Radiation combined with immune checkpoint inhibitors for unresectable locally advanced non-small cell lung cancer: synergistic mechanisms, current state, challenges, and orientations.

Until the advent of immune checkpoint inhibitors (ICIs), definitive radiotherapy (RT) concurrently with chemotherapy was recommended for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC). The trimodality paradigm with consolidation ICIs following definitive concurrent chemoradiotherapy has been the standard of care since the PACIFIC trial. Preclinical evidence has demonstrated the role of RT in the cancer-immune cycle and the synergistic effect of RT combined with ICIs (iRT). However, RT exerts a double-edged effect on immunity and the combination strategy still could be optimized in many areas. In the context of LA-NSCLC, optimized RT modality, choice, timing, and duration of ICIs, care for oncogenic addicted tumors, patient selection, and novel combination strategies require further investigation. Targeting these blind spots, novel approaches are being investigated to cross the borders of PACIFIC. We discussed the development history of iRT and summarized the updated rationale for the synergistic effect. We then summarized the available research data on the efficacy and toxicity of iRT in LA-NSCLC for cross-trial comparisons to eliminate barriers. Progression during and after ICIs consolidation therapy has been regarded as a distinct resistance scenario from primary or secondary resistance to ICIs, the subsequent management of which has also been discussed. Finally, based on unmet needs, we probed into the challenges, strategies, and auspicious orientations to optimize iRT in LA-NSCLC. In this review, we focus on the underlying mechanisms and recent advances of iRT with an emphasis on future challenges and directions that warrant further investigation. Taken together, iRT is a proven and potential strategy in LA-NSCLC, with multiple promising approaches to further improve the efficacy. Video Abstract.

A methodology to extract outcomes from routine healthcare data for patients with locally advanced non-small cell lung cancer.

BACKGROUND: Outcomes for patients in UK with locally advanced non-small cell lung cancer (LA NSCLC) are amongst the worst in Europe. Assessing outcomes is important for analysing the effectiveness of current practice. However, data quality is inconsistent and regular large scale analysis is challenging. This project investigates the use of routine healthcare datasets to determine progression free survival (PFS) and overall survival (OS) of patients treated with primary radical radiotherapy for LA NSCLC. METHODS: All LA NSCLC patients treated with primary radical radiotherapy in a 2 year period were identified and paired manual and routine data generated for an initial pilot study. Manual data was extracted information from hospital records and considered the gold standard. Key time points were date of diagnosis, recurrence, death or last clinical encounter. Routine data was collected from various data sources including, Hospital Episode Statistics, Personal Demographic Service, chemotherapy data, and radiotherapy datasets. Relevant event dates were defined by proxy time points and refined using backdating and time interval optimization. Dataset correlations were then tested on key clinical outcome indicators to establish if routine data could be used as a reliable proxy measure for manual data. RESULTS: Forty-three patients were identified for the pilot study. The manual data showed a median age of 67 years (range 46- 89 years) and all patients had stage IIIA/B disease. Using the manual data, the median PFS was 10.78 months (range 1.58-37.49 months) and median OS was 16.36 months (range 2.69-37.49 months). Based on routine data, using proxy measures, the estimated median PFS was 10.68 months (range 1.61-31.93 months) and estimated median OS was 15.38 months (range 2.14-33.71 months). Overall, the routine data underestimated the PFS and OS of the manual data but there was good correlation with a Pearson correlation coefficient of 0.94 for PFS and 0.97 for OS. CONCLUSIONS: This is a novel approach to use routine datasets to determine outcome indicators in patients with LA NSCLC that will be a surrogate to analysing manual data. The ability to enable efficient and large scale analysis of current lung cancer strategies has a huge potential impact on the healthcare system.

Development and validation of a prognostic nomogram model in locally advanced NSCLC based on metabolic features of PET/CT and hematological inflammatory indicators.

