Paul J. Zum Vörde Sive Vörding

Toward Online Adaptive Hyperthermia Treatment Planning: Correlation Between Measured and Simulated Specific Absorption Rate Changes Caused by Phase Steering in Patients

PURPOSE Hyperthermia is the clinical application of heat, in which tumor temperatures are raised to 40°C to 45°C. This proven radiation and chemosensitizer significantly improves clinical outcome for several tumor sites. Earlier studies of the use of pre-treatment planning for hyperthermia showed good qualitative but disappointing quantitative reliability. The purpose of this study was to investigate whether hyperthermia treatment planning (HTP) can be used more reliably for online adaptive treatment planning during locoregional hyperthermia treatments. METHODS AND MATERIALS This study included 78 treatment sessions for 15 patients with non-muscle-invasive bladder cancer. At the start of treatments, temperature rise measurements were performed with 3 different antenna settings optimized for each patient, from which the absorbed power (specific absorption rate [SAR]) was derived. HTP was performed based on a computed tomography (CT) scan in treatment position with the bladder catheter in situ. The SAR along the thermocouple tracks was extracted from the simulated SAR distributions. Correlations between measured and simulated (average) SAR values were determined. To evaluate phase steering, correlations between the changes in simulated and measured SAR values averaged over the thermocouple probe were determined for all 3 combinations of antenna settings. RESULTS For 42% of the individual treatment sessions, the correlation coefficient between measured and simulated SAR profiles was higher than 0.5, whereas 58% showed a weak correlation (R of <0.5). The overall correlation coefficient between measured and simulated average SAR was weak (R=0.31; P<.001). The measured and simulated changes in average SAR after adapting antenna settings correlated much better (R=0.70; P<.001). The ratio between the measured and simulated quotients of maximum and average SARs was 1.03 ± 0.26 (mean ± SD), indicating that HTP can also correctly predict the relative amplitude of SAR peaks. CONCLUSIONS HTP can correctly predict SAR changes after adapting antenna settings during hyperthermia treatments. This allows online adaptive treatment planning, assisting the operator in determining antenna settings resulting in increased tumor temperatures.

Elective re-irradiation and hyperthermia following resection of persistent locoregional recurrent breast cancer: A retrospective study

Purpose: To analyse the therapeutic effect and toxicity of re-irradiation (re-RT) combined with hyperthermia (HT) following resection or clinically complete remission (CR) of persistent locoregional recurrent breast cancer in previously irradiated area. Methods and materials: Between 1988 and 2001, 78 patients with high risk recurrent breast cancer underwent elective re-RT and HT. All patients received extensive previous treatments, including surgery and high-dose irradiation (≥50Gy). Most had received one or more lines of systemic therapy; 44% had been treated for ≥ one previous locoregional recurrences. At start of re-RT + HT there was no macroscopically detectable tumour following surgery (96%) or chemotherapy (CT). Re-RT typically consisted of eight fractions of 4Gy, given twice weekly. Hyperthermia was added once a week. Results: After a median follow up of 64.2 months, three-year survival was 66%. Three- and five-year local control rates were 78% and 65%. Acute grade 3 toxicity occurred in 32% of patients. The risk of late ≥ grade 3 toxicity was 40% after three years. Time interval to the current recurrence was found to be most predictive for local control in univariate and multivariate analysis. The extensiveness of current surgery was the most relevant treatment related factor associated with toxicity. Conclusions: For patients experiencing local recurrence in a previously radiated area, re-irradiation plus hyperthermia following minimisation of tumour burden leads to a high rate of local control, albeit with significant toxicity. The latter might be reduced by a more fractionated re-RT schedule.

FDTD simulations to assess the performance of CFMA-434 applicators for superficial hyperthermia.

