Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application

Abstract

Regional hyperthermia is described as a targeted therapy and the definitions of six hallmarks of hyperthermia are proposed, representing the pleiotropic effect of this therapeutic modality to counteract tumour growth and progression. We recommend the considerations of these hallmarks in the design of clinical trials involving regional hyperthermia as targeted therapy. Randomised clinical studies using loco-regional hyperthermia as an adjuvant to radiotherapy or to chemotherapy for locally advanced tumours demonstrate the benefit of the combination compared to either of the standard treatments alone for tumour response, disease control, and patient survival outcome. These impressive results were obtained from proof-of-concept trials for superficial or deep-seated malignancies in unselected patients. None of these trials was designed as tailored approaches for the treatment of specified targets or to select potentially more sensitive subpopulations of patients using eligibility criteria. Based upon clinical examples of targeted chemotherapy, some guidelines are described for the successful development of targeted therapeutic combinations. We also retrospectively analyse the stepwise process of generating an ongoing new clinical trial using hyperthermia as targeted therapy to evade DNA repair in combination with a DNA damaging anticancer agent to implement this new vision.

Hyperthermia and Radiotherapy Combination for Locoregional Recurrences of Breast Cancer: A Review

“…Hallmarks of HT were nicely summarized by Issels et al [31]. Direct cell killing effect that is mainly based on the denaturation and aggregation of cellular proteins which is cell-type independent predominates with temperature ≥41…”

Targeting therapy-resistant cancer stem cells by hyperthermia

“…More specifically, hyperthermia induces degradation of the BRCA2 protein and thereby inactivates homologous recombination, one of the major pathways responsible for repairing DNA double-strand breaks [161,162]. Furthermore, hyperthermia (above 43 C) has been found to interfere with base excision repair [163,164], leading to more severe breaks. Interference with DNA repair pathways is important to increase levels of DNA breaks, causing accumulation of unrepaired DNA lesions, resulting in cell death.…”

“…Clinically, hyperthermia is always combined with either radiotherapy or chemotherapy [35,[42][43][44]. When applied prior to conventional therapy, hyperthermia can increase blood flow, improve oxygenation and enhance the therapy effects by stimulating production of oxygen radicals [45][46][47][48].…”

“…Hyperthermia, defined here as local heating of the tumour to relatively moderate temperatures of [40][41][42][43] C for approximately one hour, is an excellent radiosensitiser and chemosensitiser effective in multiple tumour types [33][34][35][36][37][38][39][40][41]. Clinically, hyperthermia is always combined with either radiotherapy or chemotherapy [35,[42][43][44].…”

“…A successful anti-CSC therapy should be characterised by the ability to (i) target cells in areas populated by CSCs which are often difficult to reach by conventional therapies; (ii) destroy or modify the tumour microenvironment that sustains CSCs; (iii) kill cycling and non-cycling cells; and (iv) overcome the efficient DNA repair pathways that protect CSCs' genomes. Here we argue that hyperthermia, defined as local heating of the tumour to [40][41][42][43] C, is one anti-cancer treatment that may fit this challenging bill.…”