absolute lymphocyte count 1month after radiotherapy (post ALC) could predict clinical outcome in limited-stage small cell lung cancer (LS-SCLC) patients. We analyzed 73 LS-SCLC patients treated with chemotherapy and radiotherapy; we collected data on the min ALC from 62 patients and on the post ALC from 60 patients. Both min ALC and post ALC were statistically significant predictors of overall survival in multivariate analysis (hazard ratio [95% confidence interval] 2.67 [1.06-6.75], P = 0.038 and 2.62 [1.19-5.74], P = 0.016, respectively). The median overall survival of the patients with min ALC ≤297 and >297cells/μL was 12.2 and 35.3months, respectively (P < 0.001). Patients with post ALC ≤698 and >698cells/μL had an overall survival of 19.3 and 46.9months, respectively (P = 0.001). The median overall survival of the lymphopenia (min ALC ≤ 297cells/μL or post ALC ≤ 698cells/μL) and the non-lymphopenia group (min ALC > 297cells/μL and post ALC > 698 cells/μL) was 19.0 and 131.7months, respectively, while the median progression survival was 8.1 and 16.6months, respectively (P < 0.001 and P = 0.001). Radiation-related lymphopenia could predict poor survival in LS-SCLC. Its prognostic role should be evaluated in further prospective studies.