Introduction: Contact flexible microstrip applicators (CFMA), operating at 434 MHz, are applied at the Academic Medical Center (AMC) for superficial hyperthermia (e.g. chest wall recurrences and melanoma). This paper investigates the performance of CFMA, evaluating the stability of the specific absorption rate (SAR) distribution, effective heating depth (EHD) and effective field size (EFS) under different conditions. Methods: Simulations were performed using finite differences and were compared to existing measurement data, performed using a rectangular phantom with a superficial fat-equivalent layer of 1 cm and filled with saline solution. The electrode plates of the applicators measure ∼7 × 20, 29 × 21 and 20 × 29 cm2. Bolus thickness varied between 1 and 2 cm. The impact of the presence of possible air layers between the rubber frame and the electrodes on the SAR distribution was investigated. Results: The EHD was ∼1.4 cm and the EFS ranged between ∼60 and ∼300 cm2, depending on the applicator type. Both measurements and simulations showed a split-up of the SAR focus with a 2 cm water bolus. The extent and location of air layers has a strong influence on the shape and size of the iso-SAR contours with a value higher than 50%, but the impact on EFS and EHD is limited. Conclusion: Simulations, confirmed by measurements, showed that the presence of air between the rubber and the electrodes changes the iso-SAR contours, but the impact on the EFS and EHD is limited.

Feasibility, toxicity, and preliminary results of weekly loco-regional hyperthermia and cisplatin in patients with previously irradiated recurrent cervical carcinoma or locally advanced bladder cancer

PURPOSE The biological rationale for combining locoregional hyperthermia (HT) with cisplatin (CDDP) is the potentiating effect of HT on CDDP uptake and cytotoxicity. Feasibility, toxicity, and preliminary results of a clinical trial of weekly loco-regional HT in combination with cisplatin are described in this article. METHODS AND MATERIALS Patients with previously irradiated unresectable local recurrent cervical carcinoma or locally advanced bladder carcinoma were treated with weekly cycles of locoregional HT (70 MHz four antenna phased array system) for 1 h and CDDP 50 mg/m(2) IV for a maximum of 12 courses. RESULTS Fourteen patients, 10 patients with recurrent cervical carcinoma and 4 with locally advanced bladder carcinoma, were entered in this study. A total of 100 cycles were given. Overall toxicity was acceptable; Grade 3 (WHO) toxicity (gastrointestinal, hematological, and neurotoxicity) was observed in 5 out of 14 patients. No Grade 4 toxicity was seen. Subcutaneously fatty necrosis due to HT occurred in 11% of the cycles, while two patients developed skin burns. Two out of 10 patients with recurrent cervical carcinoma were not evaluable for response. Four out of eight evaluable cervical carcinoma patients responded (two pathologic complete responses, one pathologic confirmed partial response, one partial response): response rate 50% (95% confidence interval 15.7-84.3%). Salvage surgery became possible in three out of four responding patients, whose tumors were previously considered unresectable. Two out of the four evaluable patients with locally advanced bladder carcinoma responded (two partial responses). CONCLUSIONS Weekly loco-regional HT and CDDP 50 mg/m(2)/week for a maximum of 12 courses is feasible with an acceptable toxicity, which seems not to be enhanced by the addition of loco-regional HT. The encouraging preliminary results of this treatment schedule warrant further study, especially in patients with previously irradiated recurrent cervical carcinomas.

Combining Mitomycin C and Regional 70 MHz Hyperthermia in Patients with Nonmuscle Invasive Bladder Cancer: A Pilot Study

PURPOSE Despite intravesical therapy with immunotherapy or chemotherapy intermediate and high risk nonmuscle invasive bladder cancer is associated with a high risk of recurrence and progression to muscle invasive bladder carcinoma. While intravesical hyperthermia combined with mitomycin C has proved effective to treat nonmuscle invasive bladder cancer, there is less experience with invasive regional 70 MHz hyperthermia and mitomycin C. Therefore, we examined the safety and feasibility of this treatment combination for intermediate and high risk nonmuscle invasive bladder cancer. MATERIALS AND METHODS Between 2009 and 2011, 20 patients with intermediate and high risk nonmuscle invasive bladder cancer were treated with intravesical mitomycin C (40 mg) combined with regional hyperthermia. Treatment consisted of 6 weekly sessions followed by a maintenance period of 1 year with 1 hyperthermia-mitomycin C session every 3 months. Regional hyperthermia was administered using a 70 MHz phased array system with 4 antennas. Toxicity was scored using CTC (Common Toxicity Criteria) 3.0. RESULTS The records of 18 of 20 patients could be analyzed. Median followup was 46 months. Of the 18 patients 15 (83%) completed the induction period of 6 treatments. Four patients (22%) discontinued treatment because of physical complaints without exceeding grade 2 toxicity. Toxicity scored according to CTC 3.0 was limited to grade 1 in 43% of cases and grade 2 in 14%. Mean T90 and T50 bladder temperatures were 40.6C and 41.6C, respectively. The 24-month recurrence-free survival rate was 78%. CONCLUSIONS Treatment with regional hyperthermia combined with mitomycin C in patients with intermediate and high risk nonmuscle invasive bladder cancer is feasible with low toxicity and excellent bladder temperatures.

