The role of 18 F-FDG PET/CT in retroperitoneal sarcomas-A multicenter retrospective study.

BACKGROUND: The role of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS). METHODS: Patients with the above histological subtypes in three participating institutions with preoperative 18 F-FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse-free survival (RFS) and overall survival (OS) were also studied. RESULTS: Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2-33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003). CONCLUSION: There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.

Independent and incremental value of ventilation/perfusion PET/CT and CT pulmonary angiography for pulmonary embolism diagnosis: results of the PECAN pilot study.

PURPOSE: This pilot study assessed the independent and incremental value of 68Ga-V/Q PET/CT as compared with CT pulmonary angiography (CTPA) for the management of cancer patients with suspected acute pulmonary embolism (PE). METHODS: All 24 cancer patients with suspected acute PE prospectively recruited underwent both 68Ga-V/Q PET/CT and CTPA within 24 h. PET/CT was acquired after inhalation of Galligas prepared using a Technegas generator and administration of 68Ga-macroaggregated albumin. Initially, PET/CT and CTPA scans were read independently with the reader blinded to the results of the other imaging study. CTPA and PET/CT were then coregistered and reviewed by consensus between a radiologist and nuclear medicine physician. The therapeutic management was established by the managing physician based on all available data. RESULTS: The diagnostic conclusion was concordantly negative in 18 patients (75%). Of the six discordant diagnoses on independent reading, combined interpretation of V/Q PET/CTPA enabled a consensus conclusion in two patients, excluding PE in one and confirming PE in the other, similar to the initial diagnostic conclusion of the V/Q PET/CT. Of the remaining four patients, three had a single subsegmental thrombus on CTPA but a negative V/Q PET/CT scan, and two of these did not receive long-term anticoagulation and did not have a venous thromboembolic event during a 3-year follow-up period. The third patient, along with a patient with a positive V/Q PET/CT scan but a negative CTPA scan, presented with acute complications preventing any conclusions with regard to the appropriateness of the V/Q PET/CT results in the management of PE. Overall, V/Q PET had an impact on management in four patients (17%). CONCLUSION: In this pilot study, we demonstrated the feasibility and potential utility of V/Q PET/CT for the management of patients with suspected PE. V/Q PET/CT may be of particular relevance in patients with equivocal findings or isolated subsegmental findings on CTPA, adding further discriminatory information to allow important decision-making regarding the use or withholding of anticoagulation. Given the other advantages of V/Q PET/CT (reduced acquisition time, low radiation dose), and with the increasing availability of 68Ga generators, PET/CT is a potential replacement for V/Q SPECT/CT imaging.

PET-detected pneumonitis following curative-intent chemoradiation in non-small cell lung cancer (NSCLC): recognizing patterns and assessing the impact on the predictive ability of FDG-PET/CT response assessment.

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.

Analysis of a Length-Structured Density-Dependent Model for Fish.

We present a length-structured matrix model for fish populations in which the probability that a fish grows into the next length class is a decreasing nonlinear function of the total biomass of the population. We present mathematical results classifying the dynamics that this density-dependent model predicts. We illustrate these results with numerical simulations for an invasive white perch population and show how the mathematical results can be used to predict the persistence and/or boundedness of the population as well as an equilibrium structure that is dominated by small fish. We illustrate the results with management recommendations for an invasive white perch population.

Correction to: Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis.

On page 4 of the original version of this article, the text "Eight (29%) of the patients had significant FDG-avid disease (i.e. with intensity above liver parenchyma) prior to treatment" needs to be corrected.

Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis.

