Regional hyperthermia for soft tissue sarcoma - a survey on current practice, controversies and consensus among 12 European centers.

PURPOSE: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. METHODS: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. RESULTS: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40-43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. DISCUSSION: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. CONCLUSIONS: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

A convolutional neural network with self-attention for fully automated metabolic tumor volume delineation of head and neck cancer in [Formula: see text]F]FDG PET/CT.

PURPOSE: PET-derived metabolic tumor volume (MTV) and total lesion glycolysis of the primary tumor are known to be prognostic of clinical outcome in head and neck cancer (HNC). Including evaluation of lymph node metastases can further increase the prognostic value of PET but accurate manual delineation and classification of all lesions is time-consuming and prone to interobserver variability. Our goal, therefore, was development and evaluation of an automated tool for MTV delineation/classification of primary tumor and lymph node metastases in PET/CT investigations of HNC patients. METHODS: Automated lesion delineation was performed with a residual 3D U-Net convolutional neural network (CNN) incorporating a multi-head self-attention block. 698 [Formula: see text]F]FDG PET/CT scans from 3 different sites and 5 public databases were used for network training and testing. An external dataset of 181 [Formula: see text]F]FDG PET/CT scans from 2 additional sites was employed to assess the generalizability of the network. In these data, primary tumor and lymph node (LN) metastases were interactively delineated and labeled by two experienced physicians. Performance of the trained network models was assessed by 5-fold cross-validation in the main dataset and by pooling results from the 5 developed models in the external dataset. The Dice similarity coefficient (DSC) for individual delineation tasks and the primary tumor/metastasis classification accuracy were used as evaluation metrics. Additionally, a survival analysis using univariate Cox regression was performed comparing achieved group separation for manual and automated delineation, respectively. RESULTS: In the cross-validation experiment, delineation of all malignant lesions with the trained U-Net models achieves DSC of 0.885, 0.805, and 0.870 for primary tumor, LN metastases, and the union of both, respectively. In external testing, the DSC reaches 0.850, 0.724, and 0.823 for primary tumor, LN metastases, and the union of both, respectively. The voxel classification accuracy was 98.0% and 97.9% in cross-validation and external data, respectively. Univariate Cox analysis in the cross-validation and the external testing reveals that manually and automatically derived total MTVs are both highly prognostic with respect to overall survival, yielding essentially identical hazard ratios (HR) ([Formula: see text]; [Formula: see text] vs. [Formula: see text]; [Formula: see text] in cross-validation and [Formula: see text]; [Formula: see text] vs. [Formula: see text]; [Formula: see text] in external testing). CONCLUSION: To the best of our knowledge, this work presents the first CNN model for successful MTV delineation and lesion classification in HNC. In the vast majority of patients, the network performs satisfactory delineation and classification of primary tumor and lymph node metastases and only rarely requires more than minimal manual correction. It is thus able to massively facilitate study data evaluation in large patient groups and also does have clear potential for supervised clinical application.

Experimental and computational evaluation of capacitive hyperthermia.

OBJECTIVE: Hyperthermia as an enhancer of radio- and/or chemotherapy has been confirmed by various trials. Quite a few positive randomized trials have been carried out with capacitive hyperthermia systems (CHS), even though specific absorption rates (SAR) in deep regions are known to be inferior to the established annular-phased array techniques. Due to a lack of systematic SAR measurements for current capacitive technology, we performed phantom measurements in combination with simulation studies. MATERIALS AND METHODS: According to the current guidelines, homogeneous and inhomogeneous agarose phantoms were manufactured for the commercial CHS Celsius42. Temperature/time curves were registered, and specific absorption rate (SAR) profiles and distributions were derived using the temperature gradient method. We implemented models for electrodes and phantom setups for simulation studies using Sim4Life. RESULTS: For a standard total power of 200 W, we measured effective SAR until depths of 6-8 cm in a homogeneous phantom, which indicates fair heating conditions for tumor diseases in superficial and intermediate depths. A fat layer of 1 cm strongly weakens the SAR, but 10-20 W/kg are still achieved in intermediate to deep regions (2-10 cm). In the phantom setup with integrated bone, we measured low SAR of 5-10 W/kg in the cancellous bone. Our simulations could fairly describe the measured SAR distributions, but predict tendentially higher SAR than measured. Additional simulations suggest that we would achieve higher SAR with vital fatty tissue and bone metastases in clinical situations. CONCLUSION: Capacitive systems are suitable to heat superficial and medium-deep tumors as well as some bone metastases, and CHS application is feasible for a specific class of patients with pelvic and abdominal tumors. These findings are consistent with positive clinical studies.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study.

