Impact on Pulmonary Function in a Randomized Trial of Single-Fraction and Multifraction Stereotactic Body Radiation Therapy for Pulmonary Oligometastatic Disease: An Analysis of TROG 13.01 (SAFRON II).

PURPOSE: The TROG 13.01 (SAFRON II) trial was a phase 2 multicenter trial comparing single-fraction (SF) and multifraction (MF) stereotactic body radiation therapy. Patients with 1 to 3 peripheral pulmonary oligometastases were randomized 1:1 between 28 Gy in 1 fraction and 48 Gy in 4 fractions. There were no differences between arms in efficacy or toxicity. We performed an analysis to assess changes in pulmonary function tests (PFTs) between arms over time and assessed the effect of the number and total volume of targets on PFT change over time. METHODS AND MATERIALS: A linear mixed model was used to describe the PFTs by treatment arm over time. The effect of number and volume of targets on PFTs at 6 and 12 months was assessed by a simple linear model. RESULTS: Ninety patients were randomized; 87 were treated for 133 pulmonary oligometastases. Forty-four were randomized to the SF arm and 43 to the MF arm. There were no differences in absolute or relative PFT measures of forced expiratory volume in 1 second (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), or forced vital capacity (FVC) between the 2 arms. At 12 months, there was a reduction in absolute DLCO from baseline (-1.7 mL/min/mm Hg [95% CI, -2.5 to -1.0]), relative DLCO (-5.5% [95% CI, -8.4% to -2.6%]), absolute FEV1 (-0.17 L [95% CI, -0.23 to -0.11]), and absolute FVC (-0.20 L [95% CI, -0.27 to -0.13]). In patients with multiple pulmonary targets, increase in target number (per lesion) was associated with a reduction in the absolute FEV1 at 6 months of -0.10 L (95% CI, -0.18 to -0.03; P = .007), FEV1 at 12 months of -0.10 L (95% CI, -0.20 to -0.01; P = .04), FVC at 6 months of -0.11 L (95% CI, -0.20 to -0.03; P = .014), and FVC at 24 months of -0.13 L (95% CI, -0.25 to -0.01; P = .036). Reduction in FEV1 was also seen per 10-mL increase in PTV at 12 months (-0.03 L [95% CI, -0.06 to -0.00], P = .036). The number of targets and PTV were not associated with DLCO. CONCLUSIONS: Treating multiple targets resulted in increased loss of FEV1 and FVC but not DLCO. There were no significant differences in PFT decline between SF and MF stereotactic body radiation therapy.

Comprehensive profiling identifies tumour and immune microenvironmental differences in clinical subsets of cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinomas (cSCCs) are the second most diagnosed skin cancer worldwide; however, little is known about the pathobiological factors that contribute to the diverse clinical outcomes seen. OBJECTIVES: To profile cSCCs comprehensively and identify the pathological processes that contribute to the disparities seen in their clinical behaviour. METHODS: We characterized the genomic, transcriptomic and immunohistochemical profiles of 211 cSCC tumours, including 37 cSCCs from immunocompromised patients. RESULTS: cSCCs from immunocompromised patients were characterized by a lack of B cells in the peritumoral stroma compared with immunocompetent patients. Further, an abundance of a memory B-cell-like population in the peritumoral stroma was associated with a better prognosis in all patients (immunocompetent and immunocompromised), as well as only immunocompetent patients. No differences in genetic -variants, tumour mutational burden or mutational signatures were observed between cSCCs from immunocompetent and immunocompromised patients. Thus, differences in survival between cSCCs from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but may be associated with differential host immune response. cSCC not from a primary head and neck site had lower tumour mutational burden and exhibited upregulation of the epithelial-mesenchymal transition programme compared with head and neck cSCC. Both factors were implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. CONCLUSIONS: We identified tumour and host immune factors that contribute to the disparate clinical behaviour of cSCC, with broad translational application, including prognostication, treatment prediction to current therapies and the identification of novel anticancer therapy approaches in cSCC.

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.