BACKGROUND: We combined the metabolic features of 18F-FDG-PET/CT and hematological inflammatory indicators to establish a predictive model of the outcomes of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiotherapy. RESULTS: A predictive nomogram was developed based on sex, CEA, systemic immune-inflammation index (SII), mean SUV (SUVmean), and total lesion glycolysis (TLG). The nomogram presents nice discrimination that yielded an AUC of 0.76 (95% confidence interval: 0.66-0.86) to predict 1-year PFS, with a sensitivity of 63.6%, a specificity of 83.3%, a positive predictive value of 83.7%, and a negative predictive value of 62.9% in the training set. The calibration curves and DCA suggested that the nomogram had good calibration and fit, as well as promising clinical effectiveness in the training set. In addition, survival analysis indicated that patients in the low-risk group had a significantly longer mPFS than those in the high-risk group (16.8 months versus 8.4 months, P < 0.001). Those results were supported by the results in the internal and external test sets. CONCLUSIONS: The newly constructed predictive nomogram model presented promising discrimination, calibration, and clinical applicability and can be used as an individualized prognostic tool to facilitate precision treatment in clinical practice.

Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p < 0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p = 0.012) and OS (p = 0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2% vs. 47.2%, p = 0.011) and superior OS (median 44.8 vs. 28.6 months, p = 0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.

The impact of different modalities of chemoradiation therapy and chemotherapy regimens on lymphopenia in patients with locally advanced non-small cell lung cancer.

Background: Chemotherapy and radiotherapy (RT) would induce lymphopenia, leading to a poor prognosis. This study investigated whether chemotherapy increased lymphopenia during RT and explored the impacts of different chemotherapy regimens on the lymphocyte counts of patients receiving RT. Methods: Clinical parameters and lymphocyte data were collected from 215 patients with locally advanced non-small cell lung cancer (LA-NSCLC). Severe lymphopenia (SRL) was defined as an absolute lymphocyte count (ALC) of ≤0.2×103 cells/µL. Patient overall survival (OS) was analyzed using the Kaplan-Meier method. The predictors of SRL were extracted using univariate and multivariate regression analyses with backward likelihood ratio elimination. Results: Compared with patients without SRL, patients with SRL with LA-NSCLC showed a poorer prognosis in terms of OS (P=0.003). Of the 215 patients, 130 underwent concurrent chemoradiotherapy (CCRT) and 85 underwent sequential chemoradiotherapy (SCRT). The OS was better in patients without SRL (in the CCRT group, P=0.01 and in the SCRT group, P=0.08). The mean ALCs for CCRT and SCRT did not differ significantly (P=0.27). The minimum ALC of CCRT was significantly lower than that of SCRT (P<0.0001). CCRT was a predictor of SRL (P=0.008). However, multivariate analysis showed that the different chemotherapy regimens were not predictors of SRL (all P>0.1). Conclusions: In LA-NSCLC, the outcomes of patients with SRL were poorer than those without SRL. RT and chemotherapy were the main factors affecting SRL development, while different chemotherapy regimens were not significantly associated with lymphocyte counts in LA-NSCLC.

Chemotherapy-free radiotherapy combined with immune checkpoint inhibitors: a new regimen for locally advanced non-small cell lung cancer?

Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC. Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy (iRT) have generated encouraging results. This review discusses the existing studies and prospective directions of chemotherapy-free iRT strategies in unresectable LA-NSCLC. Although the initial findings of chemotherapy-free iRT strategies have shown promising efficacy, we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free iRT. These challenges include determining the optimal dose and fractionation, precise target volume delineation, and identification of additional suitable patient cohorts. Furthermore, the feasibility of chemotherapy-free iRT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.

Causal relation between heart irradiation and survival of lung cancer patients after radiotherapy.

INTRODUCTION: In a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT. METHOD: NSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency. RESULTS: Daily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors. CONCLUSION: Our results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted.

Erring Characteristics of Deformable Image Registration-Based Auto-Propagation for Internal Target Volume in Radiotherapy of Locally Advanced Non-Small Cell Lung Cancer.

