Response to COVID-19 vaccination imaged by PD-L1 PET scanning.

BACKGROUND: During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging. METHODS: Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection. RESULTS: Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated. CONCLUSION: Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients. TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819 .

Changes in Apparent Diffusion Coefficient (ADC) in Serial Weekly MRI during Radiotherapy in Patients with Head and Neck Cancer: Results from the PREDICT-HN Study.

Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy. Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman's correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time. Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that can be assessed on MRI, and 31 patients had nodal disease with 46 nodes assessed. Median primary GTV (GTVp) size was 14.1cc. The rate of GTVp shrinkage was highest between pre-treatment and week 4. Patients with T3-T4 tumours had a 3.8-fold decrease in GTVp compared to T1-T2 tumours. The ADC values correlated with residual GTVp. The median nodal volume (GTVn) was 12.4cc. No clinical features were found to correlate with GTVn reduction. The overall change in ADC for GTVn from pre-treatment was significant for 35th−95th percentiles in weeks 1−4 (p < 0.001). Conclusion: A discrepancy in the trajectory of ADC between primary and nodal sites suggested that they exhibit different treatment responses and should be analysed separately in future studies.

Imaging immunity in patients with cancer using positron emission tomography.

Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.

Blood-Derived Extracellular Vesicle-Associated miR-3182 Detects Non-Small Cell Lung Cancer Patients.

With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, such as tissue biopsy and imaging. Interest in the development and use of liquid biopsies has risen, due to non-invasive sample collection, and the depth of information it can provide on a disease. Small extracellular vesicles (sEVs) as viable liquid biopsies are of particular interest due to their potential as cancer biomarkers. To validate the use of sEVs as cancer biomarkers, we characterised cancer sEVs using miRNA sequencing analysis. We found that miRNA-3182 was highly enriched in sEVs derived from the blood of patients with invasive breast carcinoma and NSCLC. The enrichment of sEV miR-3182 was confirmed in oncogenic, transformed lung cells in comparison to isogenic, untransformed lung cells. Most importantly, miR-3182 can successfully distinguish early-stage NSCLC patients from those with benign lung conditions. Therefore, miR-3182 provides potential to be used for the detection of NSCLC in blood samples, which could result in earlier therapy and thus improved outcomes and survival for patients.

Prospective Phase II trial of radiation therapy in localised non-gastric marginal zone lymphoma with prospective evaluation of autoimmunity and Helicobacter pylori status: TROG 05.02/ALLG NHL15.

BACKGROUND: This Phase 2 multicentre trial in localised non-gastric marginal zone lymphoma (MZL) evaluated the effectiveness and safety of radiotherapy and documented markers of autoimmunity and Helicobacter pylori infection. PATIENTS AND METHODS: Eligible patients had Stages I and II or paired-organ, non-gastric MZL. Bone marrow evaluation, autoantibody panel, and H. pylori evaluation were mandatory. Involved-field or involved-site radiotherapy was delivered to 24-30.6 Gy. Detected H. pylori infections underwent eradication. RESULTS: Between 2006 and 2014, six centres enrolled 70 patients, and 68 commenced treatment. The median age was 59 (range: 23-84) years, and 31 (46%) were male. Overall, 55 patients had Stage I disease, nine patients had Stage II disease, and four patients had paired organ-confined disease. Involved extranodal sites with three or more cases were orbital (n = 18), conjunctiva (n = 13), lacrimal (n = 8), skin (n = 8), salivary (n = 7), and muscle (n = 4). Eight patients had primary nodal MZL. At the median follow-up of 5 years (range 0.7-9.4), progression-free survival and overall survival were 79% and 95%, respectively. One lymphoma-related death and two in-field failures (after 25 and 30 Gy, respectively) occurred. Distant relapse sites were skin (n = 2), lymph nodes (n = 2), duodenum, stomach, muscle, and conjunctiva (1 each). No paired-organ MZL relapsed. Apart from cataracts (n = 18), only three treatment-related late grade ≥3 adverse events occurred. Autoantibodies or autoimmune events were detected in 26 of 68 patients (38%). H. pylori infection was detected in 15 of 63 patients (24%) tested. Neither autoimmunity nor H. pylori was detected in 27 of 68 patients (40%). CONCLUSIONS: Radiotherapy was a potentially curative treatment with low toxicity in localised non-gastric MZL. Autoimmunity, H. pylori infection or both were detected in 60% of patients.

