Predicting Radiation-Induced Lung Injury in Patients With Lung Cancer: Challenges and Opportunities.

Radiation-induced lung injury (RILI) is one of the main dose-limiting toxicities in radiation therapy (RT) for lung cancer. Approximately 10% to 20% of patients show signs of RILI of variable severity. The reason for the wide range of RILI severity and the mechanisms underlying its development are only partially understood. A number of clinical risk factors have been identified that can aid in clinical decision making. Technological advancements in RT and the use of strict organ-at-risk dose constraints have helped to reduce RILI. Predicting patients at risk for RILI may be further improved with a combination of cytokine assessments, γH2AX-assays in leukocytes, or epigenetic markers. A complicating factor is the lack of an objective definition of RILI. Tools such as computed tomography densitometry, fluorodeoxyglucose-positron emission tomography uptake, changes in lung function measurements, and exhaled breath analysis can be implemented to better define and quantify RILI. This can aid in the search for new biomarkers, which can be accelerated by omics techniques, single-cell RNA sequencing, mass cytometry, and advances in patient-specific in vitro cell culture models. An objective quantification of RILI combined with these novel techniques can aid in the development of biomarkers to better predict patients at risk and allow personalized treatment decisions.

Photons or protons for reirradiation in (non-)small cell lung cancer: Results of the multicentric ROCOCO in silico study.

OBJECTIVE: Locally recurrent disease is of increasing concern in (non-)small cell lung cancer [(N)SCLC] patients. Local reirradiation with photons or particles may be of benefit to these patients. In this multicentre in silico trial performed within the Radiation Oncology Collaborative Comparison (ROCOCO) consortium, the doses to the target volumes and organs at risk (OARs) were compared when using several photon and proton techniques in patients with recurrent localised lung cancer scheduled to undergo reirradiation. METHODS: 24 consecutive patients with a second primary (N)SCLC or recurrent disease after curative-intent, standard fractionated radio(chemo)therapy were included in this study. The target volumes and OARs were centrally contoured and distributed to the participating ROCOCO sites. Remaining doses to the OARs were calculated on an individual patient's basis. Treatment planning was performed by the participating site using the clinical treatment planning system and associated beam characteristics. RESULTS: Treatment plans for all modalities (five photon and two proton plans per patient) were available for 22 patients (N = 154 plans). 3D-conformal photon therapy and double-scattered proton therapy delivered significantly lower doses to the target volumes. The highly conformal techniques, i.e., intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), CyberKnife, TomoTherapy and intensity-modulated proton therapy (IMPT), reached the highest doses in the target volumes. Of these, IMPT was able to statistically significantly decrease the radiation doses to the OARs. CONCLUSION: Highly conformal photon and proton beam techniques enable high-dose reirradiation of the target volume. They, however, significantly differ in the dose deposited in the OARs. The therapeutic options, i.e., reirradiation or systemic therapy, need to be carefully weighed and discussed with the patients. ADVANCES IN KNOWLEDGE: Highly conformal photon and proton beam techniques enable high-dose reirradiation of the target volume. In light of the abilities of the various highly conformal techniques to spare specific OARs, the therapeutic options need to be carefully weighed and patients included in the decision-making process.

Contact of a tumour with the pleura is not associated with regional recurrence following stereotactic ablative radiotherapy for early stage non-small cell lung cancer.

BACKGROUND AND PURPOSE: The aim was to investigate the incidence of isolated regional failure following stereotactic ablative radiotherapy (SABR) and risk factors for recurrence. MATERIALS AND METHODS: Early stage non-small cell lung cancer (NSCLC) patients treated with SABR were included in this retrospective cohort study, with isolated regional recurrence (IRR) as primary endpoint, distant recurrence (DR) and overall survival (OS) as secondary endpoints. Survival analyses were performed using the cumulative incidence function (IRR and DR) or the Kaplan-Meier method (OS) and Cox proportional hazards modelling for univariate and multivariate analyses. The prognostic effect of contact between the tumour and the pleura was investigated using the CT scans used for SABR planning. RESULTS: A total of 554 patients were included, of whom 494 could be analysed for IRR. The median follow-up for surviving patients was 48.1 months. Twenty-one patients developed an IRR (4%). The cumulative incidence of IRR and DR after 1-, 2-, and 5 years was 2%, 3%, 7% and 8%, 15% and 21%, respectively. Two year OS was 71%. The presence and type of pleural contact was not associated with any of the studied outcomes. CONCLUSION: The presence, type and length of pleural contact as surrogate for visceral pleural invasion were not predictive for outcome. Further studies focussing on risk factors for occult nodal involvement, (I)RR, distant metastases and mortality in early stage NSCLC are warranted for the development of risk adapted diagnostic, treatment and follow-up strategies as more younger, operable and fitter patients receive SABR.

Photons, protons or carbon ions for stage I non-small cell lung cancer - Results of the multicentric ROCOCO in silico study.

PURPOSE: To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial. METHODS: For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions. RESULTS: The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ. CONCLUSION: On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient.

Nodal recurrence after stereotactic body radiotherapy for early stage non-small cell lung cancer: Incidence and proposed risk factors.

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for patients with early stage non-small cell lung cancer (NSCLC) who are inoperable due to comorbid disease or who refuse surgery. SBRT results in an excellent local control rate of more than 90%, which is comparable to surgery, while short and long-term overall toxicity is low. Surgically treated patients are often more extensively staged pre-operatively, e.g. with endobronchial ultrasound and/or mediastinoscopy, and typically undergo intra-operative lymph node dissection or sampling. Occult nodal metastases (ONM), detected by lymph node dissection, have been shown to increase the incidence of regional recurrence (RR) after surgery, which is associated with poor outcome. In patients undergoing SBRT, however, definite pathological nodal staging is lacking and so other ways to identify patients at high risk for ONM and RR are desirable. The aim of this systematic review is to summarize the incidence of, and risk factors for, RR after SBRT and compare these to those after surgery. The available evidence shows the incidence of RR after SBRT or surgery to be comparable, despite more elaborate pre- and intra-operative lymph node evaluation in surgical patients. However, the fact that this finding is based on mostly retrospective studies in which the majority of patients treated with SBRT were inoperable, needs to be taken into consideration. For now, there is no evidence that inoperable clinical stage I patients with no indication of pathological lymph nodes on PET/CT will benefit from more invasive lymph node staging prior to SBRT.

Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy.

BACKGROUND AND PURPOSE: The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome. MATERIAL AND METHODS: A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS). RESULTS: No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p=0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p=0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p=0.02 and 0.03). CONCLUSIONS: Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial.

Particle therapy for non-small cell lung tumors: where do we stand? A systematic review of the literature.

This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of non-small cell lung cancer and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic particle therapy are discussed.