PURPOSE: Grade 3 NENs are aggressive tumours with poor prognosis. PRRT+/- radiosensitising chemotherapy is a potential treatment for disease with high somatostatin receptor (SSTR) expression without spatially discordant FDG-avid disease. We retrospectively evaluated the efficacy of PRRT in G3 NEN. METHODS: Kaplan-Meier estimation was used to determine progression-free survival (PFS) and overall survival (OS) defined from start of PRRT. Subgroup analysis was performed for patients with Ki-67 ≤ 55% and >55%. Anatomical response (RECIST 1.1) and toxicity 3 months after PRRT was determined. Disease control rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD) of those with prior progression. RESULTS: 28 patients (M = 17; age 16-78 years; Ki-67 ≤ 55% = 22) were reviewed. 17 patients had pancreatic, 5 small bowel, 3 large bowel, 2 bronchial and 1 unknown primary disease. 25/28 had significant FDG-avid disease prior to treatment. Most had 177Lu-DOTA-octreotate (median cumulative activity 24.4 GBq, median 4 cycles). Twenty patients had radiosensitising chemotherapy. 89% were treated for disease progression; 79% after prior chemotherapy. Median follow-up was 29 months. The median PFS was 9 months for all patients. 16 patients died (Ki-67 ≤ 55% = 11; Ki-67 > 55% = 5) with median OS of 19 months. For Ki-67 ≤ 55% (N = 22), the median PFS was 12 months and median OS 46 months. For Ki-67 > 55% (N = 6), the median PFS was 4 months and median OS 7 months. On CT imaging, DCR at 3 months post-PRRT was 74%, 35% (8/23) PR and 39% (9/23) SD. Eleven patients received further PRRT due to recrudescent disease after response. Five patients developed progression of discordant FDG-avid disease and were referred for targeted therapy/chemotherapy. Grade 3 and 4 lymphopenia and thrombocytopenia occurred in five and five patients, respectively. No renal or liver toxicity related to treatment was seen. CONCLUSIONS: PRRT achieves clinically relevant disease control with acceptable toxicity in G3 NENs.

Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing.

Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.

High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumours.

PURPOSE: Bulky disease is an adverse prognostic factor for 177Lu-DOTA-octreotate (177Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). 90Y-DOTA-octreotate (90Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than 177Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially. METHODS: We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of 90Y-DOTATATE followed by 2-3 cycles of 177Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival. RESULTS: Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq 90Y-DOTATATE, and 21 GBq 177Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months. CONCLUSION: PRCRT with 90Y -DOTATATE followed by 177Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either agent used alone or other approved treatments, particularly given the adverse prognostic features of this cohort.

Incremental diagnostic utility of gastric distension FDG PET/CT.

PURPOSE: To assess the diagnostic utility of gastric distension (GD) FDG PET/CT in both patients with known gastric malignancy and those not known to have gastric malignancy but with incidental focal FDG uptake in the stomach. METHODS: This retrospective analysis included 88 patients who underwent FDG PET/CT following GD with hyoscine N-butylbromide (Buscopan®) and water ingestion as part of routine clinical evaluation between 2004 and 2014. FDG PET/CT scans before and after GD were reported blinded to the patient clinical details in 49 patients undergoing pretreatment staging of gastric malignancy and 39 patients who underwent GD following incidental suspicious gastric uptake. The PET findings were validated by a composite clinical standard. RESULTS: In the 49 patients undergoing pretreatment staging of gastric malignancy, GD improved PET detection of the primary tumour (from 80 % to 90 %). PET evaluation of tumour extent was concordant with endoscopic/surgical reports in 31 % (interpreter 1) and 45 % (interpreter 2) using pre-GD images and 73 % and 76 % using GD images. Interobserver agreement also improved with GD (κ = 0.29 to 0.69). Metabolic and morphological quantitative analysis demonstrated a major impact of GD in normal gastric wall but no significant effect in tumour, except a minor increase in SUV related to a delayed acquisition time. The tumour to normal stomach SUVmax ratio increased from 3.8 ± 2.9 to 9.2 ± 8.6 (mean ± SD) with GD (p < 0.0001), facilitating detection and improved assessment of the primary tumour. In 25 (64 %) of the 39 patients with incidental suspicious gastric uptake, acquisition after GD correctly excluded a malignant process. In 10 (71 %) of the remaining 14 patients with persistent suspicious FDG uptake despite GD, malignancy was confirmed and in 3 (21 %) an active but benign pathology was diagnosed. CONCLUSION: GD is a simple way to improve local staging with FDG PET in patients with gastric malignancy. In the setting of incidental suspicious gastric uptake, GD is also an effective tool for ruling out malignancy and leads to the avoidance of unnecessary endoscopy.

Use of vemurafenib in a patient unable to swallow whole.