Durable Complete Remission and Long-Term Survival in FDG-PET Staged Patients with Stage III Follicular Lymphoma, Treated with Wide-Field Radiation Therapy.

Advanced-stage follicular lymphoma (FL) is generally considered incurable with conventional systemic therapies, but historic series describe long-term disease-free survival in stage III disease treated with wide-field radiation therapy (WFRT), encompassing all known disease sites. We report outcomes for patients staged with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and treated with CT-planned WFRT, given as either comprehensive lymphatic irradiation (CLI) or total nodal irradiation (TNI). This analysis of a prospective cohort includes PET-staged patients given curative-intent WFRT as a component of initial therapy, or as sole treatment for stage III FL. Thirty-three PET-staged patients with stage III FL received WFRT to 24-30Gy between 1999 and 2017. Fifteen patients also received planned systemic therapy (containing rituximab in 11 cases) as part of their primary treatment. At 10 years, overall survival and freedom from progression (FFP) were 100% and 75%, respectively. None of the 11 rituximab-treated patients have relapsed. Nine relapses occurred; seven patients required treatment, and all responded to salvage therapies. A single death occurred at 16 years. The principal acute toxicity was transient hematologic; one patient had residual grade two toxicity at one year. With FDG-PET staging, most patients with stage III FL experience prolonged FFP after WFRT, especially when combined with rituximab.

Abscopal Regressions of Lymphoma After Involved-Site Radiation Therapy Confirmed by Positron Emission Tomography.

PURPOSE: Patients with abscopal regressions of lymphoma after palliative involved-site radiation therapy (ISRT), detected on sequential 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), were identified by audit. A retrospective analysis was subsequently conducted to estimate the frequency of abscopal regression in follicular lymphoma (FL). METHODS AND MATERIALS: Potential cases were identified at multidisciplinary lymphoma meetings and fulfilled these criteria: (1) palliative ISRT given for histologically confirmed lymphoma, (2) >2 lesions visualized on FDG-PET, (3) >1 unirradiated lesion(s) outside ISRT volume, (4) no systemic therapy delivered <2 months before radiation therapy or between radiation therapy and response assessment, (5) complete metabolic response (CMR) in ≥1 unirradiated lesions detected on serial FDG-PET/CT. All ISRT patients with FL treated in 2016 to 2018 were systematically reviewed. RESULTS: Seven cases of abscopal regression were identified, including 4 patients with FL. In all cases, a CMR was apparent both within the ISRT volume and in ≥1 unirradiated lesions. One patient each was identified with mantle cell lymphoma (4 Gy in 2 fractions), Hodgkin lymphoma (20 Gy in 3 fractions, then 30 Gy in 15 fractions to the same volume), and Richter transformation of chronic lymphatic leukemia (30 Gy in 10 fractions). The 4 patients with FL received either 4 Gy in 2 fractions (n = 3) or 4 Gy followed 8 months later by 30 Gy in 15 fractions (n = 1). From 2016 to 2018, 29 courses of ISRT were prescribed for multifocal FL, after which 4 of 29 (13.8%) abscopal responses were detected, including in 4 of 9 (44.4%) patients with serial PET scans. Two patients, with relapsed disease after initial abscopal responses, experienced durable CMRs with immunotherapies. CONCLUSIONS: In 4 of 7 cases, PET-detected abscopal regression of lymphoma occurred after 4 Gy, in 2 of 7 cases after repeated ISRT to the same volume, and in 2 of 7 was associated with subsequent complete response to immunotherapy, consistent with an immune basis for the abscopal effect. Abscopal regressions in FL appear to be more common than previously suspected.

Robust, independent and relevant prognostic 18F-fluorodeoxyglucose positron emission tomography radiomics features in non-small cell lung cancer: Are there any?

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.

Predicting treatment Response based on Dual assessment of magnetic resonance Imaging kinetics and Circulating Tumor cells in patients with Head and Neck cancer (PREDICT-HN): matching 'liquid biopsy' and quantitative tumor modeling.

