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Purpose: 18 F-fluorothymidine (FLT) positron emission tomography (PET) enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/computed tomography scans before and during chemoradiation therapy (CRT) for non-small cell lung cancer were repurposed to investigate the dose-response effects of radiation on BM proliferation., Methods and Materials: Twenty-six non-small cell lung cancer patients underwent platinum-based CRT to 60 Gy in 30 fractions with FLT-PET/computed tomography scans at baseline, week 2 (20 Gy), and week 4 (40 Gy). FLT uptake in BM was isolated using Medical Image Merge software. Weeks 2 and 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (highest standardized uptake values within the volume and visual parameters) were analyzed using generalized linear and restricted cubic spline models. Percentage volumes of total BM without appreciable FLT uptake ("ablated") on weeks 2 and 4 FLT-PET scans were calculated by comparisons with baseline scans., Results: Thoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3 Gy by week 2. In all cases, BM FLT's highest standardized uptake values within the volume declined rapidly as the radiation dose increased. BM proliferation significantly decreased by >95% after ≥3 to 4 Gy at 2 weeks and ≥4 to 5 Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. The median percentage of total BM ablated was 13.1% (range, 5.6%-20.3%) at 2 weeks and 15.7% (range, 9.2%-24.1%) at 4 weeks. Mean lymphocyte counts fell from a baseline of 2.01 × 10 9 /L to 0.77 at week 2 and 0.60 at week 4. Lymphocyte decline strongly correlated with the percentage of total BM ablated by week 4 (y = -46 to 1.64x; R 2 adj = 0.34; P = .001)., Conclusions: BM ablation associated with low-dose radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ at risk, and reducing the BM volume exposed to ≥3 Gy may help preserve lymphocytes, which is essential for effective adjuvant immunotherapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite significant therapeutic advances, lung cancer remains the leading cause of cancer-related death worldwide 1 . Non-small cell lung cancer (NSCLC) patients have a very poor overall five-year survival rate of only 10-20%. Currently, TNM staging is the gold standard for predicting overall survival and selecting optimal initial treatment options for NSCLC patients, including those with curable stages of disease. However, many patients with locoregionally-confined NSCLC relapse and die despite curative-intent interventions, indicating a need for intensified, individualised therapies. Epithelial-to-mesenchymal transition (EMT), the phenotypic depolarisation of epithelial cells to elongated, mesenchymal cells, is associated with metastatic and treatment-refractive cancer. We demonstrate here that EMT-induced protein changes in small extracellular vesicles are detectable in NSCLC patients and have prognostic significance. Overall, this work describes a novel prognostic biomarker signature that identifies potentially-curable NSCLC patients at risk of developing metastatic NSCLC, thereby enabling implementation of personalised treatment decisions., (© 2023. The Author(s).)

Introduction: This study aims to investigate whether nodal metabolic tumour volume (nMTV) and nodal total lesion glycolysis (nTLG) on Fluorine-18 fluoro-deoxy-glucose positron emission tomography-computed tomography ( 18 F-FDG PET/CT) in inoperable node-positive stage II and III non-small cell lung cancer (NSCLC) are independent predictors of overall survival (OS) in patients undergoing curative-intent chemoradiotherapy/radiotherapy (CRT/RT)., Methods: Data from two prospective trials between 2004 and 2016 were analysed retrospectively. Primary, nodal and total metabolic tumour volume and total lesion glycolysis (pMTV, nMTV, tMTV, pTLG, nTLG and tTLG, respectively) were derived from baseline 18 F-FDG PET/CT. Cox regressions were used to model OS by 18 F-FDG PET/CT parameters adjusting for overall stage., Results: 89 patients with stage II (8%) and stage III (92%) were included. The median age at diagnosis was 67 years; 62% were male. The median follow-up was 6.9 years; the median OS was 2.2 years (95% CI 1.7-3.1). The median pMTV, nMTV and tMTV were 14 mL (range 0-360), 8 mL (range 0-250) and 34 mL (range 3-384), respectively. In 3 patients, the primary lesion could not be delineated from the central hilar mass. There was no association between nMTV (adjusted HR 1.04, 95% CI 0.95-1.15, P-value 0.43), pMTV (adjusted HR 1.0, 95% CI 0.96-1.04, P-value 0.92), tMTV (adjusted HR 1.0, 95% CI 0.97-1.04, P-value 0.88), nTLG, pTLG or tTLG and OS. Consistent results were noted when patients with central hilar lesions were excluded from analysis., Conclusion: In node-positive stage II and III NSCLC patients who underwent 18 F-FDG PET/CT-guided target delineation curative-intent concurrent CRT/RT, metabolic parameters did not appear to provide independent prognostication., (© 2021 The Royal Australian and New Zealand College of Radiologists.)