Purpose: Respiratory motion of locally advanced non-small cell lung cancer (LA-NSCLC) adds to the challenge of targeting the disease with radiotherapy (RT). One technique used frequently to alleviate this challenge is an internal gross tumor volume (IGTV) generated from manual contours on a single respiratory phase of the 4DCT via the aid of deformable image registration (DIR)-based auto-propagation. Through assessing the accuracy of DIR-based auto-propagation for generating IGTVs, this study aimed to identify erring characteristics associated with the process to enhance RT targeting in LA-NSCLC. Methods: 4DCTs of 19 patients with LA-NSCLC were acquired using retrospective gating with 10 respiratory phases (RPs). Ground-truth IGTVs (GT-IGTVs) were obtained through manual segmentation and union of gross tumor volumes (GTVs) in all 10 phases. IGTV auto-propagation was carried out using two distinct DIR algorithms for the manually contoured GTV from each of the 10 phases, resulting in 10 separate IGTVs for each patient per each algorithm. Differences between the auto-propagated IGTVs (AP-IGTVs) and their corresponding GT-IGTVs were assessed using Dice coefficient (DICE), maximum symmetric surface distance (MSSD), average symmetric surface distance (ASSD), and percent volume difference (PVD) and further examined in relation to anatomical tumor location, RP, and deformation index (DI) that measures the degree of deformation during auto-propagation. Furthermore, dosimetric implications due to the analyzed differences between the AP-IGTVs and GT-IGTVs were assessed. Results: Findings were largely consistent between the two algorithms: DICE, MSSD, ASSD, and PVD showed no significant differences between the 10 RPs used for propagation (Kruskal-Wallis test, ps > 0.90); MSSD and ASSD differed significantly by tumor location in the central-peripheral and superior-inferior dimensions (ps < 0.0001) while only in the central-peripheral dimension for PVD (p < 0.001); DICE, MSSD, and ASSD significantly correlated with the DI (Spearman's rank correlation test, ps < 0.0001). Dosimetric assessment demonstrated that 79% of the radiotherapy plans created by targeting planning target volumes (PTVs) derived from the AP-IGTVs failed prescription constraints for their corresponding ground-truth PTVs. Conclusion: In LA-NSCLC, errors in DIR-based IGTV propagation present to varying degrees and manifest dependences on DI and anatomical tumor location, indicating the need for personalized consideration in designing RT internal target volume.

The treatment in patients with unresectable locally advanced non-small cell lung cancer: Explorations on hot issues.

The treatment efficacy for patients with unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) stagnated for a long time until the advent of immunotherapy. Immune checkpoint inhibitors, particularly programmed cell death protein 1/programmed death-ligand 1 inhibitors, have thrived, reshaping the treatment landscape for patients with lung cancer. Based on the results of the PACIFIC trial, concurrent chemoradiotherapy followed by durvalumab has become the standard of care for patients with unresectable LA-NSCLC; however, numerous issues are yet to be resolved. Currently, several clinical trials are exploring an optimal treatment paradigm, and we have summarized them for comparison to eliminate barriers. In addition, we discuss better predictive biomarkers, therapeutic options for specific populations, and other challenges to identify directions for future research design.

Isotoxic investigation of 18F-FDG PET/CT-guided dose escalation with intensity-modulated radiotherapy for LA-NSCLC.