The treatment landscape for metastatic melanoma has increased dramatically in the past five years, with the pivotal discovery of activating BRAF mutations in half of all melanomas spurring the development for effective treatments that target mitogen-activated protein kinase (RAS/RAF/MEK/ERK) pathway. Vemurafenib, a selective mutant BRAF Val600 inhibitor, results in striking tumour responses and a survival advantage over conventional chemotherapy. We present here the case of a 38-year-old woman with metastatic BRAFV600E mutant melanoma and a severe tablet phobia, who was found to have been crushing and/or chewing her vemurafenib tablets. In this case, she attained a partial response and significant clinical benefit, albeit temporarily.

¹8F-FDG PET/CT following chemoradiation of uterine cervix cancer provides powerful prognostic stratification independent of HPV status: a prospective cohort of 105 women with mature survival data.

PURPOSE: To report 5-year outcomes of a prospective registry study investigating posttherapy FDG PET/CT in women with locally advanced cervical cancer. A secondary analysis assessing the prognostic significance of HPV infection was performed. METHODS: Patients underwent definitive chemoradiation followed by a single FDG PET/CT scan for response assessment. A complete metabolic response (CMR) was defined as no evidence of FDG-avid disease. Patients were dichotomized according to HPV infection status into a 'higher-risk' group and a 'lower-risk' group, with the higher-risk group comprising those with alpha-7 strain HPV (subtypes 18, 39 and 45) and those who were HPV-negative and the lower-risk group comprising those with alpha-9 strain HPV (subtypes 16, 31, 33, 52 and 58) and those with mixed strains. Survival outcomes, patterns of failure and salvage therapy outcomes were investigated for their association with metabolic response and HPV status. RESULTS: In 105 patients the median prospective follow-up was 5.2 years. The 5-year cancer-specific, overall and progression-free survival rates in patients with a CMR were 97 %, 93 % and 86 %, respectively. In patients without a CMR, the corresponding 5-year survival rates were 36 %, 22 % and 0 % respectively (p < 0.01). PET response was associated with patterns of failure (p < 0.01), with the 5-year freedom from local, nodal and distant failure in patients with a CMR being 94 %, 90 % and 94 %, respectively. Of 16 patients who underwent salvage therapy, 12 had disease detected on the surveillance PET scan, and 8 achieved a post-salvage CMR of whom all were alive at a median of 4.9 years. DNA adequate for HPV analysis was extracted in 68 patients. The likelihood of a PET metabolic response was not influenced by HPV infection status, with 71 % and 75 % of higher-risk and lower-risk patients, respectively, achieving CMR (p = 0.83). Higher-risk patients had a poorer OS (HR 2.6, range 1.0 - 6.6, p = 0.05) in univariable analysis but not multivariable analysis (p = 0.11). CONCLUSION: At 5 years CMR remains a powerful factor predicting survival after initial and salvage therapy. Metabolic response was not associated with HPV infection risk. Further studies are required to establish the association with HPV infection risk and survival after chemoradiation.

Harmonizing FDG PET quantification while maintaining optimal lesion detection: prospective multicentre validation in 517 oncology patients.

PURPOSE: Point-spread function (PSF) or PSF + time-of-flight (TOF) reconstruction may improve lesion detection in oncologic PET, but can alter quantitation resulting in variable standardized uptake values (SUVs) between different PET systems. This study aims to validate a proprietary software tool (EQ.PET) to harmonize SUVs across different PET systems independent of the reconstruction algorithm used. METHODS: NEMA NU2 phantom data were used to calculate the appropriate filter for each PSF or PSF+TOF reconstruction from three different PET systems, in order to obtain EANM compliant recovery coefficients. PET data from 517 oncology patients were reconstructed with a PSF or PSF+TOF reconstruction for optimal tumour detection and an ordered subset expectation maximization (OSEM3D) reconstruction known to fulfil EANM guidelines. Post-reconstruction, the proprietary filter was applied to the PSF or PSF+TOF data (PSFEQ or PSF+TOFEQ). SUVs for PSF or PSF+TOF and PSFEQ or PSF+TOFEQ were compared to SUVs for the OSEM3D reconstruction. The impact of potential confounders on the EQ.PET methodology including lesion and patient characteristics was studied, as was the adherence to imaging guidelines. RESULTS: For the 1380 tumour lesions studied, Bland-Altman analysis showed a mean ratio between PSF or PSF+TOF and OSEM3D of 1.46 (95%CI: 0.86-2.06) and 1.23 (95%CI: 0.95-1.51) for SUVmax and SUVpeak, respectively. Application of the proprietary filter improved these ratios to 1.02 (95%CI: 0.88-1.16) and 1.04 (95%CI: 0.92-1.17) for SUVmax and SUVpeak, respectively. The influence of the different confounding factors studied (lesion size, location, radial offset and patient's BMI) was less than 5%. Adherence to the European Association of Nuclear Medicine (EANM) guidelines for tumour imaging was good. CONCLUSION: These data indicate that it is not necessary to sacrifice the superior lesion detection and image quality achieved by newer reconstruction techniques in the quest for harmonizing quantitative comparability between PET systems.