Introduction: Patients with non-small cell lung cancer (NSCLC) can experience rapid disease progression between initial staging FDG-PET scans and commencement of curative-intent radiotherapy (RT). Previous studies that estimated stage migration rates by comparing staging PET/CT and treatment-planning PET/CT images were limited by small sample sizes., Methods: This multicenter, international study combined prospective data from five institutions for PET-staged patients with NSCLC who were intended to receive curative-intent RT. TNM status was compared for staging and RT planning scans and the probability of TNM status and overall stage migration was analyzed as a function of the interval between PET/CT scans. The impacts of N classification, overall stage, and pathology were also studied., Results: Pooled data from 181 patients were analyzed. The median interval between PET/CT scans was 42 days (range, 2-208). Upstaging occurred in 32 % of patients. The overall rate of stage migration was higher for patients presenting with initial stage IIIB/IIIC disease (p = 0.006) and patients with N2-3 nodal disease (p = 0.019). Upstaging to M1 disease was significantly associated with initial stage IIIB/IIIC disease (HR = 15.2) and adenocarcinoma (HR = 10) histology., Conclusion: Longer intervals between imaging and treatment in patients with NSCLC were associated with high rates disease progression with consequent risks of geographic miss in RT planning and futile treatment in patients with M1 disease. Patients with more extensive initial nodal involvement and those with adenocarcinoma had the highest rates of stage migration. Dedicated RT planning PET/CT imaging is recommended, especially if >3 weeks have elapsed after initial staging., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In locally advanced lung cancer, established baseline clinical variables show limited prognostic accuracy and 18F-fluorodeoxyglucose positron emission tomography (FDG PET) radiomics features may increase accuracy for optimal treatment selection. Their robustness and added value relative to current clinical factors are unknown. Hence, we identify robust and independent PET radiomics features that may have complementary value in predicting survival endpoints. A 4D PET dataset (n = 70) was used for assessing the repeatability (Bland-Altman analysis) and independence of PET radiomics features (Spearman rank: |ρ|<0.5). Two 3D PET datasets combined (n = 252) were used for training and validation of an elastic net regularized generalized logistic regression model (GLM) based on a selection of clinical and robust independent PET radiomics features (GLMall). The fitted model performance was externally validated (n = 40). The performance of GLMall (measured with area under the receiver operating characteristic curve, AUC) was highest in predicting 2-year overall survival (0.66±0.07). No significant improvement was observed for GLMall compared to a model containing only PET radiomics features or only clinical variables for any clinical endpoint. External validation of GLMall led to AUC values no higher than 0.55 for any clinical endpoint. In this study, robust independent FDG PET radiomics features did not have complementary value in predicting survival endpoints in lung cancer patients. Improving risk stratification and clinical decision making based on clinical variables and PET radiomics features has still been proven difficult in locally advanced lung cancer patients., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Inflammatory FDG uptake in the lung (PET-pneumonitis) following curative-intent radiotherapy (RT)/chemo-RT (CRT) in non-small cell lung cancer (NSCLC) can pose a challenge in FDG-PET/CT response assessment. The aim of this study is to describe different patterns of PET-pneumonitis to guide the interpretation of FDG-PET/CT and investigate its association with tumor response and overall survival (OS)., Methods: Retrospective analysis was performed on 87 NSCLC patients in three prospective trials who were treated with radical RT (n = 7) or CRT (n = 80), with baseline and post-treatment FDG-PET/CT. Visual criteria were performed for post-treatment FDG-PET/CT response assessment. The grading of PET-pneumonitis was based on relative lung uptake intensity compared to organs of reference and classified as per Deauville score from grade 1-5. Distribution patterns of PET-pneumonitis were defined as follows: A) patchy/sub-pleural; B) diffuse (involving more than a segment); and C) peripheral (diffusely surrounding a photopenic region)., Results: Follow-up FDG-PET/CT scans were performed approximately 3 months (median, 89 days; interquartile range, 79-93) after RT. Overall, PET-pneumonitis was present in 62/87 (71%) of patients, with Deauville 2 or 3 in 12/62 (19%) and 4 or 5 in 50/62 (81%) of patients. The frequency of patterns A, B and C of PET-pneumonitis was 19/62 (31%), 20/62 (32%) and 23/62 (37%), respectively. No association was found between grade or pattern of PET-pneumonitis and overall response at follow-up PET/CT (p = 0.27 and p = 0.56, respectively). There was also no significant association between PET-pneumonitis and OS (hazard ratio [HR], 1.3; 95% confidence interval [CI], 0.6-2.5; p = 0.45). Early FDG-PET/CT response assessment, however, was prognostic for OS (HR, 1.7; 95% CI, 1.2-2.2; p < 0.001)., Conclusion: PET-pneumonitis is common in early post-CRT/RT, but pattern recognition may assist in response assessment by FDG-PET/CT. While FDG-PET/CT is a powerful tool for response assessment and prognostication, PET-pneumonitis does not appear to confound early response assessment or to independently predict OS.