BACKGROUND: Magnetic resonance imaging (MRI) has improved capacity to visualize tumor and soft tissue involvement in head and neck cancers. Using advanced MRI, we can interrogate cell density using diffusion weighted imaging, a quantitative imaging that can be used during radiotherapy, when diffuse inflammatory reaction precludes PET imaging, and can assist with target delineation as well. Correlation of circulating tumor cells (CTCs) measurements with 3D quantitative tumor characterization could potentially allow selective, patient-specific response-adapted escalation or de-escalation of local therapy, and improve the therapeutic ratio, curing the greatest number of patients with the least toxicity. METHODS: The proposed study is designed as a prospective observational study and will collect pretreatment CT, MRI and PET/CT images, weekly serial MR imaging during RT and post treatment CT, MRI and PET/CT images. In addition, blood sample will be collected for biomarker analysis at those time intervals. CTC assessments will be performed on the CellSave tube using the FDA-approved CellSearch® Circulating Tumor Cell Kit (Janssen Diagnostics), and plasma from the EDTA blood samples will be collected, labeled with a de-identifying number, and stored at - 80 °C for future analyses. DISCUSSION: The primary objective of the study is to evaluate the prognostic value and correlation of weekly tumor response kinetics (gross tumor volume and MR signal changes) and circulating tumor cells of mucosal head and neck cancers during radiation therapy using MRI in predicting treatment response and clinical outcomes. This study will provide landmark information as to the utility of CTCs ('liquid biopsy) and tumor-specific functional quantitative imaging changes during treatment to guide personalization of treatment for future patients. Combining the biological information from CTCs and the structural information from MRI may provide more information than either modality alone. In addition, this study could potentially allow us to determine the optimal time to obtain MR imaging and/ or CTCs during radiotherapy to assess tumor response and provide guidance for patient selection and stratification for future dose escalation or de-escalation strategies. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03491176 ). Date of registration: 9th April 2018. (retrospectively registered). Date of enrolment of the first participant: 30th May 2017.

The coagulome and the oncomir: impact of cancer-associated haemostatic dysregulation on the risk of metastasis.

Patients with cancer are at high risk of both thromboembolic and haemorrhagic events during the course of their disease. The pathogenesis of haemostatic dysfunction in cancer is complex and involves the interplay of multiple factors. There is growing evidence that interactions between malignancies and the coagulation system are not random but can represent coordinated and clinically-significant adaptations that enhance tumour cell survival, proliferation and metastatic potential. A detailed understanding of the interactions between the haemostatic systems and the pathophysiology of metastasis may not only provide insight into strategies that could potentially reduce the incidence of thrombohaemorrhagic events and complications, but could also help design strategies that are capable of modifying tumour biology, progression and metastatic potential in ways that could enhance anticancer therapies and thereby improve overall survival.

Radiation therapy-induced metastasis: radiobiology and clinical implications.

Radiation therapy is an effective means of achieving local control in a wide range of primary tumours, with the reduction in the size of the tumour(s) thought to mediate the observed reductions in metastatic spread in clinical trials. However, there is evidence to suggest that the complex changes induced by radiation in the tumour environment can also present metastatic risks that may counteract the long-term efficacy of the treatment. More than 25 years ago, several largely theoretical mechanisms by which radiation exposure might increase metastatic risk were postulated. These include the direct release of tumour cells into the circulation, systemic effects of tumour and normal tissue irradiation and radiation-induced changes in tumour cell phenotype. Here, we review the data that has since emerged to either support or refute these putative mechanisms focusing on how the unique radiobiology underlying modern radiotherapy modalities might alter these risks.

Classification and evaluation strategies of auto-segmentation approaches for PET: Report of AAPM task group No. 211.