BACKGROUND: Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). METHODS: Patients with stages T2-4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57-58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41-43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. RESULTS: Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3-4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. CONCLUSION: Tetramodal therapy of T2-T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

Value of PET imaging for radiation therapy.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.

A convolutional neural network for fully automated blood SUV determination to facilitate SUR computation in oncological FDG-PET.

PURPOSE: The standardized uptake value (SUV) is widely used for quantitative evaluation in oncological FDG-PET but has well-known shortcomings as a measure of the tumor's glucose consumption. The standard uptake ratio (SUR) of tumor SUV and arterial blood SUV (BSUV) possesses an increased prognostic value but requires image-based BSUV determination, typically in the aortic lumen. However, accurate manual ROI delineation requires care and imposes an additional workload, which makes the SUR approach less attractive for clinical routine. The goal of the present work was the development of a fully automated method for BSUV determination in whole-body PET/CT. METHODS: Automatic delineation of the aortic lumen was performed with a convolutional neural network (CNN), using the U-Net architecture. A total of 946 FDG PET/CT scans from several sites were used for network training (N = 366) and testing (N = 580). For all scans, the aortic lumen was manually delineated, avoiding areas affected by motion-induced attenuation artifacts or potential spillover from adjacent FDG-avid regions. Performance of the network was assessed using the fractional deviations of automatically and manually derived BSUVs in the test data. RESULTS: The trained U-Net yields BSUVs in close agreement with those obtained from manual delineation. Comparison of manually and automatically derived BSUVs shows excellent concordance: the mean relative BSUV difference was (mean ± SD) = (- 0.5 ± 2.2)% with a 95% confidence interval of [- 5.1,3.8]% and a total range of [- 10.0, 12.0]%. For four test cases, the derived ROIs were unusable (< 1 ml). CONCLUSION: CNNs are capable of performing robust automatic image-based BSUV determination. Integrating automatic BSUV derivation into PET data processing workflows will significantly facilitate SUR computation without increasing the workload in the clinical setting.

Improved patient-specific hyperthermia planning based on parametrized electromagnetic and thermal models for the SIGMA-30 applicator.

OBJECTIVE: To create an improved planning method for pediatric regional hyperthermia (RHT) using the SIGMA-30 applicator (SIGMA-30). MATERIALS AND METHODS: An electromagnetic model of SIGMA-30 was generated for use with the finite-difference time-domain (FDTD) method. Applying special MATLAB-based algorithms, voxel models of a pediatric patient with pelvic rhabdomyosarcoma were created from Computed-Tomography (CT) contours for use with the FDTD method and the finite-difference (FD) method capable of using either temperature-independent or temperature-dependent perfusion models for solving the Bioheat Transfer Equation (BHTE). Patient models were parametrized regarding, first, the positioning in the applicator, second, the absorbed power range and, third, different perfusion models, resulting in the so-called Parametrized Treatment Models (PTMs). A novel dedicated optimization procedure was developed based on quantitative comparison of numerical calculations against temperature and power measurements from two RHT therapies. RESULTS: Using measured data, a realistic absorbed power range in the patient model was estimated. Within this range, several FDTD and BHTE runs were performed and, applying the aforementioned optimization scheme, the best PTMs and perfusion models were identified for each therapy via a retrospective comparison with measurements in 14 temperature sensor positions: 5 in the tumor, 8 in rectum and one in bladder. CONCLUSION: A novel dedicated optimization procedure for identification of suitable patient-specific electromagnetic and thermal models, which can be used for improved patient planning, was developed and evaluated by comparison with treatment-derived measurements using SIGMA-30. The optimization procedure can be extended to other hyperthermia applicators and to other patient types, including adults.