Purpose: Sarcopenia is associated with reduced survival in cancer. Currently, data on sarcopenia at presentation and muscle loss throughout treatment are unknown in patients receiving chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC). This study evaluated skeletal muscle changes in NSCLC patients receiving CRT and relationship with survival., Methods: Secondary analysis of 41 patients with NSCLC treated with CRT assessed for skeletal muscle area and muscle density by computed tomography pre-treatment and 3 months post-treatment. Images at week 4 of treatment were available for 32 (78%) patients. Linear mixed models were applied to determine changes in skeletal muscle over time and related to overall survival using Kaplan-Meier plots., Results: Muscle area and muscle density decreased significantly by week 4 of CRT (- 6.6 cm 2 , 95% CI - 9.7 to - 3.1, p < 0.001; - 1.3 HU, 95% CI - 1.9 to - 0.64, p < 0.001, respectively), with minimal change between week 4 of CRT and 3 months post-CRT follow-up (- 0.2 cm 2 , 95% CI - 3.6-3.1, p = 0.91; - 0.27, 95% CI - 0.91-0.36, p = 0.36, respectively). Sarcopenia was present in 25 (61%) and sarcopenic obesity in 6 (14%) of patients prior to CRT, but not associated with poorer survival. Median survival was shorter in patients with low muscle density prior to treatment although not statistically significant (25 months + 8.3 vs 53 months + 13.0, log-rank p = 0.17)., Conclusion: Significant loss of muscle area and muscle density occurs in NSCLC patients early during CRT. A high proportion of patients are sarcopenic prior to CRT; however, this was not significantly associated with poorer survival.

The optimal methodology for defining response with 18 F-FDG PET after curative-intent chemoradiation for non-small cell lung cancer (NSCLC) is unknown. We compared survival outcomes according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC), PERCIST 1.0, the Peter Mac metabolic visual criteria, and the Deauville criteria, respectively. Methods: Three prospective trials of chemoradiation for NSCLC, involving baseline and posttreatment 18 F-FDG PET/CT imaging, were conducted between 2004 and 2016. Responses were categorized as complete metabolic response (CMR), partial metabolic response, stable metabolic disease, or progressive metabolic disease. Cox proportional-hazards models and log-rank tests assessed the impact of each response on overall survival (OS). Results: Eighty-seven patients underwent 18 F-FDG PET/CT before and after radical chemoradiation for NSCLC. Follow-up 18 F-FDG PET/CT scans were performed at a median of 89 d (interquartile range, 79-93 d) after radiotherapy. Median follow-up and OS after PET response imaging were 49 and 28 mo, respectively. Interobserver agreements for EORTC, PERCIST, Peter Mac, and Deauville had κ values of 0.76, 0.76, 0.87, and 0.84, respectively. All 4 response criteria were significantly associated with OS. Peter Mac and Deauville showed better fit than EORTC and PERCIST and distinguished better between CMR and non-CMR. Conclusion: All 4 response criteria were highly predictive of OS, but visual criteria showed greater interobserver agreement and stronger discrimination between CMR and non-CMR, highlighting the importance of visual assessment to recognize radiation pneumonitis, changes in lung configuration, and patterns of response., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To investigate the associations between interim tumor responses on 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) and 18 F-fluorothymidine ( 18 F-FLT) PET and patient outcomes, especially progression-free survival (PFS) and overall survival (OS), in non-small cell lung cancer (NSCLC) patients., Methods and Materials: Patients with FDG-PET/computed tomography stage I-III NSCLC were prescribed concurrent chemotherapy and radiation therapy (60 Gy in 30 fractions). Scans were acquired at baseline (FDG-PET/computed tomography [FDG BL ] for radiation therapy planning and FLT-PET [FLT BL ]), week 2 (FDG wk2 and FLT wk2 ), and week 4 (FDG wk4 and FLT wk4 ) of chemoradiation therapy. Tumor responses were categorized as complete or partial responses or stable or progressive disease (SD, PD) using European Organization for Research and Treatment of Cancer criteria. Associations between response, OS, and PFS were analyzed with univariate Cox regressions and plotted using