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Small-cell lung cancer is the most aggressive form of lung neoplasia, treated in recent decades with chemoradiotherapy in case of limited stage and chemotherapy alone at the metastatic stage. In the last few years, the advent of immunotherapy has changed the landscape in the treatment of non-small-cell lung cancer, and to a lesser degree in small-cell lung cancer. Despite the recent advances in research, small-cell lung cancer is still considered an aggressive and lethal disease characterized by high recurrence or metastatic potential. As stereotactic radiotherapy has established itself as the standard of care in the early stage of inoperable non-small-cell lung cancer and in metastatic disease to treat brain and extracranial metastases, these same issues now arise in the management of small-cell lung cancer. This article aims to review the current knowledge and the potential of stereotactic radiotherapy in small-cell lung cancer., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-PET results., Methods: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [ 18 F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m 2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m 2 intravenously once every 3 weeks and vinorelbine 30 mg/m 2 intravenously on day 1 and 60 mg/m 2 orally [or 30 mg/m 2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m 2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m 2 intravenously and vinorelbine 20 mg/m 2 intravenously on day 1 and 40 mg/m 2 orally (or 20 mg/m 2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing., Findings: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [ 18 F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment)., Interpretation: A thoracic radiotherapy boost, based on interim [ 18 F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [ 18 F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC., Funding: Programme Hospitalier de Recherche Clinique National 2014., Competing Interests: Declaration of interests EM declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian Medical Systems, AstraZeneca, MSD, Janssen, and Sanofi; support for attending meetings or travel, or both, from Ipsen, Janssen, and AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca and Janssen. IB-R declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis 3A and Curium; payment for expert testimony from Curium; and support for attending meetings or travel, or both, from Novartis 3A. CLP declares payment or honoraria to her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca and Amgen; support for attending meetings or travel, or both, paid to her institution from Janssen and Roche; and participation on a data safety monitoring board or advisory board paid to her institution for AstraZeneca, Varian, MSD, and Roche. EG-L declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, and Takeda; and support for attending meetings or travel, or both, from Takeda, MSD, AstraZeneca, and Roche. CA-V declares support for attending meetings or travel, or both, from Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie; and participation on a data safety monitoring board or advisory board for Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie. ALan and EA are employees of the French Intergroup (Intergroupe Francophone de Cancérologie Thoracique). GZ declares consulting fees paid to his institution from AstraZeneca, BMS, Takeda, and Roche; payment or honoraria to his institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Inventiva, BMS, and Pfizer; support for attending meetings or travel, or both, from Roche, BMS, Abbvie, Pfizer, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services to his institution by Foundation Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. 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Background: Stereotactic Body Radiation Therapy (SBRT) is an innovative modality based on high precision planning and delivery. Cancer with bone metastases and oligometastases are associated with an intermediate or good prognosis. We assume that prolonged survival rates would be achieved if both the primary tumor and metastases are controlled by local treatment. Our purpose is to demonstrate, via a multicenter randomized phase III trial, that local treatment of metastatic sites with curative intent with SBRT associated of systemic standard of care treatment would improve the progression-free survival in patients with solid tumor (breast, prostate and non-small cell lung cancer) with up to 3 bone-only metastases compared to patients who received systemic standard of care treatment alone., Methods: This is an open-labeled randomized superiority multicenter phase III trial. Patients with up to 3 bone-only metastases will be randomized in a 1:1 ratio.between Arm A (Experimental group): Standard care of treatment & SBRT to all bone metastases, and Arm B (Control group): standard care of treatment. For patients receiving SBRT, radiotherapy dose and fractionation depends on the site of the bone metastasis and the proximity to critical normal structures. This study aims to accrue a total of 196 patients within 4 years. The primary endpoint is progression-free survival at 1 year, and secondary endpoints include Bone progression-free survival; Local control; Cancer-specific survival; Overall survival; Toxicity; Quality of life; Pain score analysis, Cost-utility analysis; Cost-effectiveness analysis and Budget impact analysis., Discussion: The expected benefit for the patient in the experimental arm is a longer expectancy of life without skeletal recurrence and the discomfort, pain and drastic reduction of mobility and handicap that the lack of local control of bone metastases eventually inflicts., Trials Registration: ClinicalTrials.gov NCT03143322 Registered on May 8th 2017. Ongoing study.

