Effect of hyperthermia and proton beam radiation as a novel approach in chordoma cells death and its clinical implication to treat chordoma.

PURPOSE: Chordoma is a locally aggressive tumor that most commonly affects the base of the skull/clivus, cervical, and sacral spine. Conventional radiotherapy (RT), cannot be safely increased further to improve disease control due to the risk of toxicity to the surrounding critical structures. Tumor-targeted hyperthermia (HT) combined with Proton Beam Radiation Therapy (PBRT) is known to act as a potent radiosensitizer in cancer control. In this study, we investigated whether PBRT efficacy for chordoma can be enhanced in combination with HT as a radiosensitizer. MATERIAL AND METHODS: Human chordoma cell lines, U-CH2 and Mug-chor1 were treated in vitro with HT followed by PBRT with variable doses. The colony-forming assay was performed, and dose-response was characterized by linear-quadratic model fits. HSP-70 and Brachyury (TBXT) biomarkers for chordoma aggression levels were quantified by western blot analysis. Gene microarray analysis was performed by U133 Arrays. Pathway Analysis was also performed using IPA bioinformatic software. RESULTS: Our findings in both U-CH2 and Mug-Chor1 cell lines demonstrate that hyperthermia followed by PBRT has an enhanced cell killing effect when compared with PBRT-alone (p < .01). Western blot analysis showed HT decreased the expression of Brachyury protein (p < .05), which is considered a biomarker for chordoma tumor aggression. HT with PBRT also exhibited an RT-dose-dependent decrease of Brachyury expression (p < .05). We also observed enhanced HSP-70 expression due to HT, RT, and HT + RT combined in both cell lines. Interestingly, genomic data showed 344 genes expressed by the treatment of HT + RT compared to HT (68 genes) or RT (112 genes) as individual treatment. We also identified activation of death receptor and apoptotic pathway in HT + RT treated cells. CONCLUSION: We found that Hyperthermia (HT) combined with Proton Beam Radiation (PBRT) could significantly increase chordoma cell death by activating the death receptor pathway and apoptosis which has the promise to treat metastatic chordoma.

Radiosensitization of high-grade gliomas through induced hyperthermia: Review of clinical experience and the potential role of MR-guided focused ultrasound.

High-grade gliomas (HGGs) are aggressive primary brain tumors that confer poor prognoses. Despite aggressive combined modality treatment, HGGs invariably recur. Considerable research efforts and resources have focused on identification of novel therapies for HGGs; however, standard treatments have not changed significantly in more than 10 years, since the introduction of concurrent chemoradiation therapy with temozolomide. Hyperthermia (HT) has been shown to enhance the efficacy of radiation treatment (RT) in numerous cancer types through multiple mechanisms, including impairment of DNA repair pathways, increased perfusion/oxygenation of tumors, and immune system activation. In the 1980s and 1990s, the combination of HT with external-beam RT and interstitial brachytherapy was extensively evaluated in HGG, culminating in a randomized controlled trial that demonstrated superior survival in patients receiving combined HT and RT. However, HT was not adopted into common practice for HGG because of the need at that time for invasive implantation procedures, challenges to monitoring and maintaining a homogeneous, localized temperature elevation within the tumor tissue, as well as other technical and logistic challenges. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is a relatively new technology in clinical use that is capable of highly accurate transcranial HT and has the potential to overcome many of the limitations faced in previous trials combining HT and RT in HGG. In this review, we detail and compile the previous clinical results of combined HT and RT in HGG patients. We also introduce and discuss the potential of MRgFUS as a noninvasive method for HT to radiosensitize HGG.

Radiation and Hyperthermia Combination Therapy for Recalcitrant Verruca Vulgaris.

