Hypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[18 F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl-bis(N4)-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models. Positron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and 64Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients. Comparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. 64Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions. Radiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, 64Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that 64Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning.

Purpose: The aim of this phase II trial (NCT02965001) was to evaluate the prognostic value of urokinase-type plasminogen activator receptor (uPAR)-PET/CT with the novel ligand ⁶⁸Ga-NOTA-AE105 in head and neck cancer and compare it to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). Materials and Methods: Patients with head and neck squamous cell carcinoma (HNSCC) referred to curatively intended radiotherapy were eligible and prospectively included in this phase II study. A ⁶⁸Ga-uPAR- and ¹⁸F-FDG-PET/CT were performed before initiation of curatively intended radiotherapy and maximum standardized uptake values (SUV_max) of the primary tumor was measured on both PET/CTs by two independent readers. Relapse-free survival (RFS) and overall survival (OS) were calculated and optimal cut-off values were established for ⁶⁸Ga-uPAR- and ¹⁸F-FDG-PET independently and compared using log rank and Kaplan-Meier statistics, and univariate and multivariate analysis in Cox proportional hazards model. Results: A total of 57 patients were included and followed for a median of 33.8 months (range 2.30-47.2). The median SUV_max of the primary tumors were 2.98 (range 1.94-5.24) for ⁶⁸Ga-uPAR and 15.7 (range 4.24-45.5) for ¹⁸F-FDG. The optimal cut-off points for ⁶⁸Ga-NOTA-AE105 SUV_max in the primary tumor was 2.63 for RFS and 2.66 for OS. A high uptake of ⁶⁸Ga-NOTA-AE105 (SUV_max above cut-off) was significantly associated with poor RFS and OS (log-rank P = 0.012 and P = 0.022). ⁶⁸Ga-NOTA-AE105-uptake in the primary tumor was significantly associated with poor RFS in univariate analysis (HR=8.53 (95% confidence interval (CI) 1.12-64.7), P = 0.038) and borderline associated with OS (HR=7.44 (95% CI 0.98-56.4), P = 0.052). For ¹⁸F-FDG-PET, the optimal cut-off points were 22.7 for RFS and 22.9 for OS. ¹⁸F-FDG SUV_max above cut-off was significantly associated with reduced RFS (log-rank P = 0.012) and OS (log-rank P = 0.000). ¹⁸F-FDG-uptake was significantly associated with reduced RFS and OS in univariate analysis (HR=3.27; 95% CI 1.237-8.66), P = 0.017) and (HR=7.10; 95% CI 2.60-19.4), p<0.001). In a multivariate analysis including ⁶⁸Ga-uPAR SUV_max, ¹⁸F-FDG SUV_max, Tumor, Node and Metastasis (TNM) stage and p16 status, only ⁶⁸Ga-uPAR SUV_max remained significant (HR 8.51 (95%CI 1.08-66.9), P = 0.042) for RFS. For OS, only TNM stage and ¹⁸F-FDG remained significant. Conclusion: The current phase II clinical trial showed promising results for the use of ⁶⁸Ga-uPAR-PET SUV_max in the primary tumor to predict RFS in HNSCC patients referred to curatively intended radiotherapy when compared to ¹⁸F-FDG-PET, TNM stage and p16 status. ⁶⁸Ga-uPAR-PET could potentially become valuable for identification of patients suited for de-escalation of treatment and risk stratified follow-up schemes.

Glycolytic activity and hypoxia are associated with poor prognosis and radiation resistance. Including both the tumor uptake of 2-deoxy-2-[18 F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer copper(II)diacetyl-bis(N4)-methylsemithio-carbazone (Cu-ATSM) in targeted therapy planning may therefore lead to improved tumor control. In this study we analyzed the overlap between sub-volumes of FDG and hypoxia assessed by the uptake of 64Cu-ATSM in canine solid tumors, and evaluated the possibilities for dose redistribution within the gross tumor volume (GTV).