Kaplan-Meier curves., Results: Between 2009 and 2013, 60 patients were recruited. Thirty-seven (62%) were male, and the median age was 66 years (range, 31-86 years). Two-year OS and PFS were 0.51 and 0.26, respectively. Unexpectedly, SD on FLT wk2 compared with complete response/partial response was associated with longer OS (hazard ratio [95% confidence interval] 2.01 [0.87-4.65], P=.082) and PFS (2.01 [0.92-4.36], P=.061). Weeks 2 and 4 FDG PET/CT were not significantly associated with survival. Study scans provided additional information to FDG BL in 21 patients (35%). Distant metastases detected in 3 patients on FLT BL and in 2 patients on FDG/FLT wk2 changed treatment intent from curative to palliative. Locoregional progression during radiation therapy was observed in 5 (8%) patients, prompting larger radiation therapy fields., Conclusions: Stable uptake of 18 F-FLT at week 2 was paradoxically associated with longer OS and PFS. This suggests that suppression of tumor cell proliferation may protect against radiation-induced tumor cell killing. Baseline FLT, FLT wk2 , and FDG wk2 detected rapid distant and locoregional progression in 10 patients (17%), prompting changes in management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Acute radiation oesophagitis (ARO) is frequently experienced by patients receiving concurrent chemo-radiation therapy (cCRT) for non-small-cell lung cancer (NSCLC). We investigated ARO symptoms (CTCAE v3.0), radiation dose and oesophageal FDG PET/CT uptake., Method: Candidates received cCRT (60 Gy, 2 Gy/fx) and sequential FDG PET/CT (baseline FDG 0 , FDG wk2 and FDG wk4 ). Mean and maximum standardized uptake value (SUVmean and SUVmax) and radiation dose (O mean and O max ) were calculated within the whole oesophagus and seven sub-regions (5-60 Gy)., Results: Forty-four patients underwent FDG 0 and FDG wk2 , and 41 (93%) received FDG wk4 , resulting in 129 PET/CT scans for analysis. Of 29 (66%) patients with ≥ grade 2 ARO, SUVmax (mean ± SD) increased from FDG 0 to FDG wk4 (3.06 ± 0.69 to 3.83 ± 1.27, P = 0.0019) and FDG wk2 to FDG wk4 (3.10 ± 0.75 to 3.83 ± 1.27, P = 0.0046). Radiation dose (mean ± SD) was higher in grade ≥2 patients; O mean (47.5 ± 20 vs 53.9 ± 10.2, P = 0.0061), O max (13.7 ± 9.6 vs 20.1 ± 10.6, P = 0.0009) and V40 Gy (8.0 ± 8.2 vs 11.9 ± 7.3, P = 0.0185)., Conclusions: FDG wk4 SUVmax and radiation dose were associated with ≥ grade 2 ARO. Compared to subjective assessments, future interim FDG PET/CT acquired for disease response assessment may also be utilized to objectively characterize ARO severity and image-guided oesophageal dose constraints., (© 2017 The Royal Australian and New Zealand College of Radiologists.)

Introduction: Cone-beam computed tomography (CBCT) is a valuable image-guidance tool in radiation therapy (RT). This study was initiated to assess the accuracy of CBCT for quantifying non-small cell lung cancer (NSCLC) tumour volumes compared to the anatomical 'gold standard', CT. Tumour regression or progression on CBCT was also analysed., Methods: Patients with Stage I-III NSCLC, prescribed 60 Gy in 30 fractions RT with concurrent platinum-based chemotherapy, routine CBCT and enrolled in a prospective study of serial PET/CT (baseline, weeks two and four) were eligible. Time-matched CBCT and CT gross tumour volumes (GTVs) were manually delineated by a single observer on MIM software, and were analysed descriptively and using Pearson's correlation coefficient (r) and linear regression (R 2 )., Results: Of 94 CT/CBCT pairs, 30 patients were eligible for inclusion. The mean (± SD) CT GTV vs CBCT GTV on the four time-matched pairs were 95 (±182) vs 98.8 (±160.3), 73.6 (±132.4) vs 70.7 (±96.6), 54.7 (±92.9) vs 61.0 (±98.8) and 61.3 (±53.3) vs 62.1 (±47.9) respectively. Pearson's correlation coefficient (r) was 0.98 (95% CI 0.97-0.99, ρ < 0.001). The mean (±SD) CT/CBCT Dice's similarity coefficient was 0.66 (±0.16). Of 289 CBCT scans, tumours in 27 (90%) patients regressed by a mean (±SD) rate of 1.5% (±0.75) per fraction. The mean (±SD) GTV regression was 43.1% (±23.1) from the first to final CBCT., Conclusion: Primary lung tumour volumes observed on CBCT and time-matched CT are highly correlated (although not identical), thereby validating observations of GTV regression on CBCT in NSCLC., (© 2016 The Royal Australian and New Zealand College of Radiologists.)

