Avoiding Pitfalls in Thermal Dose Effect Relationship Studies: A Review and Guide Forward

Abstract

The challenge to explain the diffuse and unconclusive message reported by hyperthermia studies investigating the thermal dose parameter is still to be unravelled. In the present review, we investigated a wide range of technical and clinical parameters characterising hyperthermia treatment to better understand and improve the probability of detecting a thermal dose effect relationship in clinical studies. We performed a systematic literature review to obtain hyperthermia clinical studies investigating the associations of temperature and thermal dose parameters with treatment outcome or acute toxicity. Different hyperthermia characteristics were retrieved, and their influence on temperature and thermal dose parameters was assessed. In the literature, we found forty-eight articles investigating thermal dose effect relationships. These comprised a total of 4107 patients with different tumour pathologies. The association between thermal dose and treatment outcome was the investigated endpoint in 90% of the articles, while the correlation between thermal dose and toxicity was investigated in 50% of the articles. Significant associations between temperature-related parameters and treatment outcome were reported in 63% of the studies, while those between temperature-related parameters and toxicity were reported in 15% of the studies. One clear difficulty for advancement is that studies often omitted fundamental information regarding the clinical treatment, and among the different characteristics investigated, thermometry details were seldom and divergently reported. To overcome this, we propose a clear definition of the terms and characteristics that should be reported in clinical hyperthermia treatments. A consistent report of data will allow their use to further continue the quest for thermal dose effect relationships.

Keywords: hyperthermia; hyperthermia heating systems; reporting guidelines; thermal dose effect relationships; thermometry.

Figure 1

Flow chart indicating the study selection procedure according to PRISMA statement [28].

Figure 2

Schematic illustration of the difference between temperature probes and sensors for the pelvic region. The number of probes is three and the number of sensors 14. The number of sensors per probe ranges between four and five.

Figure 3

Number of patients included in the review per tumour type.

Figure 4

Overview of published studies on thermal dose effect relationships from 1985 to the present separated into superficial HT (breast tumours) and deep HT. Both treatment outcome and toxicity endpoints are shown: (a) reported association of thermal dose with outcome for superficial HT in breast tumours and (b) for deep HT; (c) reported association of thermal dose with toxicity for superficial HT toxicity in breast tumours and (d) deep HT.

Figure 4

Overview of published studies on thermal dose effect relationships from 1985 to the present separated into superficial HT (breast tumours) and deep HT. Both treatment outcome and toxicity endpoints are shown: (a) reported association of thermal dose with outcome for superficial HT in breast tumours and (b) for deep HT; (c) reported association of thermal dose with toxicity for superficial HT toxicity in breast tumours and (d) deep HT.

Figure 5

Heatmaps showing the relative frequency of the combination of (a) HT treatment vs. HT system, (b) thermometry technology vs. HT system, (c) invasive thermometry placement vs. HT system, and (d) thermometry technology vs. invasive thermometry placement. (MW: microwave, US: ultrasound, RF: radiofrequency and C: capacitive).

Figure 5

Heatmaps showing the relative frequency of the combination of (a) HT treatment vs. HT system, (b) thermometry technology vs. HT system, (c) invasive thermometry placement vs. HT system, and (d) thermometry technology vs. invasive thermometry placement. (MW: microwave, US: ultrasound, RF: radiofrequency and C: capacitive).

Figure 6

Number of articles reporting the number of probes and sensors for (a) invasive thermometry and (b) superficial thermometry.

Figure 7

Temperature parameters as a function of the number of invasive probes (a) and invasive sensors (b).

Figure 8

Heatmap showing the association of clinical outcome with temperature and thermal dose parameters in terms of the number of patients. Brackets correspond to the number of studies. CR: complete response; DFS: disease-free survival; DSS: disease-specific survival; RFS: relapse-free survival; LC: local control; pCR: pathologic complete response; AUC: area under the curve; SAR: specific absorption rate; Tmin: minimum temperature; Tmax: maximum temperature; T90/T50: temperatures exceeded by 90%/50% of the measured temperature points; CM T90 cumulative minutes T90; CEM43: cumulative minutes at 43 °C.