Purpose: The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non-small-cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. 2-Deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) and [ 18 F]fluoromisonidazole ([ 18 F]FMISO) (hypoxia) uptake on pre-radiotherapy positron emission tomography (PET)/X-ray computed tomography (CT) have been independently reported to identify intratumor subvolumes at higher risk of relapse after radiotherapy. We have compared the [ 18 F]FDG and [ 18 F]FMISO volumes defined by PET/CT in NSCLC patients included in a prospective study., Procedures: Thirty-four patients with non-resectable lung cancer underwent [ 18 F]FDG and [ 18 F]FMISO PET/CT before (pre-RT) and during radiotherapy (around 42 Gy, per-RT). The criteria were to delineate 40 % and 90 % SUVmax thresholds on [ 18 F]FDG PET/CT (metabolic volumes), and SUV > 1.4 on pre-RT [ 18 F]FMISO PET/CT (hypoxic volume). The functional volumes were delineated within the tumor volume as defined on co-registered CTs., Results: The mean pre-RT and per-RT [ 18 F]FDG volumes were not statistically different (30.4 cc vs 22.2; P = 0.12). The mean pre-RT SUVmax [ 18 F]FDG was higher than per-RT SUVmax (12.7 vs 6.5; P < 0.0001). The mean [ 18 F]FMISO SUVmax and volumes were 2.7 and 1.37 cc, respectively. Volume-based analysis showed good overlap between [ 18 F]FDG and [ 18 F]FMISO for all methods of segmentation but a poor correlation for Jaccard or Dice Indices (DI). The DI maximum was 0.45 for a threshold at 40 or 50 %., Conclusion: The correlation between [ 18 F]FDG and [ 18 F]FMISO uptake is low in NSCLC, making it possible to envisage different management strategies as the studies in progress show.

Purpose: Chemoradiotherapy is the reference curative-intent treatment for nonresectable locally advanced non-small-cell lung carcinoma (NSCLC), with unsatisfactory survival, partially due to radiation resistance in hypoxic tissues. The objective was to update survival and toxicity at 3 years following radiotherapy boost to hypoxic tumours in NSCLC patients treated with curative-intent chemoradiotherapy., Methods: This was an open-label, nonrandomized, multicentre, phase II clinical trial. 18 F-Fluoromisonidazole ( 18 F-FMISO) PET/CT was used to determine the hypoxic profile of the patients. 18 F-FMISO-positive patients and those without organ-at-risk constraints received a radiotherapy boost (70-84 Gy); the others received standard radiotherapy (66 Gy). Overall survival (OS), progression-free survival (PFS) and safety were assessed., Results: A total of 54 patients were evaluated. OS and PFS rates at 3 years were 48.5% and 28.8%, respectively. The median OS in the 18 F-FMISO-positive patients was 25.8 months and was not reached in the 18 F-FMISO-negative patients (p = 0.01). A difference between the groups was also observed for PFS (12 months vs. 26.2 months, p = 0.048). In 18 F-FMISO-positive patients, no difference was observed in OS in relation to dose, probably because of the small sample size (p = 0.30). However, the median OS seemed to be in favour of patients who received the radiotherapy boost (26.5 vs. 15.3 months, p = 0.71). In patients who received the radiotherapy boost, no significant late toxicities were observed., Conclusion: 18 F-FMISO uptake in NSCLC patients is strongly associated with features indicating a poor prognosis. In 18 F-FMISO-positive patients, the radiotherapy boost seemed to improve the OS by 11.2 months. A further clinical trial is needed to investigate the efficacy of a radiotherapy boost in patients with hypoxic tumours.