Background and Purpose: To assess the impact of a standardized delineation protocol and training interventions on PET/CT-based target volume delineation (TVD) in NSCLC in a multicenter setting., Material and Methods: Over a one-year period, 11 pairs, comprised each of a radiation oncologist and nuclear medicine physician with limited experience in PET/CT-based TVD for NSCLC from nine different countries took part in a training program through an International Atomic Energy Agency (IAEA) study (NCT02247713). Teams delineated gross tumor volume of the primary tumor, during and after training interventions, according to a provided delineation protocol. In-house developed software recorded the performed delineations, to allow visual inspection of strategies and to assess delineation accuracy., Results: Following the first training, overall concordance indices for 3 repetitive cases increased from 0.57±0.07 to 0.66±0.07. The overall mean surface distance between observer and expert contours decreased from -0.40±0.03cm to -0.01±0.33cm. After further training overall concordance indices for another 3 repetitive cases further increased from 0.64±0.06 to 0.80±0.05 (p=0.01). Mean surface distances decreased from -0.34±0.16cm to -0.05±0.20cm (p=0.01)., Conclusion: Multiple training interventions improve PET/CT-based TVD delineation accuracy in NSCLC and reduce interobserver variation., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Introduction: The relationship between oesophageal radiation dose volume metrics and dysphagia in patients having chemoradiation (CRT) for non-small cell lung cancer (NSCLC) is well established. There is also some evidence that neutropenia is a factor contributing to the severity of oesophagitis. We retrospectively analysed acute radiation oesophagitis (ARO) rates and severity in patients with NSCLC who received concurrent chemotherapy and high dose radiation therapy (CRT). We investigated if there was an association between grade of ARO, neutropenia and radiation dose volume metrics., Material and Methods: Patients with NSCLC having concurrent CRT who had RT dose and toxicity data available were eligible. Exclusion criteria included previous thoracic RT, treatment interruptions and non-standard dose regimens. RT dosimetrics included maximum and mean oesophageal dose, oesophagus dose volume and length data., Results: Fifty four patients were eligible for analysis. 42 (78 %) patients received 60 Gy. Forty four (81 %) patients received carboplatin based chemotherapy. Forty eight (89 %) patients experienced ARO ≥ grade 1 (95 % CI: 78 % to 95 %). ARO grade was associated with mean dose (rs = 0.27, p = 0.049), V20 (rs = 0.31, p = 0.024) and whole oesophageal circumference receiving 20 Gy (rs = 0.32 p = 0.019). In patients who received these doses, V20 (n = 51, rs = 0.36, p = 0.011), V35 (n = 43, rs = 0.34, p = 0.027) and V60 (n = 25, rs = 0.59, P = 0.002) were associated with RO grade. Eleven of 25 (44 %) patients with ARO ≥ grade 2 also had ≥ grade 2 acute neutropenia compared with 5 of 29 (17 %) patients with RO grade 0 or 1 (p = 0.035)., Conclusion: In addition to oesophageal dose-volume metrics, neutropenia may also be a risk factor for higher grades of ARO.

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60 Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.

Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)-positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility., Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status., Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age., Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Molecular imaging with positron emission tomography (PET) has dramatically changed the management of patients with lung cancer who are treated with radiotherapy. Uptake of the most widely used PET radiopharmaceutical (18)F-fluorodeoxyglucose identifies lung nodules or intrathoracic lymph nodes as likely to be malignant and frequently identifies previously unsuspected sites of malignant disease outside the thorax. Patients with non-small cell lung cancer, especially those with apparently more advanced locoregional disease to start with, are often upstaged, and this has a profound effect on their subsequent management. Better patient selection, primarily by excluding patients with PET-detected advanced disease, and better targeting of radiotherapy to avoid geographic miss have contributed significantly to improvements in outcome in recent series of patients treated with definitive chemoradiation. Advances in motion management with 4-dimensional PET/computed tomography and research into sequential imaging during treatment to permit response-adapted therapy hold promise for further improvements in treatment outcomes. Research involving novel PET tracers that can characterize biological properties of tumors, such as proliferation or hypoxia, may help develop more personalized approaches to patient management in the future., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: Historically, it has been difficult to monitor the acute impact of anticancer therapies on hematopoietic organs on a whole-body scale. Deeper understanding of the effect of treatments on bone marrow would be of great potential value in the rational design of intensive treatment regimens. 