Reirradiation and hyperthermia for irresectable locoregional recurrent breast cancer in previously irradiated area: Size matters

BACKGROUND/PURPOSE Treatment options for irresectable locoregional recurrent breast cancer in previously irradiated area are limited. Hyperthermia, elevating tumor temperature to 40-45°C, sensitizes radio-and-chemotherapy. Four hundred and fourteen patients treated with reirradiation+hyperthermia (reRT+HT) in the AMC(n=301) and the BVI(n=113), from 1982 to 2005 were retrospectively analyzed for treatment response, locoregional control (LC) and prognostic factors for LC and toxicity. PATIENTS/METHODS All patients received previous irradiation (median 50 Gy). reRT consisted of 8 × 4 Gy-2/week (AMC) or 12 × 3 Gy-4/week (BVI). Hyperthermia was added once (AMC)/twice (BVI) a week. RESULTS Overall clinical response rate was 86%. The 3-year LC rate was 25%. The number of recurrence episodes, distant metastases (DM), tumor site, tumor size, time to recurrence and treatment year were significant for LC. Acute ⩾ grade 3 toxicity occurred in 24% of patients. Actuarial late ⩾ grade 3 toxicity was 23% at 3-years. In multivariable analysis reRT fraction dose was significantly related to late ⩾ grade 3 toxicity. CONCLUSION reRT+HT is an effective curative and palliative treatment option for patients with irresectable locoregional recurrent breast cancer in previously irradiated area. Early referral, treatment of chest wall recurrences ⩽ 5 cm in the absence of distant metastases, provided the highest local control rates. The cumulative effects of past and present treatments should be accounted for by adjusting treatment protocol to minimize toxicity.

Characteristics and performance evaluation of the capacitive Contact Flexible Microstrip Applicator operating at 70 MHz for external hyperthermia

Purpose: To characterise and evaluate the capacitive Contact Flexible Microstrip Applicator operating at 70 MHz, CFMA-70. This applicator is introduced for the treatment of superficial tumours with extension in depth beyond the range of regular superficial applicators. Methods: E-field measurements were performed in an elliptical phantom filled with a saline solution using an E-field vector probe. E-field distributions and SAR patterns are compared to those of the CFMA-434 and of 70 MHz waveguides. The applicator has been used for the treatment of 6 patients with breast cancer with a tumour depth exceeding 4 cm. Results: The effective heating depth of the CFMA-70 is 50% larger than for the CFMA-434. Its effective field size is 26 × 20 cm (aperture 29 × 20 cm), larger than for an equally sized CFMA-434. In contrast to the CFMA-434 the SAR pattern of this applicator is insensitive to the bolus thickness. Comparison to 70 MHz waveguides shows that the E-field component normal to the applicator is 100% larger for the CFMA-70. During clinical applications acceptable temperatures were realised for individual sessions (also at depth), but in many cases treatment limiting hot spots occurred close to superficial bony structures near the applicator edge. Both surface irregularities and the normal field component may be responsible. Conclusions: The CFMA-70 has adequate penetration depth for the treatment of superficial tumours exceeding a depth of 4 cm. However, the relatively large normal E-field component may induce treatment-limiting hot spots at tissue interfaces in the direction normal to the applicators surface.