Respiratory-gated (4D) FDG-PET detects tumour and normal lung response after stereotactic radiotherapy for pulmonary metastases.

BACKGROUND: Response assessment after stereotactic ablative body radiotherapy (SABR) in lung can be confounded by radiation-induced inflammation, fibrosis and subsequent alteration of tumour motion. The purpose of this prospective pilot study was to evaluate the utility of four-dimensional (4D) FDG-PET/CT for post-SABR tumour and normal lung response assessment in pulmonary oligometastases. MATERIAL AND METHODS: Patients enrolled from February 2010 to December 2011 in this prospective ethics approved study had 1-2 pulmonary metastases on staging FDG-PET. Serial contemporaneous 3D and 4D FDG-PET/CT scans were performed at baseline, 14 days and 70 days after a single fraction of 26 Gy SABR. Tumour response was evaluated in 3D and 4D using SUVmax, RECIST and PERCIST criteria. Normal lung radiotoxicity was evaluated using SUVmean within 0-2 Gy, 2-5 Gy, 5-10 Gy, 10-20 Gy and 20 + Gy isodose volumes. RESULTS: In total, 17 patients were enrolled of which seven were ineligible due to interval progression from staging PET to baseline 4D-PET. The mean time between scans was 62 days. At a median follow-up of 16 months, 10 patients with 13 metastases received SABR, with no patient having local progression. The vector of tumour motion was larger in patients with discordant 3D and 4D PET PERCIST response (p < 0.01), with a mean (± SEM) motion of 10.5 mm (± 0.96 mm) versus 6.14 mm (± 0.81 mm) in those patients with concordant 3D and 4D response. Surrounding normal lung FDG uptake at 70 days was strongly correlated to delivered radiation dose (r(2) = 0.99, p < 0.01), with significant elevations across all dose levels (p ≤ 0.05), except the < 2 Gy volume (p = 0.30). CONCLUSIONS: We demonstrate high rates of interval progression between staging PET scans in patients with oligometastases. We found that tumour response on conventional 3D PET is not concordant with 4D PET for tumours with large motion. Normal lung metabolic uptake is strongly dose dependent after SABR, a novel finding that should be further validated.

High-resolution imaging of pulmonary ventilation and perfusion with 68Ga-VQ respiratory gated (4-D) PET/CT.

PURPOSE: Our group has previously reported on the use of (68)Ga-ventilation/perfusion (VQ) PET/CT scanning for the diagnosis of pulmonary embolism. We describe here the acquisition methodology for (68)Ga-VQ respiratory gated (4-D) PET/CT and the effects of respiratory motion on image coregistration in VQ scanning. METHODS: A prospective study was performed in 15 patients with non-small-cell lung cancer. 4-D PET and 4-D CT images were acquired using an infrared marker on the patient's abdomen as a surrogate for breathing motion following inhalation of Galligas and intravenous administration of (68)Ga-macroaggregated albumin. Images were reconstructed with phase-matched attenuation correction. The lungs were contoured on CT and PET VQ images during free-breathing (FB) and at maximum inspiration (Insp) and expiration (Exp). The similarity between PET and CT volumes was measured using the Dice coefficient (DC) comparing the following groups; (1) FB-PET/CT, (2) InspPET/InspCT, (3) ExpPET/Exp CT, and (4) FB-PET/AveCT. A repeated measures one-way ANOVA with multiple comparison Tukey tests were performed to evaluate any difference between the groups. Diaphragmatic motion in the superior-inferior direction on the 4-D CT scan was also measured. RESULTS: 4-D VQ scanning was successful in all patients without additional acquisition time compared to the nongated technique. The highest volume overlap was between ExpPET and ExpCT and between FB-PET and AveCT with a DC of 0.82 and 0.80 for ventilation and perfusion, respectively. This was significantly better than the DC comparing the other groups (0.78-0.79, p < 0.05). These values agreed with a visual inspection of the images with improved image coregistration around the lung bases. The diaphragmatic motion during the 4-D CT scan was highly variable with a range of 0.4-3.4 cm (SD 0.81 cm) in the right lung and 0-2.8 cm (SD 0.83 cm) in the left lung. Right-sided diaphragmatic nerve palsy was observed in 3 of 15 patients. CONCLUSION: (68)Ga-VQ 4-D PET/CT is feasible and the blurring caused by respiratory motion is well corrected with 4-D acquisition, which principally reduces artefact at the lung bases. The images with the highest spatial overlap were the combined expiration phase or FB PET and average CT. With higher resolution than SPECT/CT, the PET/CT technique has a broad range of potential clinical applications including diagnostic algorithms for patients with suspected pulmonary embolism, preoperative evaluation of regional lung function and improving assessment or understanding of pulmonary physiology in the vast range of pulmonary diseases.

