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.

Hyperthermia in the treatment of high-risk soft tissue sarcomas: a systematic review.

BACKGROUND: The therapy of high-risk soft tissue sarcomas (STS) remains an interdisciplinary challenge. Regional hyperthermia (RHT) sparked interest as it has been shown to improve overall survival when added to perioperative chemotherapy (CTX). However, questions arise on how RHT should be optimally integrated into current multi-modal therapies. MATERIALS AND METHODS: We performed a systematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies written in English and focused mainly on radiative RHT and superficial hyperthermia were evaluated and included. Studies including patients below the age of 18, with metastatic disease or review articles, were excluded. RESULTS: We identified 15 clinical reports from 1990 until July 2022. Three articles combined RHT + CTX, and twelve focused on combined RHT + radiotherapy (RT) or neoadjuvant chemoradiotherapy (CRT). Most treatments were based on invasive thermometry, and less on magnetic resonance imaging (MRI)-based, noninvasive thermometry for STS of the extremities. Perioperative chemotherapy was used for the combination of RHT and CTX, mostly Ifosfamide-based. The effectiveness of RT appeared to be increased by RHT, especially with two RHT sessions/week. The trimodal simultaneous approach of neoadjuvant RHT and CRT was also feasible. No significant toxicity of RHT was reported. CONCLUSIONS: The gathered data strengthen the beneficial role of RHT in the multimodal setting. Further expert consensus and clinical trials are required to determine the optimal integration of RHT in treating STS.

Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomised clinical trial.

BACKGROUND: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. METHODS: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. RESULTS: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects. CONCLUSIONS: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS. CLINICALTRIALS: gov, number NCT01077427.

A patterns of care analysis of hyperthermia in combination with radio(chemo)therapy or chemotherapy in European clinical centers.

PURPOSE: The combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT. METHODS: A questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods. RESULTS: The response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3-100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter "cumulative equivalent minutes at 43 °C" (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order. CONCLUSION: There is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice.

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.

Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation.

The road of acceptance of oncologic thermotherapy/hyperthermia as a synergistic modality in combination with standard oncologic therapies is still bumpy [...].

Randomized Pilot Trial Using External Yarrow Liver Compress Applications With Metastatic Cancer Patients Suffering From Fatigue: Evaluation of Sympathetic Modulation by Heart Rate Variability Analysis.

BACKGROUND: Liver compresses are commonly applied in complementary medicine during cancer treatment and are believed to have an energizing effect. We conducted a pilot study to investigate the influence of external application of yarrow liver compresses on the autonomous nervous system by analyzing the heart rate variability (HRV) in metastatic cancer patients undergoing radiation therapy and suffering from cancer-related fatigue (CRF). METHODS: A randomized pilot trial was undertaken with patients suffering from CRF receiving palliative radiation therapy for bone or brain metastasis over 2 weeks. CRF patients were randomized into an intervention group receiving yarrow liver compresses and a control group receiving no external application. HRV was analyzed at the beginning (T1) and end (T2) period of the study during daytime (d) and nighttime (n) in both groups and quantified using time-, frequency-, and nonlinear dynamics domains. RESULTS: A total of 39 patients were randomized between September 2017 and August 2019 and a total of 20 patients (10 per group) were available for analysis. For both groups, significant differences in HRV analyses were found in the comparison over the timeline between the first and second measurement (T1d→T2d) during daytime. Specifically, the intervention group showed decreased HRV and complexity of heart rate regulation, indicating increased sympathetic activity at time T2d, whereas the control group showed increased HRV and complexity of heart rate regulation, indicating increased vagal activity at time T2d. Furthermore, the observed HRV analyses showed almost no significant differences between the 2 groups in a direct comparison at the beginning and the end of the study (exception: T2d). CONCLUSIONS: Yarrow liver compresses led to increased sympathetic activity during daytime in the intervention group, whereas in the control group, which did not receive any external application, increased parasympathetic activity was observed.

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.

External application of liver compresses to reduce fatigue in patients with metastatic cancer undergoing radiation therapy, a randomized clinical trial.