PURPOSE: The purpose of this educational report is to provide an overview of the present state-of-the-art PET auto-segmentation (PET-AS) algorithms and their respective validation, with an emphasis on providing the user with help in understanding the challenges and pitfalls associated with selecting and implementing a PET-AS algorithm for a particular application. APPROACH: A brief description of the different types of PET-AS algorithms is provided using a classification based on method complexity and type. The advantages and the limitations of the current PET-AS algorithms are highlighted based on current publications and existing comparison studies. A review of the available image datasets and contour evaluation metrics in terms of their applicability for establishing a standardized evaluation of PET-AS algorithms is provided. The performance requirements for the algorithms and their dependence on the application, the radiotracer used and the evaluation criteria are described and discussed. Finally, a procedure for algorithm acceptance and implementation, as well as the complementary role of manual and auto-segmentation are addressed. FINDINGS: A large number of PET-AS algorithms have been developed within the last 20 years. Many of the proposed algorithms are based on either fixed or adaptively selected thresholds. More recently, numerous papers have proposed the use of more advanced image analysis paradigms to perform semi-automated delineation of the PET images. However, the level of algorithm validation is variable and for most published algorithms is either insufficient or inconsistent which prevents recommending a single algorithm. This is compounded by the fact that realistic image configurations with low signal-to-noise ratios (SNR) and heterogeneous tracer distributions have rarely been used. Large variations in the evaluation methods used in the literature point to the need for a standardized evaluation protocol. CONCLUSIONS: Available comparison studies suggest that PET-AS algorithms relying on advanced image analysis paradigms provide generally more accurate segmentation than approaches based on PET activity thresholds, particularly for realistic configurations. However, this may not be the case for simple shape lesions in situations with a narrower range of parameters, where simpler methods may also perform well. Recent algorithms which employ some type of consensus or automatic selection between several PET-AS methods have potential to overcome the limitations of the individual methods when appropriately trained. In either case, accuracy evaluation is required for each different PET scanner and scanning and image reconstruction protocol. For the simpler, less robust approaches, adaptation to scanning conditions, tumor type, and tumor location by optimization of parameters is necessary. The results from the method evaluation stage can be used to estimate the contouring uncertainty. All PET-AS contours should be critically verified by a physician. A standard test, i.e., a benchmark dedicated to evaluating both existing and future PET-AS algorithms needs to be designed, to aid clinicians in evaluating and selecting PET-AS algorithms and to establish performance limits for their acceptance for clinical use. The initial steps toward designing and building such a standard are undertaken by the task group members.

Treatment for non-small-cell lung cancer and circulating tumor cells.

Surgery is the main curative therapy for patients with localized non-small-cell lung cancer while radiotherapy (RT), alone or with concurrent platinum-based chemotherapy, remains the primary curative modality for locoregionally advanced non-small-cell lung cancer. The risk of distant metastasis is high after curative-intent treatment, largely attributable to the presence of undetected micrometastases, but which could also be related to treatment-related increases in circulating tumor cells (CTCs). CTC mobilization by RT or systemic therapies might either reflect efficient tumor destruction with improved prognosis, or might promote metastasis and thus represent a potential therapeutic target. RT may induce prometastatic biological alterations in CTC at the cellular level, which are detectable by 'liquid biopsies', though their rarity represents a major challenge. Improved methods of isolation and ex vivo propagation will be essential for the future of CTC research.

Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?

Despite progressive improvements in the management of patients with locoregionally confined, advanced-stage solid tumours, distant metastasis remains a very common - and usually fatal - mode of failure after attempted curative treatment. Surgery and radiotherapy are the primary curative modalities for these patients, often combined with each other and/or with chemotherapy. Distant metastasis occurring after treatment can arise from previously undetected micrometastases or, alternatively, from persistent locoregional disease. Another possibility is that treatment itself might sometimes cause or promote metastasis. Surgical interventions in patients with cancer, including biopsies, are commonly associated with increased concentrations of circulating tumour cells (CTCs). High CTC numbers are associated with an unfavourable prognosis in many cancers. Radiotherapy and systemic antitumour therapies might also mobilize CTCs. We review the preclinical and clinical data concerning cancer treatments, CTC mobilization and other factors that might promote metastasis. Contemporary treatment regimens represent the best available curative options for patients who might otherwise die from locally confined, advanced-stage cancers; however, if such treatments can promote metastasis, this process must be understood and addressed therapeutically to improve patient survival.

Multiple training interventions significantly improve reproducibility of PET/CT-based lung cancer radiotherapy target volume delineation using an IAEA study protocol.

