Chemoradiotherapy plus hyperthermia (CRTH) versus chemoradiotherapy (CRT) alone in neoadjuvant treatment of soft tissue sarcoma: tumor response, treatment toxicity and disease control.

INTRODUCTION: Neoadjuvant chemotherapy and radiotherapy for the management of soft tissue sarcomas (STS) are still preferably delivered sequentially, with or without concurrent hyperthermia. Concurrent delivery of chemo-, radio- and thermotherapy may produce synergistic effects and reduce chemotherapy-free intervals. The few available studies suggest that concurrent chemoradiation (CRT) has a greater local effect. Data on the efficacy and toxicity of adding hyperthermia to CRT (CRTH) are sparse. MATERIALS AND METHODS: A cohort of 101 patients with STS of the extremities and trunk who received CRT (n = 33) or CRTH (n = 68) before resection of macroscopic tumor (CRT: n = 19, CRTH: n = 49) or re-resection following a non-oncological resection, so called 'whoops procedure', (CRT: n = 14, CRTH: n = 19) were included in this retrospective study. CRT consisted of two cycles of doxorubicine (50 mg/m2 on d2) plus ifosfamide (1500 mg/m2 on d1-5, q28) plus radiation doses of up to 60 Gy. Hyperthermia was delivered in two sessions per week. RESULTS: All patients received the minimum dose of 50 Gy. Median doses of ifosfamide and doxorubicin were comparable between CRT (75%/95%) and CRTH (78%/97%). The median number of hyperthermia sessions was seven. There were no differences in acute toxicities. Major wound complications occurred in 15% (CRT) vs. 25% (CRTH) (p = 0.19). In patients with macroscopic disease, the addition of hyperthermia resulted in a tendency toward improved remission: regression ≥90% occurred in 21/48 (CRTH) vs. 4/18 (CRT) patients (p = 0.197). With a median postoperative follow-up of 72 months, 6-year local control and overall survival rates for CRTH vs. CRT alone were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215). CONCLUSIONS: Both CRT and CRTH are well tolerated with an expected rate of wound complications. The results suggest that adding hyperthermia may improve tumor response.

A multi-institution study: comparison of the heating patterns of five different MR-guided deep hyperthermia systems using an anthropomorphic phantom.

INTRODUCTION: Within the hyperthermia community, consensus exists that clinical outcome of the treatment radiotherapy and/or chemotherapy plus hyperthermia (i.e. elevating tumor temperature to 40 - 44 °C) is related to the applied thermal dose; hence, treatment quality is crucial for the success of prospective multi-institution clinical trials. Currently, applicator quality assurance (QA) measurements are implemented independently at each institution using basic cylindrical phantoms. A multi-institution comparison of heating quality using magnetic resonance thermometry (MRT) and anatomical representative anthropomorphic phantoms provides a unique opportunity to obtain novel QA insights to facilitate multi-institution trial evaluation. OBJECTIVE: Perform a systematic QA procedure to compare the performance of MR-compatible hyperthermia systems in five institutions. METHODS AND MATERIALS: Anthropomorphic phantoms, including pelvic and spinal bones, were produced. Clinically relevant power of 600 watts was applied for ∼12 min to allow for 8 sequential MR-scans. The 3D-heating distribution, steering capabilities, and presence of off-target heating were analyzed. RESULTS: The evaluated devices show comparable heating profiles for centric and eccentric targets. The differences observed in the 3D-heating profiles are the result of variations in the exact phantom positioning and applicator characteristics, whereby positioning of the phantom followed current ESHO-QA guidelines. CONCLUSION: Anthropomorphic phantoms were used to perform QA-measurements of MR-guided hyperthermia systems operating in MR-scanners of different brands. Comparable heating profiles are shown for the five evaluated institutions. Subcentimeter differences in position substantially affected the results when evaluating the heating patterns. Integration of advanced phantoms and precise positioning in QA-guidelines should be evaluated to guarantee the best quality patient care.

Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.

PURPOSE: To compare results after chemoradiotherapy with and without deep regional hyperthermia in patients with anal cancer. METHODS: Between 2000 and 2015, a total of 112 consecutive patients with UICC stage I-IV anal cancer received chemoradiotherapy with 5­fluororuracil and mitomycin C (CRT). In case of insufficient tumor response 4-6 weeks after chemoradiotherapy, patients received an interstitial pulsed-dose-rate brachytherapy boost. Additionally, 50/112 patients received hyperthermia treatments (HCRT). RESULTS: Median follow-up was 41 (2-165) months. After 5 years follow-up, overall (95.8 vs. 74.5%, P = 0.045), disease-free (89.1 vs. 70.4%, P = 0.027), local recurrence-free (97.7 vs. 78.7%, P = 0.006), and colostomy-free survival rates (87.7 vs. 69.0%, P = 0.016) were better for the HCRT group. Disease-specific, regional failure-free, and distant metastasis-free survival rates showed no significant differences. The adjusted hazard ratios for death were 0.25 (95% CI, 0.07 to 0.92; P = 0.036) and for local recurrence 0.14 (95% CI, 0.02 to 1.09; P = 0.06), respectively. Grades 3-4 early toxicities were comparable with the exception of hematotoxicity, which was higher in the HCRT group (66 vs. 43%, P = 0.032). Incidences of late side effects were similar with the exception of a higher telangiectasia rate in the HCRT group (38.0 vs. 16.1%, P = 0.009). CONCLUSION: Additional regional hyperthermia improved overall survival, local control, and colostomy rates. Its potential beneficial role has to be confirmed in a prospective randomized setting. Therefore, the HyCAN trial has already been established by our group and is currently recruiting patients (Clinicaltrials.gov identifier: NCT02369939).

Quality assurance guidelines for superficial hyperthermia clinical trials : II. Technical requirements for heating devices.

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical trials with uniform quality hyperthermia treatments. This document outlines the requirements for appropriate QA of all current superficial heating equipment including electromagnetic (radiative and capacitive), ultrasound, and infrared heating techniques. Detailed instructions are provided how to characterize and document the performance of these hyperthermia applicators in order to apply reproducible hyperthermia treatments of uniform high quality. Earlier documents used specific absorption rate (SAR) to define and characterize applicator performance. In these QA guidelines, temperature rise is the leading parameter for characterization of applicator performance. The intention of this approach is that characterization can be achieved with affordable equipment and easy-to-implement procedures. These characteristics are essential to establish for each individual applicator the specific maximum size and depth of tumors that can be heated adequately. The guidelines in this document are supplemented with a second set of guidelines focusing on the clinical application. Both sets of guidelines were developed by the European Society for Hyperthermic Oncology (ESHO) Technical Committee with participation of senior Society of Thermal Medicine (STM) members and members of the Atzelsberg Circle.

From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.

Quality assurance for clinical studies in regional deep hyperthermia.

BACKGROUND: A guideline is provided for the implementation of regional deep hyperthermia treatments under strict rules of quality assurance. The objective is to guarantee a comparable and comprehensible method in the treatment and scientific analysis of hyperthermia. The guideline describes regional deep hyperthermia (RHT) and MR-controlled partial body hyperthermia (PBH) of children, young and adult patients. According to this guideline, hyperthermia treatment is always applied in combination with chemotherapy and/or radiotherapy. METHODS: The guideline is based on practical experience from several hyperthermia centers. The procedure allows applying jointly coordinated standards and quality control in hyperthermia for studies. RESULTS: The guideline contains recommendations for hyperthermia treatments, including indication, preparation, treatment, and standardized analysis.