Background: Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on 18 FDG and 18 F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy., Method: Twenty-one NSCLC patients, selected from a prospective phase II trial, had 18 FDG- and 18 F-miso PET/CT before the start of radiotherapy and 18 FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment 18 FDG hotspot (70% of SUV max ) (plan 2), pre-treatment 18 F-miso target (SUV max  > 1.4) (plan 3) and per-treatment 18 FDG residual (40% of SUV max ). (plan 4)., Results: The mean target volumes were 4.8 cc (± 1.1) for 18 FDG hotspot, 38.9 cc (± 14.5) for 18 F-miso and 36.0 cc (± 10.1) for per-treatment 18 FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for 18 FDG hotspot, 18 F-miso and per-treatment 18 FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in 18 FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in 18 F-miso and per-treatment 18 FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to 18 F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for 18 FDG hotspot and per-treatment 18 FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to 18 FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for 18 FDG hotspot and 18 F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios., Conclusion: Escalated doses can be selectively planned in NSCLC target volumes delineated on 18 FDG and 18 F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials., Trial Registration: (RTEP5, NCT01576796 , registered 15 june 2012).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18 F-misonidazole ( 18 F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18 F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18 F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18 F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18 F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18 F-FMISO-negative patients ( P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18 F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18 F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non-small cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. Areas of high (18)F-FDG uptake on preradiotherapy (18)F-FDG PET/CT have been reported to identify intratumor subvolumes at high risk of relapse after radiotherapy. We wanted to confirm these observations on a cohort of patients included in 3 sequential prospective studies. Our aim was to assess an appropriate threshold (percentage of maximum standardized uptake value [SUVmax]) to delineate subvolumes on staging (18)F-FDG PET/CT scans assuming that a smaller target volume would facilitate isotoxic radiotherapy dose escalation., Methods: Thirty-nine patients with inoperable stage II or III NSCLC, treated with chemoradiation or with radiotherapy alone, were extracted from 3 prospective studies (ClinicalTrials.gov identifiers NCT01261585, NCT01261598, and RECF0645). All patients underwent (18)F-FDG PET/CT at initial staging, before radiotherapy, during radiotherapy, and during systematic follow-up in a single institution. All (18)F-FDG PET/CT acquisitions were coregistered on the initial scan. Various subvolumes in the initial acquisition (30%, 40%, 50%, 60%, 70%, 80%, and 90% SUVmax thresholds) and in the 3 subsequent acquisitions (40% and 90% SUVmax thresholds) were pasted on the initial scan and compared., Results: Seventeen patients had a local relapse. The SUVmax measured during radiotherapy was significantly higher in locally relapsed tumors than in locally controlled tumors (mean, 6.8 vs. 4.6; P = 0.02). The subvolumes delineated on initial PET/CT scans with 70%-90% SUVmax thresholds were in good agreement with the recurrent volume at a 40% SUVmax threshold (common volume/baseline volume, 0.60-0.80). The subvolumes delineated on initial PET/CT scans with 30%-60% SUVmax thresholds were in good to excellent agreement with the core volume of the relapse (90% SUVmax threshold) (common volume/recurrent volume and overlap fraction indices, 0.60-0.93). The agreement was moderate (>0.51) when a 70% SUVmax threshold was used to delineate on initial PET/CT scans., Conclusion: High (18)F-FDG uptake areas on pretreatment PET/CT scans identify tumor subvolumes at greater risk of relapse in patients with NSCLC treated by concomitant chemoradiation. We propose a 70% SUVmax threshold to delineate areas of high (18)F-FDG uptake on initial PET/CT scans as the target volumes for potential radiotherapy dose