PURPOSE: This research compared differences of dosimetric and biological parameters between PET/CT-guided isotoxic SIB-IMRT plans and conventional radiotherapy plans for patients with LA-NSCLC, and it also evaluated the factors that affect dose escalation. MATERIALS AND METHODS: This study consisted of a retrospective cohort of thirty patients with IIIA-IIIB NSCLC. SIB-IMRT (Plan_iso) and conventional radiotherapy (Plan_primary) plans were generated using auto-planning. Dosimetric parameters such as mean lung dose (MLD) and other indicators were compared. Tumor control probability (TCP) of PTV and normal tissue complication probability (NTCP) of total lung, heart, esophagus, and spinal cord were calculated. The relationships between dose escalation and 3 D length of PTV and other factors were analyzed. Paired-samples t-test, Mann-Whitney U test, and Chi-Square test were performed for comparisons between datasets. A P < .05 was considered statistically significant. RESULTS: The dosimetric parameters of PTV in Plan_iso were higher than those of PTV in Plan_primary, and there were significant differences (p < .05). Compared with Plan_primary, Plan_iso slightly increased dosimetric parameters of the total lung, heart, spinal cord, esophagus, and MUs. The absolute differences were small. TCPs of PTV in Plan_iso were significantly higher than those in Plan_primary. NTCPs of the total lung, esophagus, and spinal cord in Plan_iso were higher than those in Plan_primary. There were significant differences, but the absolute differences were small. NTCP of heart in Plan_iso was slightly higher than that in Plan_primary, but there was no statistical difference. CONCLUSIONS: For LA-NSCLC, the SIB based on isotoxic radiotherapy can significantly increase TCP under the premise that the toxicity of OARs is comparable.

Enhancing Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer Patients with iCE, a Novel System for Automated Multi-Criterial Treatment Planning Including Beam Angle Optimization.

In this study, the novel iCE radiotherapy treatment planning system (TPS) for automated multi-criterial planning with integrated beam angle optimization (BAO) was developed, and applied to optimize organ at risk (OAR) sparing and systematically investigate the impact of beam angles on radiotherapy dose in locally advanced non-small cell lung cancer (LA-NSCLC). iCE consists of an in-house, sophisticated multi-criterial optimizer with integrated BAO, coupled to a broadly used commercial TPS. The in-house optimizer performs fluence map optimization to automatically generate an intensity-modulated radiotherapy (IMRT) plan with optimal beam angles for each patient. The obtained angles and dose-volume histograms are then used to automatically generate the final deliverable plan with the commercial TPS. For the majority of 26 LA-NSCLC patients, iCE achieved improved heart and esophagus sparing compared to the manually created clinical plans, with significant reductions in the median heart Dmean (8.1 vs. 9.0 Gy, p = 0.02) and esophagus Dmean (18.5 vs. 20.3 Gy, p = 0.02), and reductions of up to 6.7 Gy and 5.8 Gy for individual patients. iCE was superior to automated planning using manually selected beam angles. Differences in the OAR doses of iCE plans with 6 beams compared to 4 and 8 beams were statistically significant overall, but highly patient-specific. In conclusion, automated planning with integrated BAO can further enhance and individualize radiotherapy for LA-NSCLC.

Is a higher estimated dose of radiation to immune cells predictive of survival in patients with locally advanced non-small cell lung cancer treated with thoracic radiotherapy?

BACKGROUND AND PURPOSE: In previous studies, the estimated dose of radiation to immune cells (EDRIC) showed a correlation with overall survival (OS) of patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received thoracic radiotherapy. However, several factors such as gross tumor volume (GTV) and lymph node (N) stage may impact EDRIC. The purpose of this study was to identify the factors influencing EDRIC and to further assess the prognostic relevance of EDRIC. MATERIALS AND METHODS: We retrospectively analyzed 201 patients with LA-NSCLC who received radiotherapy between 2012 and 2017. EDRIC was calculated based on the model developed by Jin et al. Kaplan-Meier method and Cox proportional hazards regression were used to analyze the correlation of potential factors with OS, local progression-free survival (LPFS), and distant metastasis-free survival (DMFS). Spearman's rank correlation was used to assess the correlation between variables. RESULTS: Both GTV and N stage showed a positive correlation with EDRIC (r = 0.347, P < 0.001 and r = 0.249, P < 0.001, respectively). EDRIC was independently associated with DMFS (HR 1.185, P < 0.001). GTV was associated with OS (HR 1.006, P < 0.001), LPFS (HR 1.003, P = 0.017), and DMFS (HR 1.003, P = 0.032). While using GTV as a stratification factor in Kaplan-Meier analysis, EDRIC showed a trend of negative correlation with OS in GTV ≤ 66.6 cm3 group (P = 0.061). CONCLUSION: EDRIC was an independent prognostic factor for metastasis and it was affected by GTV and N stage. However, the effect of EDRIC on OS was influenced by GTV.