Comparison of Changes in Pulmonary Function After Stereotactic Body Radiation Therapy Versus Conventional 3-Dimensional Conformal Radiation Therapy for Stage I and IIA Non-Small Cell Lung Cancer: An Analysis of the TROG 09.02 (CHISEL) Phase 3 Trial.

PURPOSE: The TROG 09.02 CHISEL trial compared conventional radiation therapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomized to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the 6-minute walk test (SMWT) between patients who received SBRT and those who received CRT. METHODS AND MATERIALS: We analyzed the PFTs and SMWTs of all patients recruited to the CHISEL [trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12 months after treatment. RESULTS: One hundred and one patients were enrolled; 33 patients were treated with CRT, 61 were treated with SBRT, and 7 did not receive treatment. Primary tumor size was similar between arms: SBRT 25 mm (standard deviation [SD], 9) and CRT 28 mm (SD, 9). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. Planning target volume size was significantly larger in the CRT arm, 142.79 cc (SD, 61.14), compared with the SBRT group, 46.15 cc (SD, 23.39). The mean biologically effective dose received by the target was significantly larger in the SBRT group, 125.92 Gy (SD, 21.58), compared with CRT, 65.49 Gy (SD, 6.32). Mean dose to the lungs minus the gross target volume incorporating motion was 8.9 Gy (SD, 2.34) in the CRT group and 4.37 Gy (SD, 1.42) in the SBRT group. CONCLUSIONS: Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the 2 groups.

Avoiding Toxicity With Lung Radiation Therapy: An IASLC Perspective.

Toxicity concerns from thoracic radiation therapy in the treatment of lung cancers have changed substantially over the past few decades. Survival in the treatment of lung cancer has markedly improved and the introduction of advanced radiation and imaging techniques to treatment planning and delivery has made reducing toxicity possible. Phase 3 dose-escalation trials have revealed that excess dose to critical organs within the thorax can negatively impact overall survival. We summarize the existing literature on the known toxicities of thoracic radiation therapy, summarize the technological advances that have made toxicity reduction possible, and provide an overview of emerging technologies and biomarkers that are being evaluated to assess future toxicity reductions.

Stereotactic ablative radiation therapy for renal cell carcinoma with inferior vena cava tumor thrombus.

BACKGROUND: Inferior vena cava tumor thrombus (IVC-TT) is a rare yet deadly sequel of renal cell carcinoma (RCC) with limited treatment options. The standard treatment is extirpative surgery, which has high rates of morbidity and mortality. As a result, many patients are unfit or unwilling to undergo surgery and face poor prognosis. This stresses the need for alternative options for local disease control. Our study aims to assess the feasibility and oncological outcomes of stereotactic ablative radiation (SAbR) for IVC-TT. METHODS: A retrospective study reviewing six leading international institutions' experience in treating RCC with IVC-TT with SAbR. Primary end point was overall survival using Kaplan-Meier. RESULTS: Fifteen patients were included in the cohort. Over 50% of patients had high level IVC-TT (level III or IV), 66.7% had metastatic disease. Most eschewed surgery due to high surgical risk (7/15) or recurrent thrombus (3/15). All patients received SAbR to the IVC-TT with a median biologically equivalent dose (BED10) of 72 Gy (range: 37.5-100.8) delivered in a median of 5 fractions (range 1-5). Median overall survival was 34 months. Radiographic response was observed in 58% of patients. Symptom palliation was recorded in all patients receiving SAbR for this indication. Only grade 1 to 2 adverse events were noted. CONCLUSIONS: SAbR for IVC-TT appears feasible and safe. In patients who are not candidates for surgery, SAbR may palliate symptoms and improve outcomes. SAbR may be considered as part of a multimodal treatment approach for patients with RCC IVC-TT.

Cutaneous squamous cell carcinoma metastatic to the axilla and groin: Outcomes and prognostic factors.

