Hyperthermia, cisplatin and radiation trimodality treatment: A promising cancer treatment? A review from preclinical studies to clinical application

Abstract

This review discusses available clinical and experimental data and the underlying mechanisms involved in trimodality treatment consisting of hyperthermia, cisplatin and radiotherapy. The results of phase I/II clinical trials show that trimodality treatment is effective and feasible in various cancer types and sites with tolerable toxicity. Based on these results, phase III trials have been launched to investigate whether significant differences in treatment outcome exist between trimodality and standard treatment. In view of the clinical interest, it is surprising to find so few preclinical studies on trimodality treatment. Although little information is available on the doses of the modalities and the treatment sequence resulting in the largest degree of synergistic interaction, the results from in vivo and in vitro preclinical studies support the use of trimodality treatment for cancer patients. Animal studies show an improvement in treatment outcome after trimodality treatment compared with mono- and bimodality treatment. Studies in different human tumour cell lines show that a synergistic interaction can be obtained between hyperthermia, cisplatin and radiation and that this interaction is more likely to occur in cell lines which are more sensitive to cisplatin.

Cell survival and radiosensitisation: Modulation of the linear and quadratic parameters of the LQ model

“…Translocation of the Mre11 DSB repair protein from the nucleus to the cytoplasm has also been implicated (106,111). However, disappearance of Mre11 protein foci at the sites of irradiation-induced DNA DSBs was not observed by pre-incubation of cells at 41˚C (24,27). A role for mitotic catastrophe, occurring as a result of G2/M checkpoint abrogation, has also been suggested (112).…”

“…(40-42˚C) to increase radiosensitivity of human tumour cells has been shown to be cell line-dependent (8,26,(100)(101)(102)(103)(104)(105). In a study by Xu et al, pre-treatment of cells at 41.1˚C for 1 h did not induce radiosensitisation, whereas treatment for 2 h or more resulted in radiosensitisation in the HT-resistant but not in the HT-sensitive cell line (106).…”

“…Cisplatin-based chemoradiotherapy has become standard treatment for, among others, locally advanced cervical carcinoma (30) and locally advanced non-small-cell lung cancer (NSCLC) (31). There have been numerous studies on the radiation-sensitising effect of cisplatin; however, the results vary from a clear cisplatin-induced radiosensitisation (24,25,(32)(33)(34) to a merely additive effect on cell survival (35). Cisplatin and radiation share a common cellular target, DNA (36).…”

“…Nonetheless, satisfactory results have been obtained in locally advanced cervical cancers treated with radiotherapy plus mild HT <43˚C (13). Mild temperatures may have more subtle effects than high temperatures, such as tumour reoxygenation (23)(24)(25)(26). We recently discovered that mild HT (42˚C for 1 h) transiently breaks down the BRCA2 protein (27).…”

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

“…While radiosensitisation by increased perfusion and reoxygenation [43,44] can be observed already at 39 C, the effect increases substantially with increasing temperature with more direct radiosensitisation due to the inhibition of DNA damage repair machinery [45][46][47]. Also chemosensitisation starts at relatively low temperatures for many chemotherapy compounds, including drugs frequently used in pancreatic cancer, such as gemcitabine and fluorouracil [48][49][50][51]. For other drugs, the effect appears to be additive and only effective at higher temperatures [32].…”