Early Detection of Recurrence in Patients With Locally Advanced Non-Small-Cell Lung Cancer via Circulating Tumor Cell Analysis.

BACKGROUND: Assays to identify circulating tumor cells (CTCs) might allow for noninvasive and sequential monitoring of lung cancer. We investigated whether serial CTC analysis could complement conventional imaging for detecting recurrences after treatment in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Patients with LA-NSCLC (stage II-III) who definitively received concurrent chemoradiation were prospectively enrolled, with CTCs from peripheral blood samples identified using an adenoviral probe that detects elevated telomerase activity present in nearly all lung cancer cells. A "detectable" CTC level was defined as 1.3 green flourescent protein-positive cells per milliliter of collected blood. Samples were obtained before, during (at weeks 2, 4, and 6), and after treatment (post-radiation therapy [RT]; at months 1, 3, 6, 12, 18, and 24). RESULTS: Forty-eight patients were enrolled. At a median follow-up of 10.9 months, 22 (46%) patients had disease recurrence at a median time of 7.6 months post-RT (range, 1.3-32.0 months). Of the 20 of 22 patients for whom post-RT samples were obtained, 15 (75%) had an increase in CTC counts post-RT. In 10 of these 15 patients, CTCs were undetectable on initial post-RT draw but were then detected again before radiographic detection of recurrence, with a median lead time of 6.2 months and mean lead time of 6.1 months (range, 0.1-12.0 months) between CTC count increase and radiographic evidence of recurrence. One patient with an early recurrence (4.7 months) had persistently elevated detectable CTC levels during and after treatment. CONCLUSION: These results indicate that longitudinal CTC monitoring in patients with LA-NSCLC treated with chemoradiation is feasible, and that detectable CTC levels in many patients meaningfully precede radiologic evidence of disease recurrence.

Dosimetric comparison and biological evaluation of PET- and CT-based target delineation for LA-NSCLC using auto-planning.

Using auto-planning, the dosimetric and biological differences between PET- and CT-based target delineation in LA-NSCLC were studied. Twenty-three patients with IIIA-IIIB NSCLC were included in this retrospective study. For each patient, two AP plans (Plan_PET, Plan_CT) were generated based on PET- and CT-based gross tumor volume (GTVPET, GTVCT). The volume, boundary and center of mass (COM) of GTVPET and GTVCT were compared. Dosimetric indicators such as mean lung dose (MLD) and so on were evaluated. Tumor control probability (TCP) of GTVPET and GTVCT and normal tissue complication probability (NTCP) of total lung and heart were calculated. A paired-samples t-test was used to check for significant differences (p < 0.05) between dataset. Volume of GTVPET was significantly smaller than that of GTVCT. Under the premise that GTVPET met the clinical requirements in Plan_PET, GTVCT couldn't satisfy the requirements. GTVCT met the clinical requirements in Plan_CT, and four cases of GTVPET could not satisfy the requirements. Compared with Plan_CT, Plan_PET significantly reduced MLD, V5, V10, V13, V15, V20, V30 and V40 of total lung, and MHD, V30 and V40 of heart, and MUs. No significant difference was observed with respect to Dmax of spinal cord. TCP of GTVPET in Plan_PET was significantly higher than that of GTVCT. NTCP of total lung in Plan_PET was significantly lower than that in Plan_CT. There were differences in volume, boundary, and COM of targets based on the two delineation methods. These led to differences in dosimetric and biological indicators. For LA-NSCLC, the way that most hospitals only use CT to delineate the target should be careful consideration.

Unmet Clinical Need in the Management of Locally Advanced Unresectable Lung Cancer: Treatment Strategies to Improve Patient Outcomes.