A prospective observational study of Gallium-68 ventilation and perfusion PET/CT during and after radiotherapy in patients with non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is the leading cause of cancer deaths. Radiation therapy (RT), alone or in combination with chemotherapy, is the standard of care for curative intent treatment of patients with locally advanced or inoperable NSCLC. The ability to intensify treatment to achieve a better chance for cure is limited by the risk of injury to the surrounding lung. METHODS/DESIGN: This is a prospective observational study of 60 patients with NSCLC receiving curative intent RT. Independent human ethics board approval was received from the Peter MacCallum Cancer Centre ethics committee. In this research, Galligas and Gallium-68 macroaggregated albumin (MAA) positron emission tomography (PET) imaging will be used to measure ventilation (V) and perfusion (Q) in the lungs. This is combined with computed tomography (CT) and both performed with a four dimensional (4D) technique that tracks respiratory motion. This state-of-the-art scan has superior resolution, accuracy and quantitative ability than previous techniques. The primary objective of this research is to observe changes in ventilation and perfusion secondary to RT as measured by 4D V/Q PET/CT. Additionally, we plan to model personalised RT plans based on an individual's lung capacity. Increasing radiation delivery through areas of poorly functioning lung may enable delivery of larger, more effective doses to tumours without increasing toxicity. By performing a second 4D V/Q PET/CT scan during treatment, we plan to simulate biologically adapted RT depending on the individual's accumulated radiation injury. Tertiary aims of the study are assess the prognostic significance of a novel combination of clinical, imaging and serum biomarkers in predicting for the risk of lung toxicity. These biomarkers include spirometry, (18)F-Fluorodeoxyglucose PET/CT, gamma-H2AX signals in hair and lymphocytes, as well as assessment of blood cytokines. DISCUSSION: By correlating these biomarkers to toxicity outcomes, we aim to identify those patients early who will not tolerate RT intensification during treatment. This research is an essential step leading towards the design of future biologically adapted radiotherapy strategies to mitigate the risk of lung injury during dose escalation for patients with locally advanced lung cancer. TRIALS REGISTRATION: Universal Trial Number (UTN) U1111-1138-4421.

Mid-treatment adaptive planning during thoracic radiation using 68 Ventilation-Perfusion Positron emission tomography.