A 47-year-old white woman presented to our clinic complaining of recalcitrant warts on her trunk and extremities. She had an extensive past medical history including immunodeficiency of unknown origin, pulmonary hypertension, rheumatoid arthritis, and systemic lupus erythematosus, for which she was being treated with chronic immunosuppressive therapy with methylprednisolone and belimumab. The patient had previously failed treatments at an outside facility with liquid nitrogen, trichloroacetic acid, topical cidofovir, imiquimod, topical 5-fluorouracil, intralesional candida antigen, pulsed-dye laser (Vbeam Perfecta), surgical excision, and photodynamic therapy. (SKINmed. 2019;17:68-71).

Mild hyperthermia as a localized radiosensitizer for deep-seated tumors: investigation in an orthotopic prostate cancer model in mice.

OBJECTIVE:: Non-ablative or mild hyperthermia (HT) has been shown in preclinical (and clinical) studies as a localized radiosensitizer that enhances the tumoricidal effects of radiation. Most preclinical in vivo HT studies use subcutaneous tumor models which do not adequately represent clinical conditions (e.g. proximity of normal/critical organs) or replicate the tumor microenvironment-both of which are important factors for eventual clinical translation. The purpose of this work is to demonstrate proof-of-concept of locoregional radiosensitization with superficially applied, radiofrequency (RF)-induced HT in an orthotopic mouse model of prostate cancer. METHODS:: In a 4-arm study, 40 athymic male nude mice were inoculated in the prostate with luciferase-transfected human prostate cancer cells (PC3). Tumor volumes were allowed to reach 150-250 mm3 (as measured by ultrasound) following which, mice were randomized into (i) control (no intervention); (ii) HT alone; (iii) RT alone; and (iv) HT + RT. RF-induced HT was administered (Groups ii and iv) using the Oncotherm LAB EHY-100 device to achieve a target temperature of 41 °C in the prostate. RT was administered ~30 min following HT, using an image-guided small animal radiotherapy research platform. In each case, a dual arc plan was used to deliver 12 Gy to the target in a single fraction. One animal from each cohort was euthanized on Day 10 or 11 after treatment for caspase-9 and caspase-3 Western blot analysis. RESULTS:: The inoculation success rate was 89%. Mean tumor size at randomization (~16 days post-inoculation) was ~189 mm3 . Following the administration of RT and HT, mean tumor doubling times in days were: control = 4.2; HT = 4.5; RT = 30.4; and HT + RT = 33.4. A significant difference (p = 0.036) was noted between normalized nadir volumes for the RT alone (0.76) and the HT + RT (0.40) groups. Increased caspase-3 expression was seen in the combination treatment group compared to the other treatment groups. CONCLUSION:: These early results demonstrate the successful use of external mild HT as a localized radiosensitizer for deep-seated tumors. ADVANCES IN KNOWLEDGE:: We successfully demonstrated the feasibility of administering external mild HT in an orthotopic tumor model and demonstrated preclinical proof-of-concept of HT-based localized radiosensitization in prostate cancer radiotherapy.

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.

Hyperthermia and radiotherapy in bladder cancer.

Hyperthermia represents a unique, safe, and advantageous methodology for improving therapeutic strategies in the management of bladder cancer. This modality has shown promise in contributing to treatment regimens for both superficial and muscle-invasive disease. Especially in conjunction with intravesical chemotherapy, systemic therapy, and radiotherapy, hyperthermia shows particular synergistic benefit. As such, it should be explored further through clinical use and clinical trial in conjunction with currently available techniques and emerging technologies. However, to conceptualise the way forward, it is particularly important to understand the current challenges to widespread use of non-invasive, bladder-sparing approaches and the current state of bladder cancer care. As such, in the following article, we have focused on not only the rationale for concurrent radiotherapy and hyperthermia, but also the clinical landscape in bladder cancer as a whole.

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Thermal dosimetry characteristics of deep regional heating of non-muscle invasive bladder cancer.