Stage III locally advanced non-small cell lung cancer (LA NSCLC) comprises the most heterogeneous group of patients, accounts for one-third of patients with lung cancer, and is unresectable at presentation. Multiple treatment approaches have evolved over the past few decades focusing on timing of chemoradiation (concurrent vs. sequential) and sequencing of therapy (induction vs. consolidation). Concurrent chemoradiation (CCRT) emerged as the standard of care for the majority of the patients worldwide. Despite improvements in median and overall survival (OS) using the concurrent approach, the rate of distant failure remains high. Consolidation with chemotherapy or targeted agents, adding more radiation dose, or induction chemotherapy did not improve OS. With continued research on defining optimal radiation doses and schedules and integrating novel systemic agents, immunotherapy consolidation has renewed optimism. Synergistic use of radiation and immunotherapy can prevent micrometastatic disease and reduce local failure and may have an abscopal effect in addition to survival benefits. The PACIFIC study reported an absolute progression-free survival benefit of 11.2 months with durvalumab consolidation after standard CCRT compared with placebo. The OS data with durvalumab consolidation are encouraging. Durvalumab is the only approved immunotherapy for unresectable stage III LA NSCLC. Improved survival confirms the definitive role of durvalumab as an effective adjuvant therapy after CCRT with no new safety signals. However, the potential mechanisms driving interaction between immunotherapy and chemoradiotherapy require definitive investigation. These mechanisms may help define the timing of immunotherapy initiation as neoadjuvant, adjuvant, or consolidation and maintenance therapy after progression. FUNDING: AstraZeneca Pharma India Limited.

Serial 4DCT/4DPET imaging to predict and monitor response for locally-advanced non-small cell lung cancer chemo-radiotherapy.

BACKGROUND AND PURPOSE: A FDG-PET/CT image feature with optimal prognostic potential for locally-advanced non-small cell lung cancer (LA-NSCLC) patients has yet to be identified, and neither has the optimal time for FDG-PET/CT response assessment; furthermore, nodal features have been largely ignored in the literature. We propose to identify image features or imaging time point with maximal prognostic power. MATERIALS AND METHODS: Consecutive consenting patients with LA-NSCLC receiving curative intent CRT were enrolled. 4DPET/4DCT scans were acquired 0, 2, 4, and 7 weeks during IMRT treatment. Eleven image features and their rates of change were recorded for each time point and tested for each of the possible outcome 2 years post CRT using the Kaplan-Meier method. RESULTS: 32 consecutive patients were recruited, 27 completing all scans. Restricting analysis to 4DPET/4DCT features and rates of change with p < 0.005, several volume-based features and their rates of change reached significance. Image features involving nodal disease were the only ones associated with overall survival. CONCLUSIONS: Several 4DPET/CT features and rates of change can reach significant association (p < 0.005) with outcomes, including overall survival, at many time points. The optimal time for adaptive CRT is therefore not constrained uniquely on imaging.

Rationale and Protocol for a Canadian Multicenter Phase II Randomized Trial Assessing Selective Metabolically Adaptive Radiation Dose Escalation in Locally Advanced Non-small-cell Lung Cancer (NCT02788461).

We explain the rationale for metabolically adaptive radiation dose escalation in stage III non-small-cell lung cancer and describe the design of a Canadian phase II randomized trial investigating this approach. In the trial, patients are randomized to either conventional chemoradiation treatment (60 Gy in 30 fractions) or metabolically adaptive chemoradiation, where fluorodeoxyglucose-avid tumor sub-volumes receive an integrated boost dose to a maximum of 85 Gy in 30 fractions. The trial sample size is 78 patients, and the target population is patients with newly diagnosed, inoperable stage III non-small-cell lung cancer treated with radical intent chemoradiation. The primary objective of the trial is to determine if dose escalation to metabolically active sub-volumes will reduce 2-year local-regional failure rate from 42.3% to 22.3%, when compared with standard treatment. The secondary objectives are to determine the effect of dose escalation on overall survival, progression-free survival, quality of life, and rate of grade 3 to 5 toxicities.

Equivalent Outcome of Patients with Locally Advanced NSCLC Treated with Salvage Surgery Compared to Induction Chemotherapy Followed by Surgical Resection.