Quantitative volumetric assessment of baseline enhancing tumor volume as an imaging biomarker predicts overall survival in patients with glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the commonest malignant primary brain tumor and still has one of the worst prognoses among cancers in general. There is a need for non-invasive methods to predict individual prognosis in patients with GBM. PURPOSE: To evaluate quantitative volumetric tissue assessment of enhancing tumor volume on cranial magnetic resonance imaging (MRI) as an imaging biomarker for predicting overall survival (OS) in patients with GBM. MATERIAL AND METHODS: MRI scans of 49 patients with histopathologically confirmed GBM were analyzed retrospectively. Baseline contrast-enhanced (CE) MRI sequences were transferred to a segmentation-based three-dimensional quantification tool, and the enhancing tumor component was analyzed. Based on a cut-off percentage of the enhancing tumor volume (PoETV) of >84.78%, samples were dichotomized, and the OS and intracranial progression-free survival (PFS) were evaluated. Univariable and multivariable analyses, including variables such as sex, Karnofsky Performance Status score, O6-methylguanine-DNA-methyltransferase status, age, and resection status, were performed using the Cox regression model. RESULTS: The median OS and PFS were 16.9 and 7 months in the entire cohort, respectively. Patients with a CE tumor volume of >84.78% showed a significantly shortened OS (12.9 months) compared to those with a CE tumor volume of ≤84.78% (17.7 months) (hazard ratio [HR] 2.72; 95% confidence interval [CI] 1.22-6.03; P = 0.01). Multivariable analysis confirmed that PoETV had a significant prognostic role (HR 2.47; 95% CI 1.08-5.65; P = 0.03). CONCLUSION: We observed a correlation between PoETV and OS. This imaging biomarker may help predict the OS of patients with GBM.

Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer.

We have investigated the prognostic value of two novel interim 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters in patients undergoing chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): one tumor parameter (maximal standardized uptake ratio rSUR) and one normal tissue parameter (change of FDG uptake within irradiated nontumor-affected esophagus ∆SUVNTO ). PET data of 134 European and Chinese patients were analyzed. Parameter establishment was based on 36 patients undergoing preoperative CRT plus surgery, validation was performed in 98 patients receiving definitive CRT. Patients received PET imaging prior and during fourth week of CRT. Clinical parameters, baseline PET parameters, and interim PET parameters (rSUR and ∆SUVNTO ) were analyzed and compared to event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Combining rSUR and ∆SUVNTO revealed a strong prognostic impact on EFS, OS, LRC and FFDM in patients undergoing preoperative CRT. In the definitive CRT cohort, univariate analysis with respect to EFS revealed several staging plus both previously established interim PET parameters as significant prognostic factors. Multivariate analyses revealed only rSUR and ∆SUVNTO as independent prognostic factors (p = 0.003, p = 0.008). Combination of these parameters with the cutoff established in preoperative CRT revealed excellent discrimination of patients with a long or short EFS (73% vs. 17% at 2 years, respectively) and significantly discriminated all other endpoints (OS, p < 0.001; LRC, p < 0.001; FFDM, p = 0.02), even in subgroups. Combined use of interim FDG-PET derived parameters ∆SUVNTO and rSUR seems to have predictive potential, allowing to select responders for definitive CRT and omission of surgery.

Image-guided dose-escalated radiation therapy for localized prostate cancer with helical tomotherapy.

PURPOSE: To evaluate treatment outcomes for patients with localized prostate cancer who were treated with dose-escalated primary image-guided radiation therapy (IGRT). METHODS: We retrospectively analyzed 88 consecutive patients treated using helical tomotherapy with daily megavoltage CTs (MVCT). Patients were prescribed daily doses of 1.8 Gy to the planning target volume (PTV) and 2 Gy to the clinical target volume (CTV). Low- and favorable intermediate-risk patients received a minimum total dose of 72 Gy to the PTV and up to 80 Gy to the CTV. Unfavorable intermediate-risk and high-risk patients received a minimum total dose of 75.6 Gy to the PTV and up to 84 Gy to the CTV. We assessed freedom from biochemical relapse (FFBF), 5­year biochemical recurrence-free survival (5-bRFS), distant metastasis-free survival (5-dMFS), and cancer-specific survival (5-CSS) as well as acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. RESULTS: Among our cohort, 11.4% were low-risk, 50% intermediate-risk, and 38.6% high-risk patients according to the D'Amico criteria. Median follow-up was 66 months (range 8-83 months). FFBF was 100%, 97.7%, and 90.7%; 5­bRFS was 100%, 92.8%, and 70.4%; 5­dMFS was 100%, 92.7%, and 70.4%; and 5­CSS was 100%, 97.4%, and 89.8% for low-, intermediate-, and high-risk patients, respectively. Grades 2 and 3 toxicity occurred at the following rates: acute GU toxicity 39.8% and 1.1%, acute GI toxicity 12.5% and 0%, late GU toxicity 19.3% and 4.5%, and late GI toxicity 4.5% and 1.1% of patients, respectively. No toxicity >grade 3 was observed. CONCLUSION: Risk-adapted dose-escalated IGRT with helical tomotherapy of up to 84 Gy is a feasible and well-tolerable treatment scheme with promising oncological results.