PURPOSE: The aim of this paper is to report thermal dosimetry characteristics of external deep regional pelvic hyperthermia combined with intravesical mitomycin C (MMC) for treating bladder cancer following transurethral resection of bladder tumour, and to use thermal data to evaluate reliability of delivering the prescribed hyperthermia dose to bladder tissue. MATERIALS AND METHODS: A total of 14 patients were treated with MMC and deep regional hyperthermia (BSD-2000, Sigma Ellipse or Sigma 60). The hyperthermia objective was 42° ± 2 °C to bladder tissue for ≥40 min per treatment. Temperatures were monitored with thermistor probes and recorded values were used to calculate thermal dose and evaluate treatment. Anatomical characteristics were examined for possible correlations with heating. RESULTS: Combined with BSD-2000 standard treatment planning and patient feedback, real-time temperature monitoring allowed thermal steering of heat sufficient to attain the prescribed thermal dose to bladder tissue within patient tolerance in 91.6% of treatments. Mean treatment time for bladder tissue >40 °C was 61.9 ± 11.4 min and mean thermal dose was 21.3 ± 16.5 CEM43. Average thermal doses obtained in normal tissues were 1.6 ± 1.2 CEM43 for the rectum and 0.8 ± 1.3 CEM43 in superficial normal tissues. No significant correlation was seen between patient anatomical characteristics and thermal dose achieved in bladder tissue. CONCLUSIONS: This study demonstrates that a hyperthermia prescription of 42° ± 2 °C for 40-60 min can be delivered safely to bladder tissue with external radiofrequency phased array applicators for a typical range of patient sizes. Using the available thermometry and treatment planning, the BSD-2000 hyperthermia system was shown to be an effective method of focusing heat regionally around the bladder with good patient tolerance.

A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer.

PURPOSE: This paper aims to evaluate the safety and heating efficiency of external deep pelvic hyperthermia combined with intravesical mitomycin C (MMC) as a novel therapy for non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We enrolled subjects with bacillus Calmette-Guérin (BCG) refractory NMIBC to an early phase clinical trial of external deep pelvic hyperthermia (using a BSD-2000 device) combined with MMC. Bladders were heated to 42 °C for 1 h during intravesical MMC treatment. Treatments were given weekly for 6 weeks, then monthly for 4 months. Heating parameters, treatment toxicity, and clinical outcomes were systematically measured. RESULTS: Fifteen patients were enrolled on the clinical trial. Median age was 66 years and 87% were male. Median European Organisation for Research and Treatment of Cancer (EORTC) recurrence and progression scores were 6 and 8, respectively. The full treatment course was attained in 73% of subjects. Effective bladder heating was possible in all but one patient who could not tolerate the supine position due to lung disease. Adverse events were all minor (grade 2 or less) and no systemic toxicity was observed. The most common adverse effects were Foley catheter pain (40%), abdominal discomfort (33%), chemical cystitis symptoms (27%), and abdominal skin swelling (27%). With a median follow-up of 3.18 years, 67% experienced another bladder cancer recurrence (none were muscle invasive) and 13% experienced an upper tract recurrence. CONCLUSIONS: External deep pelvic hyperthermia using the BSD-2000 device is a safe and reproducible method of heating the bladder in patients undergoing intravesical MMC. The efficacy of this treatment modality should be explored further in clinical trials.

Identification and quantitation of biomarkers for radiation-induced injury via mass spectrometry.

Biomarker identification and validation for radiation exposure is a rapidly expanding field encompassing the need for well defined animal models and advanced analytical techniques. The resources within the consortium, Medical Countermeasures Against Radiological Threats (MCART), provide a unique opportunity for accessing well defined animal models that simulate the key sequelae of the acute radiation syndrome and the delayed effects of acute radiation exposure. Likewise, the use of mass spectrometry-based analytical techniques for biomarker discovery and validation enables a robust analytical platform that is amenable to a variety of sample matrices and considered the benchmark for biomolecular identification and quantitation. Herein, the authors demonstrate the use of two targeted mass spectrometry approaches to link established MCART animal models to identified metabolite biomarkers. Circulating citrulline concentration was correlated to gross histological gastrointestinal tissue damage, and retinoic acid production in lung tissue was established to be reduced at early and late time points post high dose irradiation. Going forward, the use of mass spectrometry-based metabolomics coupled to well defined animal models provides the unique opportunity for comprehensive biomarker discovery.