escalation., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: As the preparation phase of a multicenter clinical trial using (18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG), (18)F-fluoromisonidazole ((18)F-FMISO), and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) in non-small cell lung cancer (NSCLC) patients, we investigated whether 18 nuclear medicine centers would score tracer uptake intensity similarly and define hypoxic and proliferative volumes for 1 patient and we compared different segmentation methods., Methods: Ten (18)F-FDG, ten (18)F-FMISO, and ten (18)F-FLT PET/CT examinations were performed before and during curative-intent radiotherapy in 5 patients with NSCLC. The gold standards for uptake intensity and volume delineation were defined by experts. The between-center agreement (18 nuclear medicine departments connected with a dedicated network, SFMN-net [French Society of Nuclear Medicine]) in the scoring of uptake intensity (5-level scale, then divided into 2 levels: 0, normal; 1, abnormal) was quantified by κ-coefficients (κ). The volumes defined by different physicians were compared by overlap and κ. The uptake areas were delineated with 22 different methods of segmentation, based on fixed or adaptive thresholds of standardized uptake value (SUV)., Results: For uptake intensity, the κ values between centers were, respectively, 0.59 for (18)F-FDG, 0.43 for (18)F-FMISO, and 0.44 for (18)F-FLT using the 5-level scale; the values were 0.81 for (18)F-FDG and 0.77 for both (18)F-FMISO and (18)F-FLT using the 2-level scale. The mean overlap and mean κ between observers were 0.13 and 0.19, respectively, for (18)F-FMISO and 0.2 and 0.3, respectively, for (18)F-FLT. The segmentation methods yielded significantly different volumes for (18)F-FMISO and (18)F-FLT (P < 0.001). In comparison with physicians, the best method found was 1.5 × maximum SUV (SUVmax) of the aorta for (18)F-FMISO and 1.3 × SUVmax of the muscle for (18)F-FLT. The methods using the SUV of 1.4 and the method using 1.5 × the SUVmax of the aorta could be used for (18)F-FMISO and (18)F-FLT. Moreover, for (18)F-FLT, 2 other methods (adaptive threshold based on 1.5 or 1.6 × muscle SUVmax) could be used., Conclusion: The reproducibility of the visual analyses of (18)F-FMISO and (18)F-FLT PET/CT images was demonstrated using a 2-level scale across 18 centers, but the interobserver agreement was low for the (18)F-FMISO and (18)F-FLT volume measurements. Our data support the use of a fixed threshold (1.4) or an adaptive threshold using the aorta background to delineate the volume of increased (18)F-FMISO or (18)F-FLT uptake. With respect to the low tumor-on-background ratio of these tracers, we suggest the use of a fixed threshold (1.4).

Purpose: The aim of the study was to evaluate the relationship between serum carcinoembryonic antigen (CEA) kinetic and response to chemotherapy in patients with unresectable metastasis of colorectal cancer., Patients and Methods: The kinetic was calculated using the slope of an exponential-regressive curve connecting the semi-logarithmic values of CEA. Receiver operating characteristic (ROC) curves were drawn to select the CEA slope thresholds to define patients with progressive or responsive disease with the highest sensitivity, specificity, and diagnosis accuracy odds ratio (DOR). The correlation between the CEA slopes and progression-free survival (PFS) was evaluated by the Cox model and Kaplan-Meier methods., Results: A total of 122 patients were included. Progression defined by CEA slope greater than +0.05 resulted in sensitivity of 85.7%, specificity of 85.1%, and DOR of 34. The area under the ROC (AUROC) curve was 0.885 (95% CI, 0.815 to 0.936; P = .0001). Response defined by CEA slope less than -0.2 resulted in sensitivity of 74.7%, specificity of 82.5%, and DOR of 16. The AUROC curve was 0.847 (95% CI, 0.770 to 0.906; P = .0001). The difference between AUROC curves calculated with six or four CEA values was not significant. PFS was correlated with CEA slopes (hazard ratio, 4.6; 95% CI, 2.48 to 8.57). The median PFS was 10 months for patients with CEA slope values less than -0.2 months versus 6 months for patients with CEA slope values greater than -0.2 (P < .0001)., Conclusion: These results suggest that the CEA kinetic is an accurate, simple, and noninvasive method to identify the disease progression in patients with unresectable metastasis of colorectal cancer.