Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer

Andreas R Thomsen; Jörg Sahlmann; Peter Bronsert; Oliver Schilling; Felicia Poensgen; Annette M May; Sylvia Timme-Bronsert; Anca-Ligia Grosu; Peter Vaupel; Jan-Olaf Gebbers; Gabriele Multhoff; Anne-Marie Lüchtenborg

doi:10.3389/fonc.2023.1275222

Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer

Front Oncol. 2023 Dec 19:13:1275222. doi: 10.3389/fonc.2023.1275222. eCollection 2023.

Authors

Andreas R Thomsen^{1

2}, Jörg Sahlmann³, Peter Bronsert^{4

5}, Oliver Schilling^{2

5}, Felicia Poensgen^{1

6}, Annette M May^{5

7}, Sylvia Timme-Bronsert^{2

5}, Anca-Ligia Grosu^{1

2}, Peter Vaupel^{1

2}, Jan-Olaf Gebbers⁸, Gabriele Multhoff⁹, Anne-Marie Lüchtenborg^{1

2}

Affiliations

¹ Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
² German Cancer Consortium (DKTK), Partner Site DKTK-Freiburg, Freiburg, Germany.
³ Institute for Medical Biometry and Statistics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Tumobank Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁵ Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁶ Pediatric Department, Black Forest Baar Clinic, Villingen-Schwenningen, Germany.
⁷ Medizinisches Versorgungszentrum Laaff, Freiburg, Germany.
⁸ Department of Pathology, Working Group Digital Pathology, University of Berne, Bern, Switzerland.
⁹ Center for Translational Cancer Research, Klinikum rechts der Isar, Department of Radiation Oncology, Technical University Munich (TUM), Munich, Germany.

Abstract

Introduction: Breast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study.

Methods and analyses: Patients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated.

Registration: The study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).

Keywords: breast cancer; hyperthermia; hypofractionated radiotherapy; longitudinal study; predictive markers; re-irradiation; recurrent breast cancer; regression.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Dr. med. h. c. Erwin Braun Foundation, Basel, Switzerland. The funding source did not and will not have any role in design of the study, its execution, data analyses and interpretation. The authors also acknowledge support from the Open Access Publication Fund of the University of Freiburg.