Role of combined radiation and androgen deprivation therapy in intermediate-risk prostate cancer : Statement from the DEGRO working group on prostate cancer.

OBJECTIVE: This article aims to provide an overview of the role of combined radiation and androgen deprivation (ADT) therapy in patients with intermediate-risk prostate cancer. MATERIALS AND METHODS: The current German, European, and NCCN (National Comprehensive Cancer Network) guidelines as well as relevant literature in the PubMed database which provide information on sub-classification within the intermediate-risk group and the use of ADT in terms of oncological outcome were reviewed. RESULTS: Different recommendations for risk-group assessment of patients with localized prostate cancer are available. Subdivision of intermediate risk into a favorable and an unfavorable group seems to be justified to allow for a more individualized therapy in a quite heterogenous group of patients. So far, multiple randomized trials have shown a benefit when radiation therapy (RT) is combined with ADT. The use of dose-escalated RT without ADT also appears to be an adequate therapy associated with a very low rate of cancer-specific deaths. Therefore, taking into account the increased rate of toxicity associated with ADT, dose-escalated RT alone might be justified, especially in favorable intermediate-risk patients. CONCLUSION: Dose-escalated RT alone appears to be an appropriate treatment in favorable intermediate-risk patients. Addition of short course ADT (4-6 months) might improve outcomes in unfavorable intermediate-risk patients.

Radiofrequency applicator concepts for thermal magnetic resonance of brain tumors at 297 MHz (7.0 Tesla).

Purpose: Thermal intervention is a potent sensitizer of cells to chemo- and radiotherapy in cancer treatment. Glioblastoma multiforme (GBM) is a potential clinical target, given the cancer's aggressive nature and resistance to current treatment options. The annular phased array (APA) technique employing electromagnetic waves in the radiofrequency (RF) range allows for localized temperature increase in deep seated target volumes (TVs). Reports on clinical applications of the APA technique in the brain are still missing. Ultrahigh field magnetic resonance (MR) employs higher frequencies than conventional MR and has potential to provide focal temperature manipulation, high resolution imaging and noninvasive temperature monitoring using an integrated RF applicator (ThermalMR). This work examines the applicability of RF applicator concepts for ThermalMR of brain tumors at 297 MHz (7.0 Tesla).Methods: Electromagnetic field (EMF) simulations are performed for clinically realistic data based on GBM patients. Two algorithms are used for specific RF energy absorption rate based thermal intervention planning for small and large TVs in the brain, aiming at maximum RF power deposition or RF power uniformity in the TV for 10 RF applicator designs.Results: For both TVs , the power optimization outperformed the uniformity optimization. The best results for the small TV are obtained for the 16 element interleaved RF applicator using an elliptical antenna arrangement with water bolus. The two row elliptical RF applicator yielded the best result for the large TV.Discussion: This work investigates the capacity of ThermalMR to achieve targeted thermal interventions in model systems resembling human brain tissue and brain tumors.

Confirmation of the prognostic value of pretherapeutic tumor SUR and MTV in patients with esophageal squamous cell carcinoma.