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a functional radiotracer used to study cellular proliferation. It is trapped in cells in proportion to thymidine-kinase 1 enzyme expression, which is upregulated during DNA synthesis. This study investigates the potential of (18)F-FLT to monitor acute effects of chemotherapy on cellular proliferation and its recovery in bone marrow, spleen, and liver during treatment with 2 different chemotherapy regimens., Methods: Sixty patients with non-small cell lung cancer underwent concurrent radical chemoradiotherapy to 60 Gy in 6 wk with either cisplatin/etoposide (C/E, n = 28) weeks 1 and 5 or weekly carboplatin/paclitaxel (C/P, n = 32) regimens. (18)F-FLT and (18)F-FDG PET with CT were performed at baseline, week 2 (day 9 for (18)F-FLT and day 10 for (18)F-FDG PET), and week 4 (day 23 for (18)F-FLT and day 24 for (18)F-FDG PET). Visual and semiquantitative standardized uptake value (SUV) measurements were performed in bone marrow outside the radiotherapy field, liver, spleen, and small bowel. These were correlated to blood counts and smears in a subset of patients., Results: The C/E group exhibited a drop in bone marrow (18)F-FLT uptake at week 2 (median SUVmax [maximum SUV] decrease to 31%, 8.7-6.0, P < 0.001), with recovery at week 4, reflecting the absence of chemotherapy between these times. By contrast, the weekly C/P group showed gradually declining bone marrow uptake (P > 0.05). Spleen uptake in both cohorts decreased at week 2, with intense rebound activity at week 4 (SUVmax week 4 at 58% above baseline: 2.4-3.8, for C/E, respectively, 30% for C/P: 2.7-3.5, P < 0.001). Liver uptake changed little. (18)F-FLT changes preceded neutrophil count reductions. (18)F-FDG uptake in marrow liver and spleen changed much less than (18)F-FLT., Conclusion: (18)F-FLT imaging may be used to quantify impairment and recovery of bone marrow by specific chemotherapy regimens and may also enable imaging of organ-specific processes such as spleen activation. (18)F-FLT is superior to (18)F-FDG for this purpose. This technology may support novel treatment planning and monitoring approaches in oncology patients., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: We aimed to prospectively observe cellular metabolism and proliferation in patients with non-small-cell lung cancer (NSCLC) during radical chemoradiation therapy using serial PET/CT with (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)., Methods: Twenty patients with stage I-III NSCLC and candidates for radical chemoradiation therapy (60 Gy in 30 fractions over 6 wk) were recruited. (18)F-FDG and (18)F-FLT PET/CT were performed at baseline and during therapy (weeks 2 and 4). Tumor response was assessed semiquantitatively and using visual response criteria., Results: The median and range for primary tumor volume (cm(3)) at baseline on (18)F-FDG were 28 and 2-241, respectively, and on (18)F-FLT 31 and 2-184, respectively. At week 2, (18)F-FDG was 26 (range, 2-164), and (18)F-FLT was 11 (range, 0-111). At week 4, (18)F-FDG was 19 (1-147), and (18)F-FLT was 7 (0-48). The median and range of maximum standardized uptake value (SUVmax) at baseline on (18)F-FDG were 14 and 4-31, respectively, and on (18)F-FLT 6 and 2-12, respectively. Week 2 (18)F-FDG median SUVmax was 10 (2-31), and (18)F-FLT median SUVmax was 3 (1-15); week 4 (18)F-FDG median SUVmax was 10 (2-15), and (18)F-FLT median SUVmax was 2 (2-9). There was fair agreement between visual tumor response on (18)F-FDG and (18)F-FLT during therapy (Cohen's unweighted κ statistic, 0.27 at week 2 and 0.355 at week 4). Cerebral metastases were detected on 1 baseline (18)F-FLT scan, resulting in palliative management. Progressive disease was detected on week 2 scans in 3 patients, resulting in changes to radiation therapy (2 patients) and treatment intent (1 patient)., Conclusion: This study demonstrates that (18)F-FLT PET/CT is a more sensitive tracer of early treatment response than (18)F-FDG PET/CT. The ability of these tracers to detect distinct biologic processes may lead to their use as biomarkers for personalized radiation therapy and prognosis in the future., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: Concurrent chemoradiation therapy (CCRT) improves survival compared with sequential treatment for locally advanced non-small cell lung cancer, but it increases toxicity, particularly radiation esophagitis (RE). Validated predictors of RE for clinical use are lacking. We performed an individual-patient-data meta-analysis to determine factors predictive of clinically significant RE., Methods and Materials: After a systematic review of the literature, data were obtained on 1082 patients who underwent CCRT, including patients from Europe, North America, Asia, and Australia. Patients were randomly divided into training and validation sets (2/3 vs 1/3 of patients). Factors predictive of RE (grade≥2 and grade≥3) were assessed using logistic modeling, with the concordance statistic (c statistic) used to evaluate the performance of each model., Results: The median radiation therapy dose delivered was 65 Gy, and the median follow-up time was 2.1 years. Most patients (91%) received platinum-containing CCRT regimens. The development of RE was common, scored as grade 2 in 348 patients (32.2%), grade 3 in 185 (17.1%), and grade 4 in 10 (0.9%). There were no RE-related deaths. On univariable analysis using the training set, several baseline factors were statistically predictive of RE (P<.05), but only dosimetric factors had good discrimination scores (c>.60). On multivariable analysis, the esophageal volume receiving ≥60 Gy (V60) alone emerged as the best