BACKGROUND: Liver compresses are frequently used in integrative medicine as supportive therapy during cancer treatment in order to reduce fatigue. We performed a pilot study to test whether the external application of yarrow liver compresses impacts fatigue in patients with metastatic cancer undergoing radiation therapy. METHODS: A randomized prospective pilot trial was performed including patients with brain metastasis or bone metastasis of solid tumors. Patients underwent either palliative radiation therapy (RT) of the metastatic lesions (control group) over two weeks or the same RT with additional external application of yarrow liver compresses once daily during RT. The primary objective was improvement on the general fatigue subscale of the multidimensional fatigue inventory (MFI-20) at the end of treatment, where a mean difference of two points is considered clinically relevant. Secondary objectives included psychological distress, quality of life and qualitative analysis with self-established visual analogue scales (VAS). Mean differences in general fatigue at the end of treatment compared to baseline were analyzed using the ANCOVA test. RESULTS: From 09/2017 to 08/2019 a total of 39 patients were randomized. Due to drop outs 24 patients (12 per group) were available for analysis. Patients in the intervention group received a mean number of 10.5 (range, 7-14) applications of yarrow liver compresses. The mean improvement at the end of therapy on the general fatigue subscale of the MFI-20 was 2 points in favor of the intervention group (p = 0.13), and all other MFI-20 subscales showed at least a trend towards improvement in favor of the intervention group. Likewise, psychological distress and VAS data was improved, the latter reaching statistical significance for the symptoms fatigue, tension and lack of drive. Major toxicities were not observed. CONCLUSIONS: External application of liver compresses appears to reduce fatigue within a clinical relevant range in patients with metastatic cancer undergoing radiation therapy. TRIAL REGISTRATION: ISRCTN, ICTRP DRKS00012999.

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.

Fever range whole body hyperthermia for re-irradiation of head and neck squamous cell carcinomas: Final results of a prospective study.

OBJECTIVES: Fever-range whole body hyperthermia (FRWBH) has been shown to improve tumor oxygenation in vivo. A prospective pilot study addressed the question if addition of FRWBH to re-irradiation is feasible in recurrent head and neck squamous cell carcinomas (HNSCC) with unfavorable prognostic features. MATERIALS AND METHODS: The study completed accrual with the recruitment of ten patients between April 2018 and March 2020. Re-irradiation was administered using volumetric arc hyperfractionated radiotherapy with bi-daily 1.2 Gray (Gy) single fractions and a total dose of 66 Gy to all macroscopic tumor lesions. Concomitant chemotherapy consisted mostly of cisplatin (7 patients). FRWBH was scheduled weekly during re-irradiation. The study was registered in the clinicaltrials.gov database (NCT03547388). RESULTS: Only five patients received all cycles of FRWBH. Poor patient compliance, active infections during treatment and study restrictions due to the Covid-19 pandemic were the main reasons for omitting FRWBH. No increase of acute toxicity was observed by FRWBH. Exploratory evaluation of outcome data suggests that FRWBH treatment according to protocol does not seem to have a detrimental effect on tumor control or survival and might even increase treatment efficacy. CONCLUSION: FRWBH is difficult to apply concomitant to re-irradiation in HNSCC. No excess toxicity was observed in patients receiving FRWBH and exploratory analyses suggest potential anti-tumor activity and decreased patient-reported depression scores after FRWBH.

The Relevance of Complementary and Integrative Medicine in the COVID-19 Pandemic: A Qualitative Review of the Literature.

Background: During the COVID-19 pandemic people are facing risks of adverse health effects due to the restrictions implemented such as quarantine measures, reduced social contact, and self-isolation. In this qualitative review, we collected data on potential preventive and therapeutic health benefits of Complementary and Integrative Medicine (CIM) that might be useful during the COVID-19 pandemic. We have reviewed the scientific literature to summarize CIM practices that could be beneficial for improving physical and mental health and well-being of the population under the current pandemic circumstances. It must be noted that this review is not SARS-CoV-2 specific and we explicitly do not intend to make any SARS-CoV-2 specific health claims in this article. Methods and Findings: A qualitative, non-systematic literature review was conducted in Medline to identify literature describing preventive and therapeutic CIM approaches for strengthening mental and physical health. For a variety of CIM approaches clinical evidence was identified, indicating beneficial effects. CIM approaches include specific dietary measures and selected micronutrients, physical activity, techniques from Mind-Body Medicine, single botanicals or botanical compounds, and spending time in nature among others. The effects of CIM measures on conditions like obesity and hypertension are of special relevance here, as these conditions are considered as risk factors for a severe course of COVID-19. Moreover, a possibly direct effect of CIM approaches on immune functions and clinical parameters in respiratory tract infections, such as influenza, were identified. The findings of this review could be helpful for clinicians, patients, and the general population during the current pandemic when discussing and/or considering CIM options. Conclusions: CIM offers a variety of preventive and therapeutic options for strengthening physical and mental resilience, which could also be useful in the current COVID-19 pandemic. The evidence of CIM approaches with a potential benefit in the COVID-19 pandemic in different areas is worth to be analyzed. While this qualitative review has several obvious limitations, it might serve as useful starting point for further research on this topic.