BACKGROUND: There have, so far, been few previous reports concerning the use of salvage surgery in small number of patients with primary lung cancer and there are no reports currently available regarding salvage surgery compared to other treatments. PATIENTS AND METHODS: The postoperative complications and long-term survival of patients with non-small cell lung cancer (NSCLC) who received salvage surgery compared to induction chemotherapy followed by surgery from 2000 and 2013, were evaluated. RESULTS: During the study period, 1,847 consecutive patients with lung cancer underwent pulmonary resection at our Institution. Salvage operations were performed in 16 (0.9%) patients. The clinical stages were diagnosed as stage IIB in 1, IIIA in 8, IIIB in 6 and stage IV in 1 patient. The mean interval between initial treatment and surgery was 31.4 months. The surgical procedures were lobectomy in 9, pneumonectomy in 4 and partial resection in 3 patients. The operation was performed during a mean of 303 min; no case required blood transfusion. Complete resection was performed in 81% of the patients. Thus, the morbidity was 31.3% and the mortality rate was 0%. The five-year overall survival (OS) rates in the patients with induction chemotherapy followed by surgery and salvage surgery were 65.2 and 62.2%, respectively, (p=0.460) when OS was calculated from the date of registration to the date of initial treatment. The median survival for patients receiving salvage surgery was 64.4 months at any rate when OS was calculated from the date of registration for initial treatment or surgery. CONCLUSION: Salvage surgery can be performed safely with no mortality and is associated with a reasonable long-term survival, equivalent to the outcome of induction chemotherapy followed by surgical resection.

Is performing lobectomy after the use of bevacizumab for a lung tumor dangerous?

Recent new drugs, such as bevacizumab (Bev), also result in a remarkable response. However, the safety of major lung resection after the use of Bev remains controversial. Is it really dangerous to perform major lung resection after the use of Bev for a lung tumor? In this report, we describe two patients who underwent surgery safely without fragile pathological findings of the vessels.

A phase II single-arm study of induction chemotherapy with cisplatin and gemcitabine followed by concurrent cisplatin and gemcitabine with thoracic radiation for unresectable locally advanced non-small cell lung cancer.

OBJECTIVES: The aim of this study was to evaluate the efficacy and tolerability of the combination of cisplatin-gemcitabine with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: This was a phase II, multicenter, open-label, single-arm trial in treatment-naïve patients with stage IIIA and IIIB LA-NSCLC. After three induction cycles with gemcitabine 1250 mg/m(2) plus cisplatin 80 mg/m(2), two concurrent chemoradiotherapy cycles with gemcitabine 300 mg/m(2), cisplatin 80 mg/m(2), and radiotherapy (63 Gy) were administered. The primary endpoint was response rate after induction chemotherapy followed by concurrent chemoradiotherapy. Secondary endpoints included time to progressive disease (TtPD), overall survival (OS), and safety. RESULTS: Overall, 49 patients (median age 63.4 years; 73.5% male; Karnofsky performance status scores of 80, 85, 90, and 100 [16.3%, 2.0%, 49.0%, and 32.7%, respectively]; disease stage IIIA or IIIB 28.6% and 71.4%, respectively) were enrolled and treated. Response rate was 38.8% (95% confidence interval [CI] 25.2-53.8%). Median TtPD was 11.4 months (95% CI 9.4-12.9). Median OS was 21.8 months (95% CI 17.5-26.0), with 1- and 2-year survival rates of 70.8% and 43.7%, respectively. Overall, six patients discontinued from study treatment due to adverse events (AEs), of which two were serious AEs. The most relevant grade 3/4 AEs were neutropenia and thrombocytopenia in induction chemotherapy and chemoradiotherapy, and grade 3 events related to radiation in acute chemoradiotherapy, e.g. dysphagia, radiation pneumonitis, and radiation esophagitis. CONCLUSIONS: Induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine (300 mg/m(2)) and cisplatin was associated with acceptable toxicity. The observed median OS time was 21.8 months. Response evaluation was difficult as in many cases it was not possible to differentiate tumor progression from local radiofibrosis.