predictor of grade≥2 and grade≥3 RE, with good calibration and discrimination. Recursive partitioning identified 3 risk groups: low (V60<0.07%), intermediate (V60 0.07% to 16.99%), and high (V60≥17%). With use of the validation set, the predictive model performed inferiorly for the grade≥2 endpoint (c=.58) but performed well for the grade≥3 endpoint (c=.66)., Conclusions: Clinically significant RE is common, but life-threatening complications occur in <1% of patients. Although several factors are statistically predictive of RE, the V60 alone provides the best predictive ability. Efforts to reduce the V60 should be prioritized, with further research needed to identify and validate new predictive factors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Purpose: To investigate the impact of treatment delays on radiation therapy (RT) target volumes and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) who underwent two baseline FDG PET/CT scans., Material and Methods: Patients underwent a staging (PET1) and RT planning (PET2) FDG PET/CT scan. At PET1 all patients were eligible for radical chemo-RT. OS and progression-free survival (PFS) were compared for patients remaining eligible for radical RT and those treated palliatively because PET2 showed progression. RT target volumes were contoured using PET1 and PET2. Normal tissue doses were compared for patients remaining eligible for radical RT., Results: Eighty-two patients underwent PET2 scans between October 2004 and February 2007. Of these, 21 had a prior PET1 scan, median 23 days apart (range 8-176 days). Six patients (29%) were unsuitable for radical RT after PET2; five received palliative treatment and one received no treatment. Patients treated palliatively had significantly worse OS and PFS than patients treated radically p<0.001. Mean RT tumour volume increased from 105cc to 198cc (p<0.005) between scans., Conclusions: Disease progression while awaiting initiation of curative RT in NSCLC is associated with larger treatment volumes and worse survival., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: This prospective study investigated the impact of radiotherapy (RT)-planning FDG-PET/CT on management of non-small cell lung cancer (NSCLC)., Materials and Methods: Patients still eligible for radical RT after conventional staging underwent RT-planning PET/CT and, if disease was still treatable to 60 Gy, they entered our planning study, where visually-contoured tumour volumes derived with and without PET information were compared. If PET/CT detected advanced disease, palliative therapy was given. Overall survival (OS) for palliative and curative patients was compared., Results: Of 76 eligible patients, only 50 (66%) received radical chemoRT after PET/CT while 26 (34%) received palliative therapies because PET/CT detected advanced disease. Without PET, FDG-avid tumour would reside outside the planning target volume (PTV) in 36% of radical cases and in 25% <90% of the PTV would have received >95% prescribed dose. OS for all patients was 56.8% and 24.9% at 1 and 4 years, respectively. OS for patients given chemoRT was 77.5% and 35.6% at 1 and 4 years, respectively and was 32% for stage IIIA patients at 4 years. OS for patients treated palliatively was inferior (P<0.001); 16.3% and 4.1% at 1 and 4 years, respectively., Conclusions: Planning PET/CT frequently changed management and was associated with excellent survival. Survival data from this study were presented in part at the 2011 World Lung Cancer Conference, Amsterdam and planning data at the 2010 Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, Chicago., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The authors studied growth and progression of untreated nonsmall cell lung cancer (NSCLC) by comparing diagnostic and radiotherapy (RT) planning fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans before proposed radical chemo-RT., Methods: Patients enrolled on a prospective clinical trial were eligible for this analysis if they underwent 2 pretreatment whole body FDG-PET/CT scans, >7 days apart. Scan 1 was performed for diagnosis/disease staging and scan 2 for RT planning. Interscan comparisons included disease stage, metabolic characteristics, tumor doubling times, and change in treatment intent., Results: Eighty-two patients underwent planning PET/CT scans between October 2004 and February 2007. Of these, 28 patients (61% stage III, 18% stage II) had undergone prior staging PET/CT scans. The median interscan period was 24 days (range, 8-176 days). Interscan disease progression (TNM stage) was detected in 11 (39%) patients. The probability of upstaging within 24 days was calculated to be 32% (95% confidence interval [CI], 18%-49%). Treatment intent changed from curative to palliative in 8 (29%) cases, in 7 because of PET. For 17 patients who underwent serial PET/CT scans under standardized conditions, there was a mean relative interscan increase of 19% in tumor maximum standardized uptake value (SUV) (P=.022), 16% in average SUV (P=.004), and 116% in percentage injected dose (P=.002). Estimated doubling time of FDG avid tumor was 66 days (95% CI, 51-95 days)., Conclusions: Rapid tumor progression was detected in patients with untreated, predominantly stage III, NSCLC on serial FDG-PET/CT imaging, highlighting the need for prompt diagnosis, staging, and initiation of therapy in patients who are candidates for potentially curative therapy., (Copyright © 2010 American Cancer Society.)