PURPOSE: This study examined the clinical outcomes and prognostic factors of patients with metastatic cutaneous SCC metastatic to the axilla and groin when managed with curative-intent lymphadenectomy and received (neo)adjuvant treatment. METHODS AND MATERIALS: We conducted a single institution retrospective review. Patients who had nodal disease without distant spread were 18 years or older with no non-cutaneous primary identified. RESULTS: From January 2000 to July 2015, 78 patients were treated for axilla (64, 82%) or inguinal (14, 18%) involvement with cSCC. The median age was 75.5 years (range: 29-95), and 8 patients (11%) were immunosuppressed. The median size of the largest node was 45 mm (range: 8-135), and extracapsular extension was found in 63 (81%) cases. A majority of patients were treated with surgery alone (21, 26.9%) and surgery with adjuvant radiation therapy (54, 69%). The 2-year OS and PFS were 50% (95% CI: 40%-63%) and 43% (95% CI: 33%-56%), and 5-year OS and PFS were 33% (95% CI:23%-47%) and 32% (95% CI:22%-46%) respectively in the entire cohort. On univariable analysis, factors associated with longer OS were as follows: younger age (HR 1.1, 95% CI: 0.9-1.3 P = 0.021), improved performance status (HR 1.5, 95% CI:1.0-2.3 P = 0.026), lack of immunosuppression (HR 3.3, 95% CI: 1.5-7.3 P = 0.001), lower lymph node ratio (HR 1.2, 95% CI:1.0-1.3 P = 0.007), lower number of positive nodes (HR 1.1, 95% CI:1.0-1.2 P = 0.004) and the use of radiation therapy (HR 0.5, 95% CI:0.3-0.9 P = 0.012). CONCLUSION: Metastasis to the axilla and groin with cSCC has poor outcomes with standard treatment. The addition of immunotherapy warrants investigation.

Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients.

Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated toxicities. We collected PBMC from 38 patients enrolled on a prospective clinical trial who received definitive fractionated RT for non-small cell lung cancer. DDR was measured by automated counting of nuclear γ-H2AX foci in immunofluorescence images. Analysis of samples collected before, during and after RT demonstrated the induction of DNA damage in PBMC collected shortly after RT commenced, however, this damage repaired later. Radiation dose to the tumour and lung contributed to the in vivo induction of γ-H2AX foci. Aliquots of PBMC collected before treatment were also irradiated ex vivo, and γ-H2AX kinetics were analyzed. A trend for increasing of fraction of irreparable DNA damage in patients with higher toxicity grades was revealed. Slow DNA repair in three patients was associated with a combined dysphagia/cough toxicity and was confirmed by elevated in vivo RT-generated irreparable DNA damage. These results warrant inclusion of an assessment of DDR in PBMC in a panel of predictive biomarkers that would identify patients at a higher risk of toxicity.

Functional lung imaging in radiation therapy for lung cancer: A systematic review and meta-analysis.

RATIONALE: Advanced imaging techniques allow functional information to be derived and integrated into treatment planning. METHODS: A systematic review was conducted with the primary objective to evaluate the ability of functional lung imaging to predict risk of radiation pneumonitis. Secondary objectives were to evaluate dose-response relationships on post treatment functional imaging and assess the utility in including functional lung information into treatment planning. A structured search for publications was performed following PRISMA guidelines and registered on PROSPERO. RESULTS: 814 articles were screened against review criteria and 114 publications met criteria. Methods of identifying functional lung included using CT, MRI, SPECT and PET to image ventilation or perfusion. Six studies compared differences between functional and anatomical lung imaging at predicting radiation pneumonitis. These found higher predictive values using functional lung imaging. Twenty-one studies identified a dose-response relationship on post-treatment functional lung imaging. Nineteen planning studies demonstrated the ability of functional lung optimised planning techniques to spare regions of functional lung. Meta-analysis of these studies found that mean (95% CI) functional volume receiving 20 Gy was reduced by 4.2% [95% CI: 2.3: 6.0] and mean lung dose by 2.2 Gy [95% CI: 1.2: 3.3] when plans were optimised to spare functional lung. There was significant variation between publications in the definition of functional lung. CONCLUSION: Functional lung imaging may have potential utility in radiation therapy planning and delivery, although significant heterogeneity was identified in approaches and reporting. Recommendations have been made based on the available evidence for future functional lung trials.