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.

Radiotherapy for Non-Small Cell Lung Cancer Induces DNA Damage Response in Both Irradiated and Out-of-field Normal Tissues.

PURPOSE: To study the response of irradiated and out-of-field normal tissues during localized curative intent radiotherapy. EXPERIMENTAL DESIGN: Sixteen patients with non-small cell lung carcinoma (NSCLC) received 60 Gy in 30 fractions of definitive thoracic radiotherapy with or without concurrent chemotherapy. Peripheral blood lymphocytes (PBL) and eyebrow hairs were sampled prior, during, and after radiotherapy. Clinical variables of radiotherapy dose/volume, patient age, and use of chemoradiotherapy were tested for association with γ-H2AX foci, a biomarker of DNA damage that underlies cellular response to irradiation. RESULTS: Radiotherapy induced an elevation of γ-H2AX foci in PBL, representing normal tissues in the irradiated volume, 1 hour after fraction one. The changes correlated directly with mean lung dose and inversely with age. γ-H2AX foci numbers returned to near baseline values in 24 hours and were not significantly different from controls at 4 weeks during radiotherapy or 12 weeks after treatment completion. In contrast, unirradiated hair follicles, a surrogate model for out-of-field normal tissues, exhibited delayed "abscopal" DNA damage response. γ-H2AX foci significantly increased at 24 hours post-fraction one and remained elevated during treatment, in a dose-independent manner. This observed abscopal effect was associated with changes in plasma levels of MDC/CCL22 and MIP-1α/CCL3 cytokines. No concordant changes in size and concentration of circulating plasma exosomes were observed. CONCLUSIONS: Both localized thoracic radiotherapy and chemoradiotherapy induce pronounced systemic DNA damage in normal tissues. Individual assessment of biologic response to dose delivered during radiotherapy may allow for therapeutic personalization for patients with NSCLC. Clin Cancer Res; 22(19); 4817-26. ©2016 AACRSee related commentary by Verma and Lin, p. 4763.

Ga-68 MAA Perfusion 4D-PET/CT Scanning Allows for Functional Lung Avoidance Using Conformal Radiation Therapy Planning.

BACKGROUND: Ga-68-macroaggregated albumin ((68)Ga-perfusion) positron emission tomography/computed tomography (PET/CT) is a novel imaging technique for the assessment of functional lung volumes. The purpose of this study was to use this imaging technique for functional adaptation of definitive radiotherapy plans in patients with non-small cell lung cancer (NSCLC). METHODS: This was a prospective clinical trial of patients with NSCLC who received definitive 3-dimensional (3D) conformal radiotherapy to 60 Gy in 30 fx and underwent pretreatment respiratory-gated (4-dimensional [4D]) perfusion PET/CT. The "perfused" lung volume was defined as all lung parenchyma taking up radiotracer, and the "well-perfused" lung volume was contoured using a visually adapted threshold of 30% maximum standardized uptake value (SUV max). Alternate 3D conformal plans were subsequently created and optimized to avoid perfused and well-perfused lung volumes. Functional dose volumetrics were compared using mean lung dose (MLD), V5 (volume receiving 5 Gy or more), V10, V20, V30, V40, V50, and V60 parameters. RESULTS: Fourteen consecutive patients had alternate radiotherapy plans created based on functional lung volumes. When considering the original treatment plan, the dose to perfused and well-perfused functional lung volumes was similar to that of the conventional anatomical lung volumes with an average MLD of 12.15, 12.67, and 12.11 Gy, respectively. Plans optimized for well-perfused lung improved functional V30, V40, V50, and V60 metrics (all P values <.05). The functional MLD of well-perfused lung was improved by a median of 0.86 Gy, P < .01. However, plans optimized for perfused lung only showed significant improvement in the functional V60 dose parameter (median 1.00%, P = .04) but at a detriment of a worse functional V5 (median 3.33%, P = .05). CONCLUSIONS: This study demonstrates proof of principle that 4D-perfusion PET/CT may enable functional lung avoidance during treatment planning of patients with NSCLC. Radiotherapy plans adapted to well-perfused but not perfused functional lung volumes allow for reduction in dose to functional lung using 3D conformal radiotherapy.