Purpose: Positron emission tomography/computed tomography (PET/CT) is increasingly used for delineating gross tumor volume (GTV) in non-small-cell lung cancer (NSCLC). The methodology for contouring tumor margins remains controversial. We developed a rigorous visual protocol for contouring GTV that uses all available clinical information and studied its reproducibility in patients from a prospective PET/CT planning trial., Methods and Materials: Planning PET/CT scans from 6 consecutive patients were selected. Six "observers" (two radiation oncologists, two nuclear medicine physicians, and two radiologists) contoured GTVs for each patient using a predefined protocol and subsequently recontoured 2 patients. For the estimated GTVs and axial distances, least-squares means for each observer and for each case were calculated and compared, using the F test and pairwise t-tests. In five cases, tumor margins were also autocontoured using standardized uptake value (SUV) cutoffs of 2.5 and 3.5 and 40% SUV(max)., Results: The magnitude of variation between observers was small relative to the mean (coefficient of variation [CV] = 3%), and the total variation (intraclass correlation coefficient [ICC] = 3%). For estimation of superior/inferior (SI), left/right (LR), and anterior/posterior (AP) borders of the GTV, differences between observers were also small (AP, CV = 2%, ICC = 0.4%; LR, CV = 6%, ICC = 2%; SI, CV 4%, ICC = 2%). GTVs autocontoured generated using SUV 2.5, 3.5, and 40% SUV(max) differed widely in each case. An SUV contour of 2.5 was most closely correlated with the mean GTV defined by the human observers., Conclusions: Observer variation contributed little to total variation in the GTV and axial distances. A visual contouring protocol gave reproducible results for contouring GTV in NSCLC., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To establish whether (18)F-3'-deoxy-3'-fluoro-L-thymidine ((18)F-FLT) can monitor changes in cellular proliferation of non-small-cell lung cancer (NSCLC) during radical chemo-radiotherapy (chemo-RT)., Methods and Materials: As part of a prospective pilot study, 5 patients with locally advanced NSCLC underwent serial (18)F-FLT positron emission tomography (PET)/computed tomography (CT) scans during treatment. Baseline (18)F-FLT PET/CT scans were compared with routine staging (18)F-FDG PET/CT scans. Two on-treatment (18)F-FLT scans were performed for each patient on Days 2, 8, 15 or 29, providing a range of time points for response assessment., Results: In all 5 patients, baseline lesional uptake of (18)F-FLT on PET/CT corresponded to staging (18)F-FDG PET/CT abnormalities. (18)F-FLT uptake in tumor was observed on five of nine (55%) on-treatment scans, on Days 2, 8 and 29, but not Day 15. A "flare" of (18)F-FLT uptake in the primary tumor of one case was observed after 2 Gy of radiation (1.22 x baseline). The remaining eight on-treatment scans demonstrated a mean reduction in (18)F-FLT tumor uptake of 0.58 x baseline. A marked reduction of (18)F-FLT uptake in irradiated bone marrow was observed for all cases. This reduction was observed even after only 2 Gy, and all patients demonstrated a complete absence of proliferating marrow after 10 Gy., Conclusions: This proof of concept study indicates that (18)F-FLT uptake can monitor the distinctive biologic responses of epithelial cancers and highly radiosensitive normal tissue changes during radical chemo-RT. Further studies of (18)F-FLT PET/CT imaging during therapy may suggest that this tracer is useful in developing response-adapted RT for NSCLC.

PET-CT is an exciting new imaging technology that simultaneously acquires detailed structural and functional imaging information. PET is having an increasing impact on the management of loco-regionally advanced non-small cell lung cancer with radiotherapy. PET combined with CT is much more accurate than CT alone in staging lung cancer and patients treated with radical radiotherapy or chemoradiotherapy have better outcomes because of superior patient selection. PET also has the potential to improve radiotherapy planning by minimizing unnecessary irradiation of normal tissues and by reducing the risk of geographic miss. PET influences treatment planning in a high proportion of cases and therefore radiotherapy dose escalation without PET may be futile.