Interesting times for establishing the future of multimodal cancer therapy

**Celsius42 is ready for state-of-the-art standardized applicability of hyperthermia and beyond** *Novel treatment methods such as hyperthermia are the future of cancer therapy. Patient safety and technical soundness as well as standardized therapy processes are the key to a full-scale applicability. Recent clinical successes in hyperthermic treatment of high-risk sarcoma tumors mark an important step in the direction of improved cancer therapy, but reign not fully unchallenged yet. The technical cancer treatment specialist Celsius42 applies established safety guidelines in combination with latest clinical applicability to deliver powerful and sustainable hyperthermia therapy options for the future.* In cancer therapy, the patient as a human being is at the center of attention. As a dangerous disease, cancer treatment demands adherence to the highest safety standards and application of the most effective therapy assets. One such asset to improve tumor therapy is the use of regional mild hyperthermia (with temperatures below 42°C) to amplify radiation and chemotherapy therapy effects. The European Society for Hyperthermic Oncology (ESHO) set quality guidelines for the use of regional hyperthermia, describing general measures for conducting hyperthermia therapy safely and effectively [1]. These guidelines translate into eight recommendation as follows: (#1) Adjunct therapy: efficiency of regional hyperthermia is only clinically proven in combination with radio- and/or chemotherapy. (#2) Determining target region: the target tumor region must be clearly determined via medical imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT). Otherwise no action should be taken. (#3) Positioning: Flexible positioning of the patient and the hyperthermia device relative to the patient must be ensured for safe regional hyperthermia application. (#4) Treatment planning: A treatment plan is recommended especially for difficult-to-treat tumors. Treatment planning should be based on phantom measurement assessment. (#5) Temperature measurement: the temperature should ideally be measured intratumorally during hyperthermia treatment or paratumorally otherwise. If intratumoral measurement is applied, the position of the temperature probe must be checked via medical imaging techniques. (#6) Temperature recordings: Should be taken at least once a minute during hyperthermia application. (#7) Documentation of treatment: For application standardization, the start and end time of treatment as well as relevant patient parameters (e.g. blood pressure, pulse, medication administered during treatment) must be documented. (#8) Skillful application: The treatment should be applied by a qualified engineer or physicist or at least be supervised by one during the entire treatment duration. These guidelines frame the general applicability of clinical regional hyperthermia therapy for the past two decades. They also established the basis for novel advancements in treating high-risk soft tissue sarcomas with radio- and/or chemotherapy in combination with regional hyperthermia in 2018 at Charité, Berlin, [2] and LMU, Munich, [3]. We believe to see the advent of regional hyperthermia as a neoadjuvant option in multimodal tumor treatment, but we are also aware that the full-scale clinical application is still to be discussed controversially [4,5]. We at Celsius42 welcome this controversy and want to be part of the advancement of hyperthermia in these interesting times! We offer supportive cooperation as we are happy to announce that our therapy options do not only comply with the ESHO standardization guidelines, but in fact adapt them in combination with the state-of-the-art clinical applications to advance technical cancer treatment. The Celsius42 Tumor Cell Solution (TCS) system is designed to induce regional mild hyperthermia with temperatures of 42°C and below. Applying such therapeutic temperatures during radiation and chemotherapy improves tumor responsiveness to therapy. This intended use complies directly with ESHO guideline number 1 (cf. #1). The TCS system is constructed as an integrated stand-alone system with comfortable patient bedding and a C-arm mounted electrode, allowing both flexible patient and electrode placement depending on the position of the target tumor (cf. #3). The system is furthermore accompanied by an integrated data management system (SQL-based), which automatically identifies and records therapy-relevant patient parameters such as treatment duration (start and end time stamp), applied energy, tumor entity, and selected individual therapy options from the multimodal. Additional patient parameters such as blood pressure, pulse, etc. can be added manually by the physician / MTA and individually integrated in the graphic user interface (GUI) (cf. #7). All this information is automatically collected in a background system, which serves as a therapy database for evaluation of past therapies and planning of future ones. This measure exceeds #7 and allows to establish a resourceful and comprehensive basis for pre-therapy planning (cf. #4). In fact, we at Celsius42 are working on establishing an open data hub with our clinical partners that provides successful therapy plans and the corresponding TCS system parameters during therapy for different tumor entities. Furthermore, temperature simulations are planned to improve the therapy plan predictions on a theoretical basis. Such a therapy planning data hub will be successively build up and access will be provided to our valued customers. Such pre-planning data could also include CT and MRT images of the tumor entities across all our users, allowing a comparatively easy tumor entity identification (cf. #2). Therapy effectiveness is mainly dependent on the absolute temperature reached in the tumor during therapy and the therapy duration at such elevated temperatures. Therefore, Celsius42 has developed a flexible catheter-guided temperature sensor (available early 2020), allowing to measure paratumoral temperatures minimal-invasively via hollow organ access to the target tumor. Our solution is even ahead of #5 and #6, as the temperature is recorded continuous with a resolution of 0.1 degree Celsius. CT and MRI-visibility of the temperature probe allows image-guided therapy during paratumoral temperature measurements as required by #5. (side note: the temperature probe is also MR-compatible, using only non-metal components). Following German engineering tradition, we always adopt highest quality standards to ensure maximum patient safety as well as ideal therapy outcomes using state-of-the-art technologies. In contrast to statement #8 that holds for antenna-frequency driven hyperthermia devices, mild hyperthermia therapies with our capacitive (2-electrode) system can be performed by an trained MTA with ease and requires only partly supervision by an engineer or physicist: We carefully and comprehensively invest in an intuitively and easy-to-use GUI as well as focused training of our customers personal working with our TCS device. In this way, effective therapy can be performed efficiently, while remaining cost-sensitive. We believe that effective and easy therapy application also implies ease in therapy outcome and patient healing! We at Celsius42 are proud to improve the effectiveness of cancer therapy and contribute to technical cancer therapy as a whole with dedication, passion and care – all that in compliance with ESHO guidelines and beyond. We are open to engage in discussion and happy to offer cooperative support and partnerships to advance the future of hyperthermic cancer treatment together with you! [1] Lagendijk, J. J. W., et al. "ESHO quality assurance guidelines for regional hyperthermia."International journal of hyperthermia" 14.2 (1998): 125-133. [2] Zschaeck, Sebastian, et al. "Neoadjuvant chemotherapy plus radiation versus chemotherapy plus regional hyperthermia in high-grade soft tissue sarcomas: a retrospective comparison." International Journal of Hyperthermia 35.1 (2018): 314-322. [3] Issels, Rolf D., et al. "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." JAMA oncology 4.4 (2018): 483-492. [4] Roussakow, Sergey. "Regional Hyperthermia With Neoadjuvant Chemotherapy for Treatment of Soft Tissue Sarcoma." JAMA oncology 5.1 (2019): 113-114. [5] Mansmann, Ulrich, Lars H. Lindner, and Rolf Issels. "Regional Hyperthermia With Neoadjuvant Chemotherapy for Treatment of Soft Tissue Sarcoma—Reply." JAMA oncology 5.1 (2019): 114-114. Your Celsius42 Team