Novel Multisensor Probe for Monitoring Bladder Temperature During Locoregional Chemohyperthermia for Nonmuscle-Invasive Bladder Cancer: Technical Feasibility Study

BACKGROUND AND PURPOSE The effectiveness of locoregional hyperthermia combined with intravesical instillation of mitomycin C to reduce the risk of recurrence and progression of intermediate- and high-risk nonmuscle-invasive bladder cancer is currently investigated in clinical trials. Clinically effective locoregional hyperthermia delivery necessitates adequate thermal dosimetry; thus, optimal thermometry methods are needed to monitor accurately the temperature distribution throughout the bladder wall. The aim of the study was to evaluate the technical feasibility of a novel intravesical device (multi-sensor probe) developed to monitor the local bladder wall temperatures during loco-regional C-HT. MATERIALS AND METHODS A multisensor thermocouple probe was designed for deployment in the human bladder, using special sensors to cover the bladder wall in different directions. The deployment of the thermocouples against the bladder wall was evaluated with visual, endoscopic, and CT imaging in bladder phantoms, porcine models, and human bladders obtained from obduction for bladder volumes and different deployment sizes of the probe. Finally, porcine bladders were embedded in a phantom and subjected to locoregional heating to compare probe temperatures with additional thermometry inside and outside the bladder wall. RESULTS The 7.5 cm thermocouple probe yielded optimal bladder wall contact, adapting to different bladder volumes. Temperature monitoring was shown to be accurate and representative for the actual bladder wall temperature. CONCLUSIONS Use of this novel multisensor probe could yield a more accurate monitoring of the bladder wall temperature during locoregional chemohyperthermia.

Comparison of two different 70 MHz applicators for large extremity lesions: Simulation and application

Introduction: Motivation for this research was a patient with large and bulky melanoma lesions on a leg, treated with hyperthermia in a special set-up with an open water bolus and two opposing applicators. Treatment planning was used to find the most suitable heating method, comparing 70 MHz capacitive contact flexible microstrip applicators (CFMAs) and 70 MHz waveguides. Methods: The first three sessions were performed with CFMA applicators; the last session with waveguides. Power and water temperature were adjusted to achieve clinically relevant temperatures. Finite difference time domain (FDTD) simulations were performed for a CFMA and waveguide on a fat-muscle geometry to compare effective field size (EFS) and effective heating depth (EHD). A CT scan of the patients leg was automatically segmented into muscle, fat and bone; tumour lesions were outlined manually. Patient simulations were performed to evaluate the 3D heating pattern and to compare CFMAs and waveguides for equal power and water temperature. Results: Hyperthermia treatment was well tolerated. Temperature measurements indicated mainly superficial heating with CFMAs. Simulated EHD was 2.1 and 2.4 cm for CFMA and waveguide, respectively and EFS was 19.6 × 16.2 cm2 and 19.4 × 16.3 cm2. Simulation results showed a better tumour coverage using waveguides; absorbed power in the tumour was ∼75% higher with waveguides and absorption in fat was approximately twice as high with CFMAs. Simulations showed that a relatively high water temperature (∼42°C) improves the overall temperature distribution. Conclusion: CFMAs and waveguides have a similar EFS and EHD, but for large extremity lesions, the performance of 70 MHz waveguides is favourable compared to 70 MHz CFMA applicators.

A flexible 70 MHz phase-controlled double waveguide system for hyperthermia treatment of superficial tumours with deep infiltration

Abstract Purpose: Superficial tumours with deep infiltration in the upper 15 cm of the trunk cannot be treated adequately with existing hyperthermia systems. The aim of this study was to develop, characterise and evaluate a new flexible two-channel hyperthermia system (AMC-2) for tumours in this region. Materials and methods: The two-channel AMC-2 system has two horizontally revolving and height adjustable 70 MHz waveguides. Three different interchangeable antennas with sizes 20 × 34, 15 × 34 and 8.5 × 34 cm were developed and their electrical properties were determined. The performance of the AMC-2 system was tested by measurements of the electric field distribution in a saline water filled elliptical phantom, using an electric field vector probe. Clinical feasibility was demonstrated by treatment of a melanoma in the axillary region. Results: Phantom measurements showed a good performance for all waveguides. The large reflection of the smallest antenna has to be compensated by increased forward power. Field patterns become asymmetrical when using smaller top antennas, necessitating phase corrections. The clinical application showed that tumours deeper than 4 cm can be heated adequately. A median tumour temperature of 42 °C can be reached up to 12 cm depth with adequate antenna positioning and phase-amplitude steering. Conclusions: This 70 MHz AMC-2 waveguide system is a useful addition to existing loco-regional hyperthermia equipment as it is capable of heating axillary tumours and other tumours deeper than 4 cm.