PURPOSE: The prognosis for patients with inoperable esophageal carcinoma is still poor and the reliability of individual therapy outcome prediction based on clinical parameters is not convincing. In a recent publication, we were able to show that PET can provide independent prognostic information in such a patient group and that the tumor-to-blood standard uptake ratio (SUR) can improve the prognostic value of tracer uptake values. The present investigation addresses the question of whether the distinctly improved prognostic value of SUR can be confirmed in a similar patient group that was examined and treated at a different site. METHODS: 18F-FDG PET/CT was performed in 147 consecutive patients (115 male, 32 female, mean age: 62 years) with newly diagnosed esophageal squamous cell carcinoma prior to definitive radiochemotherapy. In the PET images, the metabolic active volume (MTV) of the primary tumor was delineated with an adaptive threshold method. For the resulting ROIs, SUVmax and total lesion glycolysis (TLG = MTV × SUVmean) were computed. The blood SUV was determined by manually delineating the aorta in the low-dose CT. SUR values were computed as ratio of tumor SUV and blood SUV. Univariate Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), distant-metastases-free survival (DM), and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. RESULTS: Univariate Cox regression revealed MTV, TLG, and SURmax as significant prognostic factors for OS. MTV as well as TLG were significant prognostic factors for LRC while SURmax showed only a trend for significance. None of the PET parameters was prognostic for DM. In univariate analysis, SUVmax was not prognostic for any of the investigated clinical endpoints. In multivariate analysis (T-stage, N-stage, MTV, and SURmax), MTV was an independent prognostic factor for OS and showed a trend for significance for LRC. SURmax was not an independent predictor for OS or LRC. When including the PET parameters separately in multivariate analysis, MTV as well as SURmax were prognostic factors for OS indicating that SURmax is independent from the clinical parameters but not from MTV. In addition, MTV was an independent prognostic factor for LRC in this separate analysis. CONCLUSIONS: Our study revealed a clearly improved prognostic value of tumor SUR compared to tumor SUV and confirms our previously published findings regarding OS. Furthermore, SUR delivers prognostic information beyond that provided by the clinical parameters alone, but does not add prognostic information beyond that provided by MTV in this patient group. Therefore, our results suggest that pretherapeutic MTV is the parameter of choice for PET-based risk stratification in the considered setting but further investigations are necessary to demonstrate that this suggestion is correct.

Physical analysis of temperature-dependent effects of amplitude-modulated electromagnetic hyperthermia.

Purpose: Preclinical studies and clinical observations suggest that amplitude modulation (AM) below 100 kHz may enhance the intratumoral power absorption of radiofrequency hyperthermia at 13.56 MHz; however, it remains unclear whether AM induces temperature-dependent effects.Methods: We established tumor models assuming typical tumor architectures or cell suspensions to analyze the effects of additional power dissipation. The preconditions for demodulation at cell membranes in situ were outlined. The bioheat transfer equation was solved analytically for the selected models and the possibility of circumscribed temperature increases (point heating) with dependency on the specific absorption rate (SAR) peaks was estimated for centimeter down to nanometer scales.Results: Very-low-frequency (VLF) AM radiofrequency can increase the SAR in the extracellular space or necrosis of tumors as compared to radiofrequencies alone. Such modulation-derived SAR peaks can induce higher temperatures (hot spots) in tumors with necrotic areas of millimeter to centimeter size. However, for lesions <1 cm, excessive (unrealistic) SAR > 1000, 10,000 and 1014 W/kg for diameters of ∼5 mm, ∼1 mm and ∼10 nm (nanoheating), respectively, would be required to explain the cell kill observed in pre-clinical and clinical data, even with VLF modulation.Conclusion: Our analysis suggests that VLF AM of radiofrequency hyperthermia for a theoretical tumor model cannot induce relevant temperature-dependent effects, as the associated temperature increases caused by the resultant SAR peaks are too small. Further investigation of possible non-temperature-dependent effects is recommended.

Ga-68-PSMA PET/CT in treatment-naïve patients with prostate cancer: Which clinical parameters and risk stratification systems best predict PSMA-positive metastases?

PURPOSE: To evaluate the accuracy of clinical parameters and established pre-treatment risk stratification systems for prostate cancer (PCa) in predicting PSMA-positive metastases in men undergoing Ga-68-PSMA PET/CT as initial staging examination. MATERIALS AND METHODS: A retrospective analysis in 108 consecutive treatment-naïve patients with biopsy-proven PCa undergoing Ga-68-PSMA PET/CT (median age, 72 years [range, 49-82 years]) was performed. Prediction of PSMA-positive metastases by serum PSA, clinical T stage (cT), ISUP group, percentage of positive biopsy cores, and derived risk scores (D'Amico risk classification system, Roach [RF], Yale formula [YF], and Briganti nomogram [BN]) was examined with ROC analysis. RESULTS: Any PSMA-positive metastases were found in 36 of 108 patients, including LN metastases in 28 patients, extrapelvic LN metastases in 15 patients, and organ metastases in 19 patients (bone, 19; lung, 1). AUCs for PSA, cT, ISUP, and percentage of positive biopsy cores regarding PSMA-positive metastases did not differ significantly (range, 0.6-0.8; each P > 0.05). D'Amico (AUC, 0.61-0.64) was inferior to RF (0.76-0.83), YF (0.81-0.86), and BN (0.73 to 0.88; each P < 0.05). Among the 89 high-risk patients (D'Amico), decision for or against PET imaging based on RF (cut-off, >18.0), YF (>10.8), or BN (>8.0) would have prevented PSMA PET/CT in 4 (5%), 15 (17%), or 18 patients (20%), respectively, while preserving a sensitivity ≥95% for PSMA-positive metastases. CONCLUSIONS: Clinical parameters and established risk stratification systems for PCa can predict Ga-68-PSMA PET-positive metastases in treatment-naïve patients. Especially YF and BN may improve identification of patients with the highest probability of metastatic disease detected by Ga-68-PSMA PET/CT.