Components of a hyperthermia clinic: recommendations for staffing, equipment, and treatment monitoring.

Like other technically sophisticated medical endeavours, a hyperthermia clinic relies on skilled staffing. Physicians, physicists and technologists perform multiple tasks to ensure properly functioning equipment, appropriate patient selection, and to plan and administer this treatment. This paper reviews the competencies and tasks that are used in a hyperthermia clinic.

Utility of treatment planning for thermochemotherapy treatment of nonmuscle invasive bladder carcinoma.

PURPOSE: A recently completed Phase I clinical trial combined concurrent Mitomycin-C chemotherapy with deep regional heating using BSD-2000 Sigma-Ellipse applicator (BSD Corporation, Salt Lake City, UT, U.S.A.) for the treatment of nonmuscle invasive bladder cancer. This work presents a new treatment planning approach, and demonstrates potential impact of this approach on improvement of treatment quality. METHODS: This study retrospectively analyzes a subset of five patients on the trial. For each treatment, expert operators selected "clinical-optimal" settings based on simple model calculation on the BSD-2000 control console. Computed tomography (CT) scans acquired prior to treatment were segmented to create finite element patient models for retrospective simulations with Sigma-HyperPlan (Dr. Sennewald Medizintechnik GmbH, Munchen, Germany). Since Sigma-HyperPlan does not account for the convective nature of heat transfer within a fluid filled bladder, an effective thermal conductivity for bladder was introduced. This effective thermal conductivity value was determined by comparing simulation results with clinical measurements of bladder and rectum temperatures. Regions of predicted high temperature in normal tissues were compared with patient complaints during treatment. Treatment results using "computed-optimal" settings from the planning system were compared with clinical results using clinical-optimal settings to evaluate potential of treatment improvement by reducing hot spot volume. RESULTS: For all five patients, retrospective treatment planning indicated improved matches between simulated and measured bladder temperatures with increasing effective thermal conductivity. The differences were mostly within 1.3 °C when using an effective thermal conductivity value above 10 W/K/m. Changes in effective bladder thermal conductivity affected surrounding normal tissues within a distance of ∼1.5 cm from the bladder wall. Rectal temperature differences between simulation and measurement were large due to sensitivity to the sampling locations in rectum. The predicted bladder T90 correlated well with single-point bladder temperature measurement. Hot spot locations predicted by the simulation agreed qualitatively with patient complaints during treatment. Furthermore, comparison between the temperature distributions with clinical and computed-optimal settings demonstrated that the computed-optimal settings resulted in substantially reduced hot spot volumes. CONCLUSIONS: Determination of an effective thermal conductivity value for fluid filled bladder was essential for matching simulation and treatment temperatures. Prospectively planning patients using the effective thermal conductivity determined in this work can potentially improve treatment efficacy (compared to manual operator adjustments) by potentially lower discomfort from reduced hot spots in normal tissue.

Hyperthermia as a treatment for bladder cancer.

Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non-muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy.

BACKGROUND AND PURPOSE: Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. METHODS: Twenty-seven patients received ThChRT for chest wall failure from 2/1995 to 6/2007 and make up this retrospective series. All received concurrent superficial hyperthermia twice weekly (median 8 sessions), chemotherapy (capecitabine in 21, vinorelbine in 2, and paclitaxel in 4), and radiation (median 45 Gy). Patients were followed up every 1.5-3 months and responses were graded with RECIST criteria and toxicities with the NCI CTC v4.0. RESULTS: Twenty-three (85%) patients were previously irradiated (median 60.4 Gy) and 22 (81%) patients received prior chemotherapy. Median follow-up was 11 months. Complete response (CR) was achieved in 16/20 (80%) of patients with follow-up data, and 1 year LPFS was 76%. Overall survival was 23 months for patients with CR, and 5.4 months in patients achieving a partial response (PR) (p=0.01). Twenty-two patients experienced acute grade 1/2 treatment related toxicities, primarily moist desquamation. Two patients experienced 3rd degree burns; all resolved with conservative measures. CONCLUSIONS: ThChRT offers durable palliation and prolonged LPFS with tolerable acute toxicity, especially if CR is achieved.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Magnetic resonance imaging: a potential tool in assessing the addition of hyperthermia to neoadjuvant therapy in patients with locally advanced breast cancer.