Locoregional peritoneal hyperthermia to enhance the effectiveness of chemotherapy in patients with peritoneal carcinomatosis: a simulation study comparing different locoregional heating systems.

Introduction: Intravenous chemotherapy plus abdominal locoregional hyperthermia is explored as a noninvasive alternative to hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment of peritoneal carcinomatosis (PC). First clinical results demonstrate feasibility, but survival data show mixed results and for pancreatic and gastric origin results are not better than expected for chemotherapy alone. In this study, computer simulations are performed to compare the effectiveness of peritoneal heating for five different locoregional heating systems.Methods: Simulations of peritoneal heating were performed for a phantom and two pancreatic cancer patients, using the Thermotron RF8, the AMC-4/ALBA-4D system, the BSD Sigma-60 and Sigma-Eye system, and the AMC-8 system. Specific absorption rate (SAR) distributions were optimized and evaluated. Next, to provide an indication of possible enhancement factors, the corresponding temperature distributions and thermal enhancement ratio (TER) of oxaliplatin were estimated.Results: Both phantom and patient simulations showed a relatively poor SAR coverage for the Thermotron RF8, a fairly good coverage for the AMC-4/ALBA-4D, Sigma-60, and Sigma-Eye systems, and the best and most homogeneous coverage for the AMC-8 system. In at least 50% of the peritoneum, 35-45 W/kg was predicted. Thermal simulations confirmed these favorable peritoneal heating properties of the AMC-8 system and TER values of ∼1.4-1.5 were predicted in at least 50% of the peritoneum.Conclusion: Locoregional peritoneal heating with the AMC-8 system yields more favorable heating patterns compared to other clinically used locoregional heating devices. Therefore, results of this study may promote the use of the AMC-8 system for locoregional hyperthermia in future multidisciplinary studies for treatment of PC.

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.

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.

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.

Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial.

IMPORTANCE: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. OBJECTIVE: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival. DESIGN, SETTING, AND PARTICIPANTS: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014. INTERVENTIONS: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia. MAIN OUTCOMES AND MEASURES: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up. RESULTS: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%). CONCLUSIONS AND RELEVANCE: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003052.

Regional hyperthermia combined with chemotherapy in paediatric, adolescent and young adult patients: current and future perspectives.

Here we evaluate the current status of clinical research on regional hyperthermia (RHT) in combination with chemotherapy or radiation therapy in paediatric oncology.Data were identified in searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using medical subject headings including hyperthermia, cancer, paediatric oncology, children, radiation therapy and chemotherapy. Currently, only two RHT centres exist in Europe which treat children. Clinical RHT research in paediatric oncology has as yet been limited to children with sarcomas and germ cell tumours that respond poorly to or recur after chemotherapy. RHT is a safe and effective treatment delivering local thermic effects, which may also stimulate immunological processes via heat-shock protein reactions. RHT is used chiefly in children and adolescents with sarcomas or germ cell tumours located in the abdomino-pelvic region, chest wall or extremities to improve operability or render the tumour operable. It could potentially be combined with radiation therapy in a post-operative R1 setting where more radical surgery is not possible or combined with chemotherapy instead of radiation therapy in cases where the necessary radiation dose is impossible to achieve or would have mutilating consequences. RHT might also be an option for chemotherapy intensification in the neoadjuvant first-line treatment setting for children and adolescents, as was recently reflected in the promising long-term outcome data in adults with high-risk soft tissue sarcomas (EORTC 62961/ESHO trial).The limited data available indicate that combining RHT with chemotherapy is a promising option to treat germ cell tumours and, potentially, sarcomas. RHT may also be beneficial in first-line therapy in children, adolescents and young adults. The research should focus on optimising necessary technical demands and then initiate several clinical trials incorporating RHT into interdisciplinary treatment of children, adolescents and young adults that include translational research components exploring potential immunological mechanisms of action.