Publications by authors named "Dietmar Marder"

9 Publications

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Quantification of thermal dose in moderate clinical hyperthermia with radiotherapy: a relook using temperature-time area under the curve (AUC).

Int J Hyperthermia 2021 ;38(1):296-307

Department of Radiation Oncology KSA-KSB, Kantonsspital Aarau, Aarau, Switzerland.

Background: Thermal dose in clinical hyperthermia reported as cumulative equivalent minutes (CEM) at 43 °C (CEM43) and its variants are based on direct thermal cytotoxicity assuming Arrhenius 'break' at 43 °C. An alternative method centered on the actual time-temperature plot during each hyperthermia session and its prognostic feasibility is explored.

Methods And Materials: Patients with bladder cancer treated with weekly deep hyperthermia followed by radiotherapy were evaluated. From intravesical temperature (T) recordings obtained every 10 secs, the area under the curve (AUC) was computed for each session for  > 37 °C (AUC > 37 °C) and  ≥ 39 °C (AUC ≥ 39 °C). These along with CEM43, CEM43(>37 °C), CEM43(≥39 °C), , and were evaluated for bladder tumor control.

Results: Seventy-four hyperthermia sessions were delivered in 18 patients (median: 4 sessions/patient). Two patients failed in the bladder. For both individual and summated hyperthermia sessions, the , CEM43, CEM43(>37 °C), CEM43(≥39 °C), AUC > 37 °C and AUC ≥ 39 °C were significantly lower in patients who had a local relapse. Individual AUC ≥ 39 °C for patients with/without local bladder failure were 105.9 ± 58.3 °C-min and 177.9 ± 58.0 °C-min, respectively ( = 0.01). Corresponding summated AUC ≥ 39 °C were 423.7 ± 27.8 °C-min vs. 734.1 ± 194.6 °C-min ( < 0.001), respectively. The median AUC ≥ 39 °C for each hyperthermia session in patients with bladder tumor control was 190 °C-min.

Conclusion: AUC ≥ 39 °C for each hyperthermia session represents the cumulative time-temperature distribution at clinically defined moderate hyperthermia in the range of 39 °C to 45 °C. It is a simple, mathematically computable parameter without any prior assumptions and appears to predict treatment outcome as evident from this study. However, its predictive ability as a thermal dose parameter merits further evaluation in a larger patient cohort.
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July 2021

A Pilot Study of Radiotherapy and Local Hyperthermia in Elderly Patients With Muscle-Invasive Bladder Cancers Unfit for Definitive Surgery or Chemoradiotherapy.

Front Oncol 2019 10;9:889. Epub 2019 Sep 10.

Center for Radiation Oncology KSA-KSB, Kantonsspital Aarau, Aarau, Switzerland.

To present the outcomes of a pilot study with hyperthermia (HT) and radiotherapy (RT) in elderly patients of muscle-invasive bladder cancers (MIBC) unfit for surgery or chemoradiotherapy (CTRT). Sixteen elderly patients with unifocal or multifocal MIBCs received a total dose of 48 Gy/16 fractions/4 weeks or 50 Gy/20 fractions/4 weeks, respectively. HT with a radiofrequency HT unit was delivered once weekly for 60 min before RT and a mean temperature of 41.3°C was attained (maximum temperature 41.1-43.5°C). Local control was assessed using RECIST criteria at 3-monthly intervals by cystoscopy with or without biopsy. The median age, KPS and age-adjusted Charlson comorbidity index were 81 years, 70 and 5, respectively. At median follow-up of 18.5 months (range: 4-65), bladder preservation was 100% with satisfactory function. 11/16 patients (68.7%) had no local and/or distant failure, while isolated local, distant and combined local and distant failures were evident in 2, 2, and 1 patient, respectively. Two local failures were salvaged by TUR-BT resulting in a local control rate of 93.7%. The 5-year cause-specific (CS) local disease free survival (LDFS), disease free survival (DFS), and overall survival (OS) were 64.3, 51.6, and 67.5%, respectively while 5-year non-cause-specific (NCS)-LDFS, NCS-DFS, and NCS-OS were 26.5, 23.2, and 38%, respectively. None of the patients had acute or late grade 3/4 gastrointestinal or genitourinary toxicities. The outcomes from this pilot study indicate that thermoradiotherapy is a feasible therapeutic modality in elderly MIBC patients unfit for surgery or CTRT. HTRT is well-tolerated, allows bladder preservation and function, achieves long-term satisfactory locoregional control and is devoid of significant treatment-related morbidity. This therapeutic approach deserves further evaluation in randomized studies.
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September 2019

Early results and volumetric analysis after spot-scanning proton therapy with concomitant hyperthermia in large inoperable sacral chordomas.

Br J Radiol 2020 Mar 14;93(1107):20180883. Epub 2019 May 14.

Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen PSI, Switzerland.

Objective: Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT).

Methods: : Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed.

Results: : Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture.

Conclusion: Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial.

Advances In Knowledge: : This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
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March 2020

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

Strahlenther Onkol 2017 May 1;193(5):351-366. Epub 2017 Mar 1.

Radiation Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

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.
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May 2017

Quality assurance guidelines for superficial hyperthermia clinical trials: I. Clinical requirements.

Int J Hyperthermia 2017 Jun 31;33(4):471-482. Epub 2017 Jan 31.

i Radiation Oncology , Erasmus MC Daniel den Hoed Cancer Center , Rotterdam , The Netherlands.

Quality assurance guidelines are essential to provide uniform execution of clinical trials and treatment in the application of hyperthermia. This document provides definitions for a good hyperthermia treatment and identifies the clinical conditions where a certain hyperthermia system can or cannot adequately heat the tumour volume. It also provides brief description of the characteristics and performance of the current electromagnetic (radiative and capacitive), ultrasound and infra-red heating techniques. This information helps to select the appropriate heating technique for the specific tumour location and size, and appropriate settings of the water bolus and thermometry. Finally, requirements of staff training and documentation are provided. The guidelines in this document focus on the clinical application and are complemented with a second, more technical quality assurance document providing instructions and procedure to determine essential parameters that describe heating properties of the applicator for superficial hyperthermia. Both sets of guidelines were developed by the ESHO Technical Committee with participation of senior STM members and members of the Atzelsberg Circle.
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June 2017

Proton Irradiation with Hyperthermia in Unresectable Soft Tissue Sarcoma.

Int J Part Ther 2016 30;3(2):327-336. Epub 2016 Dec 30.

Centre for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland.

Purpose: Unresectable soft tissue sarcomas (STSs) do not usually exhibit significant tumor downstaging with preoperative radiotherapy and/or chemotherapy due to their limited radiosensitivity/chemosensitivity. Limb amputations for tumors of the extremities inevitably lead to considerable loss of function and impairment in quality of life. Local hyperthermia at 39°C to 43°C and proton irradiation combine thermoradiobiological and physical dose distribution advantages, possibly mimicking those of a C ion therapy. We report the first 2 patients treated with this unique approach of proton thermoradiotherapy.

Materials And Methods: Both patients had an unresectable STS of the left lower leg (1 grade 2 myxoid fibrosarcoma, 1 grade 3 undifferentiated pleomorphic sarcoma). Both patients had declined the above-knee amputation that had been advised due to their involvement of the neurovascular bundles. They were, therefore recruited to the Hyperthermia and Proton Therapy in Unresectable Soft Tissue Sarcoma (HYPROSAR) study protocol ( NCT01904565). Local hyperthermia was delivered using radiofrequency waves at 100 Mhz once a week after proton therapy. Proton irradiation was undertaken to a dose of 70 to 72 Gy (relative biological effectiveness) delivered at 2.0 Gy (relative biological effectiveness)/ fraction daily for 7 weeks.

Results: Patients tolerated the treatment well with no significant acute or late morbidity. Both primary tumors showed a near complete response on serial magnetic resonance imaging. At a follow-up of 5 and 14 months, the patients were able to carry out indoor and outdoor activities with normal limb function.

Conclusion: This is the first report of proton beam irradiation combined with hyperthermia for cancer therapy. Our first experience in 2 consecutive patients with unresectable STSs shows that the approach is safe, feasible, and effective, achieving functional limb preservation with near total tumor control.
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December 2016

Radiotherapy infrastructure and human resources in Switzerland : Present status and projected computations for 2020.

Strahlenther Onkol 2016 Sep 25;192(9):599-608. Epub 2016 Jul 25.

RadioOnkologieZentrum, KSA-KSB, Kantonsspital Aarau, Tellstrasse, 5001, Aarau, Switzerland.

Purpose: The purpose of this study was to evaluate the present status of radiotherapy infrastructure and human resources in Switzerland and compute projections for 2020.

Materials And Methods: The European Society of Therapeutic Radiation Oncology "Quantification of Radiation Therapy Infrastructure and Staffing" guidelines (ESTRO-QUARTS) and those of the International Atomic Energy Agency (IAEA) were applied to estimate the requirements for teleradiotherapy (TRT) units, radiation oncologists (RO), medical physicists (MP) and radiotherapy technologists (RTT). The databases used for computation of the present gap and additional requirements are (a) Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) for cancer incidence (b) the Directory of Radiotherapy Centres (DIRAC) of the IAEA for existing TRT units (c) human resources from the recent ESTRO "Health Economics in Radiation Oncology" (HERO) survey and (d) radiotherapy utilization (RTU) rates for each tumour site, published by the Ingham Institute for Applied Medical Research (IIAMR).