Increased evidence for the prognostic value of FDG uptake on late-treatment PET in non-tumour-affected oesophagus in irradiated patients with oesophageal carcinoma.

PURPOSE: 18F-FDG uptake in irradiated non-tumour-affected oesophagus (NTO) on restaging PET is a potential surrogate for the measurement of radiation-induced inflammation. Radiation-induced inflammation itself has been shown to be of high prognostic relevance in patients undergoing preoperative radiochemotherapy (RCT) for locally advanced oesophageal cancer. We assessed the prognostic relevance of FDG uptake in the NTO in an independent cohort of patients treated with definitive RCT. METHODS: This retrospective evaluation included 72 patients with oesophageal squamous cell carcinoma treated with definitive RCT with curative intent. All patients underwent pretreatment and restaging FDG PET after receiving a radiation dose of 40-50 Gy. Standardized uptake values (SUVmax/SUVmean), metabolic tumour volume (MTV) and relative changes from pretreatment to restaging PET (∆SUVmax/∆SUVmean) were determined within the tumour and NTO. Univariate Cox regression with respect to overall survival (OS), local control (LC), distant metastases (DM) and treatment failure (TF) was performed. Independence of parameters was tested by multivariate Cox regression. RESULTS: ∆SUVmax NTO and MTV were prognostic factors for all investigated clinical endpoints (OS, LC, DM, TF). Inclusion of clinical and PET tumour parameters in multivariate analysis showed that ∆SUVmax NTO was an independent prognostic factor. Furthermore, multivariate analysis of ∆SUVmax NTO using previously published cut-off values from preoperatively treated patients revealed that ∆SUVmax NTO was independent prognostic factor for OS (HR = 1.88, p = 0.038), TF (HR = 2.11, p = 0.048) and DM (HR = 3.02, p = 0.047). CONCLUSION: NTO-related tracer uptake during the course of treatment in patients with oesophageal carcinoma was shown to be of high prognostic relevance. Thus, metabolically activity of NTO measured in terms of ∆SUVmax NTO is a potential candidate for future treatment individualization (i.e. organ preservation).

Neoadjuvant chemotherapy plus radiation versus chemotherapy plus regional hyperthermia in high-grade soft tissue sarcomas: a retrospective comparison.

PURPOSE: Localized adult high-grade soft tissue sarcomas (STS) usually require multimodality treatment including surgery, radiotherapy, chemotherapy and hyperthermia. If maximal preoperative tumor-shrinkage is envisaged, neoadjuvant chemotherapy + radiation (CRT) is often applied, however at the expense of relatively high toxicities and increased postoperative complication rates. This study aims to compare preoperative CRT with neoadjuvant chemotherapy + regional hyperthermia (HCT) regarding histopathological response, toxicity and outcome. METHODS: In this retrospective analysis, 61 consecutive high-grade STS patients treated between 2009 and 2016 were included. All patients were treated within a prospective treatment protocol. 28 patients received neoadjuvant CRT 33 patients HCT. CRT consisted of four cycles doxorubicin/ifosfamide and two cycles ifosfamide concomitant to 50.4 Gray external beam radiotherapy. HCT consisted of 4-6 cycles doxorubicin/ifosfamide with deep regional hyperthermia administered bi-weekly during each cycle. Association of treatment modality with overall survival (OS), local control (LC) and freedom from distant metastases (FFDM) was evaluated by Kaplan-Meier and log-rank analyses. RESULTS: The overall patient characteristics were well balanced. Histopathological tumor response did not differ significantly between both groups (p = .67), neither did higher-grade toxicities during neoadjuvant treatment. Wound dehiscence (p = .018) and surgical hospital re-admissions (p < .001) were both significantly more frequent in the CRT group. Two-year OS, LC and FFDM rates of all patients were 93, 85 and 71% with no significant differences between CRT and HCT. CONCLUSION: Compared to CRT, HCT seems equally efficient and appears to bear less surgical complications. Interpretation should be cautious due to the low number of patients and the retrospective nature of this study.