Ventilation/Perfusion Positron Emission Tomography--Based Assessment of Radiation Injury to Lung.

PURPOSE: To investigate (68)Ga-ventilation/perfusion (V/Q) positron emission tomography (PET)/computed tomography (CT) as a novel imaging modality for assessment of perfusion, ventilation, and lung density changes in the context of radiation therapy (RT). METHODS AND MATERIALS: In a prospective clinical trial, 20 patients underwent 4-dimensional (4D)-V/Q PET/CT before, midway through, and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT, and isodose volumes were averaged into 10-Gy bins. Within each dose bin, relative loss in standardized uptake value (SUV) was recorded for ventilation and perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models, and goodness of fit was assessed with Akaike Information Criterion (AIC). RESULTS: A total of 179 imaging datasets were available for analysis (1 scan was unrecoverable). An almost perfectly linear negative dose-response relationship was observed for perfusion and air-filled fraction (r(2)=0.99, P<.01), with ventilation strongly negatively linear (r(2)=0.95, P<.01). Logistic models did not provide a better fit as evaluated by AIC. Perfusion, ventilation, and the air-filled fraction decreased 0.75 ± 0.03%, 0.71 ± 0.06%, and 0.49 ± 0.02%/Gy, respectively. Within high-dose regions, higher baseline perfusion SUV was associated with greater rate of loss. At 50 Gy and 60 Gy, the rate of loss was 1.35% (P=.07) and 1.73% (P=.05) per SUV, respectively. Of 8/20 patients with peritumoral reperfusion/reventilation during treatment, 7/8 did not sustain this effect after treatment. CONCLUSIONS: Radiation-induced regional lung functional deficits occur in a dose-dependent manner and can be estimated by simple linear models with 4D-V/Q PET/CT imaging. These findings may inform future studies of functional lung avoidance using V/Q PET/CT.

Accuracy and Utility of Deformable Image Registration in (68)Ga 4D PET/CT Assessment of Pulmonary Perfusion Changes During and After Lung Radiation Therapy.

PURPOSE: Measuring changes in lung perfusion resulting from radiation therapy dose requires registration of the functional imaging to the radiation therapy treatment planning scan. This study investigates registration accuracy and utility for positron emission tomography (PET)/computed tomography (CT) perfusion imaging in radiation therapy for non-small cell lung cancer. METHODS: (68)Ga 4-dimensional PET/CT ventilation-perfusion imaging was performed before, during, and after radiation therapy for 5 patients. Rigid registration and deformable image registration (DIR) using B-splines and Demons algorithms was performed with the CT data to obtain a deformation map between the functional images and planning CT. Contour propagation accuracy and correspondence of anatomic features were used to assess registration accuracy. Wilcoxon signed-rank test was used to determine statistical significance. Changes in lung perfusion resulting from radiation therapy dose were calculated for each registration method for each patient and averaged over all patients. RESULTS: With B-splines/Demons DIR, median distance to agreement between lung contours reduced modestly by 0.9/1.1 mm, 1.3/1.6 mm, and 1.3/1.6 mm for pretreatment, midtreatment, and posttreatment (P < .01 for all), and median Dice score between lung contours improved by 0.04/0.04, 0.05/0.05, and 0.05/0.05 for pretreatment, midtreatment, and posttreatment (P < .001 for all). Distance between anatomic features reduced with DIR by median 2.5 mm and 2.8 for pretreatment and midtreatment time points, respectively (P = .001) and 1.4 mm for posttreatment (P > .2). Poorer posttreatment results were likely caused by posttreatment pneumonitis and tumor regression. Up to 80% standardized uptake value loss in perfusion scans was observed. There was limited change in the loss in lung perfusion between registration methods; however, Demons resulted in larger interpatient variation compared with rigid and B-splines registration. CONCLUSIONS: DIR accuracy in the data sets studied was variable depending on anatomic changes resulting from radiation therapy; caution must be exercised when using DIR in regions of low contrast or radiation pneumonitis. Lung perfusion reduces with increasing radiation therapy dose; however, DIR did not translate into significant changes in dose-response assessment.