Arginine-Glycine-Aspartate (RGD)-recognizing cell surface integrins are involved in tumor growth, invasiveness/metastases, and angiogenesis, and are therefore an attractive treatment target in cancers. The subtype integrin α_vβ₃ is upregulated on endothelial cells during angiogenesis and on tumor cells. In vivo assessment of integrin α_vβ₃ is possible with positron emission tomography (PET). Preclinical data on radiochemical properties, tumor uptake and radiation exposure identified [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ as a promising candidate for clinical translation. In this first-in-human phase I study, we evaluate [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ PET in patients with neuroendocrine neoplasms (NEN) and breast cancer (BC). The aim was to investigate safety, biodistribution and dosimetry as well as tracer uptake in tumor lesions. A total of 10 patients (5 breast cancer, 5 neuroendocrine neoplasm) received a single intravenous dose of approximately 200 MBq [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂. Biodistribution profile and dosimetry were assessed by whole-body PET/CT performed at 10 min, 1 h and 2 h after injection. Safety assessment with vital parameters, electrocardiograms and blood tests were performed before and after injection. In vivo stability of [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ was determined by analysis of blood and urine. PET images were analyzed for tracer uptake in tumors and background organs. No adverse events or pharmacologic effects were observed in the 10 patients. [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ exhibited good in vivo stability and fast clearance, primarily by renal excretion. The effective dose was 0.022 mSv/MBq, equaling a radiation exposure of 4.4 mSv at an injected activity of 200 MBq. The tracer demonstrated stable tumor retention and good image contrast. In conclusion, this first-in-human phase I trial demonstrated safe use of [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ for integrin α_vβ₃ imaging in cancer patients, low radiation exposure and favorable uptake in tumors. Further studies are warranted to establish whether [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ may become a tool for early identification of patients eligible for treatments targeting integrin α_vβ₃ and for risk stratification of patients.

PURPOSE: Remote symptom monitoring of patients with cancer has previously shown potential for improving clinical outcomes. This study aimed to evaluate the effects of remote symptom monitoring in patients with lung cancer after palliative induction treatment. METHODS: In a Danish multicenter randomized controlled trial, patients were randomly assigned 1:1 to remote symptom monitoring (intervention arm) added to standard of care versus standard of care (control arm). Key eligibility criteria were stage III-IV lung cancer (small cell lung cancer and non–small cell lung cancer), Eastern Cooperative Oncology Group performance status ≤2, and no sign of disease progression after initial induction treatment. Patients in the intervention arm completed a weekly electronic questionnaire, assessing 14 common symptoms related to lung cancer. When a patient reported a severity exceeding a predefined threshold, the patient was subsequently contacted by phone to address potential clinical needs. Symptom monitoring was discontinued after progression. The primary outcome was overall survival (OS). Secondary measures included assessment of health-related quality of life (HRQoL). RESULTS: Of 494 randomly assigned patients, 240 were assigned to the intervention arm and 254 were assigned to the control arm. At a median follow-up of 3.5 years, symptom monitoring did not significantly improve OS compared with standard care (hazard ratio [HR], 0.93 [95% CI, 0.75 to 1.16]; P = .53). Exploratory subgroup analyses indicated improved survival for patients treated with carboplatin/vinorelbine (HR, 0.67 [95% CI, 0.45 to 0.98]; P = .04) and in departments with previous implementation of patient-reported outcomes (HR, 0.66 [95% CI, 0.44 to 0.98]; P = .04). HRQoL analyses did not reveal clinically meaningful effects. CONCLUSION: In the Danish health care system, remote symptom monitoring did not improve OS but led to modest improvements in HRQoL for patients with advanced lung cancer.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of lung cancer with dismal prognosis. Long-term outcomes after primarily video-assisted thoracoscopic surgery (VATS) have not yet been described in LCNEC. This study aims to determine overall survival and recurrence-free survival after VATS as well as to identify prognostic factors for survival and recurrence. Data were obtained from a prospective institutional database. Kaplan-Meier estimates of overall survival and recurrence-free survival were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model. Data from 82 consecutive patients undergoing surgical resection from 2009 to 2020 were included. All patients underwent surgical resection with curative intent, of whom 96.3% were by a VATS approach. Morbidity was low without any conversions or 30-day mortality. Lobectomy was performed in 87.8% of patients, followed by wedge resection in 4.9% and segmentectomy in 3.7%. No pneumonectomies were performed. Radical resection (R0) was achieved in 97.6%. Thirty-four patients (41.5%) had adjuvant platinum-based chemotherapy and high proportion completed at least four series (76.7%). The mean follow-up was 5.1 years. The 1-year, 3-year, and 5-year overall survival rates were 86%, 54%, and 45%, while the corresponding recurrence-free survival rates were 67%, 45%, and 35%. Advanced age was an independent predictor of poor overall survival (HR 2.08; 95% CI 1.04-4.17; p = 0.038). A 96.3% VATS rate was feasible in LCNEC and associated with a low morbidity rate and a high compliance with adjuvant chemotherapy. Overall survival and recurrence-free survival was comparable to previous series using thoracotomy.