Spinal cord constraints in the era of high-precision radiotherapy : Retrospective analysis of 62 spinal/paraspinal lesions with possible infringements of spinal cord constraints within a minimal volume.

OBJECTIVE: Current constraints aim to minimize the risk of radiation myelitis by the use of restrictive maximal spinal cord doses, commonly 50 Gy. However, several studies suggested that a dose-volume effect could exist. Based on these observations, we evaluated patients receiving potentially excessive doses to the spinal cord within minimal volumes. PATIENTS AND METHODS: Patients receiving radiotherapy between June 2010 and May 2015 using the NovalisTM (Varian, Palo Alto, CA, USA; Brainlab, Heimstetten, Germany) radiosurgery system were retrospectively analyzed. A total of 56 patients with 62 treated lesions that had been prescribed radiation doses close to the spinal cord potentially higher than the common 50 Gy 2­Gy equivalent-dose (EQD2) constraint were selected for further analysis. Of these patients, 26 with 31 lesions had no history of previous irradiation, while 30 patients with 31 lesions had been previously irradiated within the treatment field. RESULTS: According to different dose evaluation approaches (spinal canal, spinal cord contour), 16 and 10 out of 31 primary irradiated lesions infringed constraints. For the 16 lesions violating spinal canal doses, the maximum doses ranged from 50.5 to 61.9 Gy EQD2. Reirradiated lesions had an average and median cumulative dose of 70.5 and 69 Gy, respectively. Dose drop-off was steep in both groups. Median overall survival was 17 months. No radiation myelitis or radiomorphological alterations were observed during follow-up. CONCLUSION: This study adds to the increasing body of evidence indicating that excessive spinal cord doses within a minimal volume, especially in a reirradiation setting with topographically distinct high-point doses, may be given to patients after careful evaluation of treatment- and tumor-associated risks.

Increased FDG uptake on late-treatment PET in non-tumour-affected oesophagus is prognostic for pathological complete response and disease recurrence in patients undergoing neoadjuvant radiochemotherapy.

PURPOSE: Early side effects including oesophagitis are potential prognostic factors in patients undergoing radiochemotherapy (RCT) for locally advanced oesophageal cancer (LAEC). We assessed the prognostic value of 18F-fluorodeoxyglucose (FDG) uptake within irradiated non-tumour-affected oesophagus (NTO) during restaging positron emission tomography (PET) as a surrogate for inflammation/oesophagitis. METHODS: This retrospective evaluation included 64 patients with LAEC who had completed neoadjuvant RCT and had successful oncological resection. All patients underwent FDG PET/CT before and after RCT. In the restaging PET scan maximum and mean standardized uptake values (SUVmax, SUVmean) were determined in the tumour and NTO. Univariate Cox regression with respect to overall survival, local control, distant metastases and treatment failure was performed. Independence of clinically relevant parameters was tested in a multivariate Cox regression analysis. RESULTS: Increased FDG uptake, measured in terms of SUVmean in NTO during restaging was significantly associated with complete pathological remission (p = 0.002) and did not show a high correlation with FDG response of the tumour (rho < 0.3). In the univariate analysis, increased SUVmax and SUVmean in NTO was associated with improved overall survival (p = 0.011, p = 0.004), better local control (p = 0.051, p = 0.044), a lower rate of treatment failure (p < 0.001 for both) and development of distant metastases (p = 0.012, p = 0.001). In the multivariate analysis, SUVmax and SUVmean in NTO remained a significant prognostic factor for treatment failure (p < 0.001, p = 0.004) and distant metastases (p = 0.040, p = 0.011). CONCLUSIONS: FDG uptake in irradiated normal tissues measured on restaging PET has significant prognostic value in patients undergoing neoadjuvant RCT for LAEC. This effect may potentially be of use in treatment personalization.