Four-Dimensional Gallium 68 Ventilation-Perfusion Positron Emission Tomography (68Ga-4D-V/Q PET/CT) allows for dynamic imaging of lung function. To date there has been no assessment of the feasibility of adapting radiation therapy plans to changes in lung function imaged at mid-treatment function using 68Ga-4D-V/Q PET/CT. This study assessed the potential reductions of dose to the functional lung when radiation therapy plans were adapted to avoid functional lung at the mid-treatment timepoint using volumetric arc radiotherapy (VMAT). Methods: A prospective clinical trial (U1111-1138-4421) was performed in patients undergoing conventionally fractionated radiation therapy for non-small cell lung cancer (NSCLC). A 68Ga-4D-V/Q PET/CT was acquired at baseline and in the 4th week of treatment. Functional lung target volumes using the ventilated and perfused lung were created. Baseline functional volumes were compared to the week 4 V/Q functional volumes to describe the change in function over time. For each patient, 3 VMAT plans were created and optimised to spare ventilated, perfused or anatomical lung. All key dosimetry metrics were then compared including dose to target volumes, dose to organs at risk and dose to the anatomical and functional sub-units of lung. Results: 25 patients had both baseline and 4 week mid treatment 68Ga-4D-V/Q PET/CT imaging. This resulted in a total of 75 adapted VMAT plans. The HPLung volume decreased in 16/25 patients with a mean of the change in volume (cc) -28 ± 515 cc [±SD, range -996 cc to 1496 cc]. The HVLung volume increased in 13/25 patients with mean of the change in volume (cc) + 112 ± 590 cc. [±SD, range -1424 cc to 950 cc]. The functional lung sparing technique was found to be feasible with no significant differences in dose to anatomically defined organs at risk. Most patients did derive a benefit with a reduction in functional volume receiving 20 Gy (fV20) and/or functional mean lung dose (fMLD) in either perfusion and/or ventilation. Patients with the most reduction in fV20 and fMLD were those with stage III NSCLC. Conclusion: Functional lung volumes change during treatment. Some patients benefit from using 68Ga-4D-V/Q PET/CT in the 4th week of radiation therapy to adapt radiation plans. In these patients, the role of mid-treatment adaptation requires further prospective investigation.

The HI-FIVE Trial: A Prospective Trial Using 4-Dimensional 68Ga Ventilation-Perfusion Positron Emission Tomography-Computed Tomography for Functional Lung Avoidance in Locally Advanced Non-small Cell Lung Cancer.

PURPOSE: Functional lung avoidance (FLA) radiation therapy aims to spare regions of functional lung to reduce toxicity. We report the results of the first prospective trial of FLA using 4-dimensional gallium 68 ventilation-perfusion positron emission tomography-computed tomography (68Ga-4D-V/Q PET/CT). METHODS AND MATERIALS: Inclusion criteria required a diagnosis of stage III non-small cell lung cancer and the ability to undergo radical-intent chemoradiation therapy. Functional volumes were generated using planning 68Ga-4D-V/Q PET/CT. These volumes were used to generate a clinical FLA plan to 60 Gy in 30 fractions. The primary tumor was boosted to 69 Gy. A comparison anatomic plan was generated for each patient. Feasibility was met if FLA plans (compared with anatomic plans) allowed (1) a reduction in functional mean lung dose of ≥2% and a reduction in the functional lung volume receiving 20 Gy (fV20Gy) of ≥4%, and (2) a mean heart dose ≤30 Gy and relative heart volume receiving 50 Gy of <25%. RESULTS: In total, 19 patients were recruited; 1 withdrew consent. Eighteen patients underwent chemoradiation with FLA. Of the 18 patients, 15 met criteria for feasibility. All patients completed the entire course of chemoradiation therapy. Using FLA resulted in an average reduction of the functional mean lung dose of 12.4% (SD, ±12.8%) and a mean relative reduction of the fV20Gy of 22.9% (SD, ±11.9%). At 12 months, Kaplan-Meier estimates for overall survival were 83% (95% CI, 56%-94%) and estimates for progression-free survival were 50% (95% CI, 26%-70%). Quality-of-life scores were stable across all time points. CONCLUSIONS: Using 68Ga-4D-V/Q PET/CT to image and avoid functional lung is feasible.

Quantitative assessment of ventilation-perfusion relationships with gallium-68 positron emission tomography/computed tomography imaging in lung cancer patients.

Pulmonary functional imaging has demonstrated potential to improve thoracic radiotherapy. The purpose of this study was twofold: 1) to quantify ventilation/perfusion relationships in lung cancer patients using a new functional imaging approach, gallium-68 (68Ga)-positron emission tomography/computed tomography (PET/CT); and 2) to compare ventilation/perfusion matching with diffusing capacity of the lung for carbon monoxide (DLCO). Voxel-wise correlations between ventilation and perfusion varied widely among 19 patients (range: 0.26-0.88). 68Ga-PET/CT-measured percent gas exchanging lung volume was moderately correlated with DLCO (≤0.59). Our findings suggested that 68Ga-PET/CT ventilation/perfusion imaging provided complementary information and a reasonable surrogate for gas exchange in lung cancer patients.