Results: In 2015, 30,999 of 45,903 cancer patients would have required radiotherapy. By 2020, this will have increased to 34,041 of 50,427 cancer patients. Switzerland presently has an adequate number of TRTs, but a deficit of 57 ROs, 14 MPs and 36 RTTs. By 2020, an additional 7 TRTs, 72 ROs, 22 MPs and 66 RTTs will be required. In addition, a realistic dynamic model for calculation of staff requirements due to anticipated changes in future radiotherapy practices has been proposed. This model could be tailor-made and individualized for any radiotherapy centre.

Conclusion: A 9.8 % increase in radiotherapy requirements is expected for cancer patients over the next 5 years. The present study should assist the stakeholders and health planners in designing an appropriate strategy for meeting future radiotherapy needs for Switzerland.
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September 2016

Is hyperthermia combined with radiotherapy adequate in elderly patients with muscle-invasive bladder cancers? Thermo-radiobiological implications from an audit of initial results.

Int J Hyperthermia 2016 06 22;32(4):390-7. Epub 2016 Jan 22.

c Centre for Radiation Oncology , KSA-KSB , Kantonsspital Aarau , Switzerland , and.

Purpose: The aim of this study was to evaluate the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in elderly patients with muscle-invasive bladder cancers (MIBC).

Material And Methods: Twenty consecutive MIBC patients were treated with HTRT (n = 8) or HTCTRT (n = 12) following transurethral resection of their bladder tumours. Weekly HT was administered prior to RT to a mean temperature of 40.6-42.7 °C for 60 min. A mean RT dose of 54.6 Gy (SD ± 4.2) was delivered. Single-agent cisplatin (n = 2) or carboplatin (n = 10) was used in HTCTRT patients.

Results: The median age was 81 years. HTRT patients received a mean RT dose of 51.0 Gy compared to 57.1 Gy with HTCTRT (p < 0.001) in a shorter overall treatment time (OTT) (30.8 ± 6.9 versus 43.9 ± 4.0 days, p < 0.001). All HTRT patients had long-term local disease control, while 41.6% of HTCTRT recurred during follow-up. None of the HTRT patients experienced grade III/IV acute and late toxicities, while these were evident in two and one HTCTRT patients respectively. Taken together, the 3-year bladder preservation, local disease-free survival, cause-specific survival and overall survival were 86.6%, 60.7%, 55% and 39.5% respectively. Even though the mean biological effective dose (BED) for both groups was similar (57.8 Gy15), the thermo-radiobiological BED estimated from HT-induced reduction of α/β was significantly higher for HTRT patients (91 ± 4.4 versus 85.8 ± 4.3 Gy3, p = 0.018).

Conclusions: Thermal radiosensitisation with consequent reduction in α/β results in a higher thermo-radiobiological BED with a relatively higher RT dose/fraction and shorter OTT. This translates into a favourable outcome in elderly MIBC patients. Any benefit of CT in these patients needs further investigation.
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June 2016

Hyperthermia and reirradiation for locoregional recurrences in preirradiated breast cancers: a single institutional experience.

Swiss Med Wkly 2015 23;145:w14133. Epub 2015 Apr 23.

RadioOnkologieZentrum, KSA-KSB, Kantonsspital Aarau, Switzerland and Department of Radiation Oncology, University Hospital Zurich, Switzerland.

Questions Under Study: The aim of this retrospective analysis was to evaluate the safety and efficacy of local hyperthermia (HT) and reirradiation (ReRT) in the management of preirradiated locoregional recurrent breast cancers at Kantonsspital Aarau, Switzerland.

Methods: Twenty-four previously irradiated patients who had developed locoregional recurrences in the chest wall or breast, with or without regional lymph node involvement, were reirradiated to a mean dose of 36.8 Gy (range 20-50 Gy) delivered at a mean dose per fraction of 2.33 Gy (range 1.8-4.0 Gy). All patients received local HT at 41 to 43 °C, once or twice a week prior to radiotherapy. Online thermometry was carried out during the hyperthermia sessions.

Results: An overall objective response rate of 91.7% (22/24) with a complete response in 66.7% (16/24) of patients and partial response in 25% (6/24) of patients was observed. Post-thermoradiotherapy follow-up ranged from 1 to 38 months (median 10 months). The 3-year actuarial local control rate was 59.7%. More patients who attained complete response had sustained locoregional control until their death or last follow-up when compared with those who were partial or non-responders (median local disease-free survival for complete responders not reached; for partial and non-responders 4 months; p <0.001). Post-retreatment median overall survival for all 24 patients was 10 months. Grade III/IV acute toxicity was seen in only one patient and no patient had any significant late morbidity.

Conclusions: ReRT and HT is an effective and a safe modality to treat locoregional recurrences in previously irradiated breast cancers. The approach can lead to sustainable long-term palliation with minimal morbidity.
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January 2016