The poor overall survival for patients with locally advanced breast cancers has led over the past decade to the introduction of numerous neoadjuvant combined therapy regimens to down-stage the disease before surgery. At the same time, more evidence suggests the need for treatment individualisation with a wide variety of new targets for cancer therapeutics and also multi modality therapies. In this context, early determination of whether the patient will fail to respond can enable the use of alternative therapies that can be more beneficial. The purpose of this review is to examine the potential role of magnetic resonance imaging (MRI) in early prediction of treatment response and prognosis of overall survival in locally advanced breast cancer patients enrolled on multi modality therapy trials that include hyperthermia. The material is organised with a review of dynamic contrast (DCE)-MRI and diffusion weighted (DW)-MRI for characterisation of phenomenological parameters of tumour physiology and their potential role in estimating therapy response. Most of the work published in this field has focused on responses to neoadjuvant chemotherapy regimens alone, so the emphasis will be there, however the available data that involves the addition of hyperthermia to the regimen will be discussed The review will also include future directions that include the potential use of MRI imaging techniques in establishing the role of hyperthermia alone in modifying breast tumour microenvironment, together with specific challenges related to performing such studies.

Conformal microwave array (CMA) applicators for hyperthermia of diffuse chest wall recurrence.

PURPOSE: This article summarises the evolution of microwave array applicators for heating large area chest wall disease as an adjuvant to external beam radiation, systemic chemotherapy, and potentially simultaneous brachytherapy. METHODS: Current devices used for thermotherapy of chest wall recurrence are reviewed. The largest conformal array applicator to date is evaluated in four studies: (1) ability to conform to the torso is demonstrated with a CT scan of a torso phantom and MR scan of the conformal water bolus component on a mastectomy patient; (2) specific absorption rate (SAR) and temperature distributions are calculated with electromagnetic and thermal simulation software for a mastectomy patient; (3) SAR patterns are measured with a scanning SAR probe in liquid muscle phantom for a buried coplanar waveguide CMA; and (4) heating patterns and patient tolerance of CMA applicators are characterised in a clinical pilot study with 13 patients. RESULTS: CT and MR scans demonstrate excellent conformity of CMA applicators to contoured anatomy. Simulations demonstrate effective control of heating over contoured anatomy. Measurements confirm effective coverage of large treatment areas with no gaps. In 42 hyperthermia treatments, CMA applicators provided well-tolerated effective heating of up to 500 cm(2) regions, achieving target temperatures of T(min) = 41.4 ± 0.7°C, T(90) = 42.1 ± 0.6°C, T(ave) = 42.8 ± 0.6°C, and T(max) = 44.3 ± 0.8°C as measured in an average of 90 points per treatment. CONCLUSION: The CMA applicator is an effective thermal therapy device for heating large-area superficial disease such as diffuse chest wall recurrence. It is able to cover over three times the treatment area of conventional hyperthermia devices while conforming to typical body contours.

Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.

BACKGROUND: The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. METHODS: Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (> or = 5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. FINDINGS: 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20-67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41-0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6-26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54-0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45-0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. INTERPRETATION: To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location. FUNDING: Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).

A phase I/II study of neoadjuvant liposomal doxorubicin, paclitaxel, and hyperthermia in locally advanced breast cancer.

PURPOSE: The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50-60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia. MATERIALS AND METHODS: Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30-75 mg/m(2)), paclitaxel (100-175 mg/m(2)), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy. RESULTS: Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%-76%) and the four-year overall survival was 75% (95% CI, 58-86%). CONCLUSIONS: Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.