includes cancers of lip, oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, salivary glands and thyroid; Data as on 12 September 2021 [1].

#### *1.2. Hyperthermia as a "Potential Game-Changer"*

Loco-regional hyperthermia (HT) or thermotherapy, at 40–44 ◦C, has been shown to be a potent radiosensitizer, a chemosensitizer and an immunomodulator with no significantly added side effects [3–5]. HT sensitizes the hypoxic tumour cells and inhibits the repair of RT- and/or CT-induced DNA damage. In addition, cells in radioresistant "S" phase are heat sensitive [3]. Furthermore, thermoradiobiologically, HT has been shown to impart high LET properties to low LET proton or photon beams [6]. The addition of HT to photons creates a radiobiological advantage in tumours akin to fast beam neutrons. The physiological vasodilation at temperatures of 39–45 ◦C allows rapid heat dissipation from normal tissues, thereby sparing the normal tissues from HT-induced morbidity. On the contrary, the chaotic and relatively rigid tumour vasculature results in heat retention leading to higher intratumoural temperatures. Consequently, the high LET attributes of HT with photon radiations are mostly limited to the confines of the heated tumour, while the normothermic normal tissues get irradiated with low LET photons. HT thereby augments photon therapy by conferring therapeutic advantages of high LET radiations to the tumours akin to neutrons, while the 'heat-sink' effect spares the normal tissues from thermal radiosensitization. Thus, photon thermoradiotherapy imparts radiobiological advantages selectively to tumours analogous to neutrons without exaggerating normal tissue morbidities.

*1.1. Cancer Status in Low-Middle-Income Group Countries* 

**1. Introduction** 

**Figure 1.** Age-standardized rates of (ASR) for incidence and mortality for (**a**,**b**) breast cancer (**c**,**d**) cervical cancer and (**e**,**f**) head and neck cancers, respectively in low-middle-income group countries. Based on data from Global Cancer Observatory [1]. **Figure 1.** Age-standardized rates of (ASR) for incidence and mortality for (**a**,**b**) breast cancer (**c**,**d**) cervical cancer and (**e**,**f**) head and neck cancers, respectively in low-middle-income group countries. Based on data from Global Cancer Observatory [1].

**Keywords:** low-middle-income group countries; cancer; hyperthermia; radiotherapy; chemotherapy; recurrent breast cancers; cervical cancer; head and neck cancers; cost-effective; meta-analysis

According to the Global Cancer Observatory of the World Health Organization (WHO), the total cancer incidence estimated in 2020 was 19.3 M and is expected to rise to 24.1 M in 2030 [1]. In 2020, 11.4 M (59%) of these cases were reported in the low-middleincome countries (LMICs) where the cancer burden is projected to escalate to 14.6 M (+28.2%) and 17.9 M (+56.8%) by 2030 and 2040, respectively. Of the 11.4 M cancer cases in LMICs, presently, cancers of breast, cervix and head and neck regions combined constitutes around 3 M (26.2%) of cases. Furthermore, the cancers in these sites in LMICs constitute 61.1%, 88.1% and 71.8% of the global cancers, respectively (Table 1). In view of the advanced stages of their presentation, most of these cases are inoperable. Thus, radiotherapy (RT) and/or chemotherapy (CT) forms the mainstay of their treatment, resulting in a %mortality/incidence at 36%, 58.7% and 38.2% in cancers of the breast, cervix and head and neck, respectively in LMICs (Figure 1, Table 1). Certainly, there is a need to explore other cost-effective options to improve these treatment outcomes in LMICs [2].

Accordingly, HT could be an effective therapeutic modality in conjunction with RT and/or CT. Moderate HT, as defined by the Kadota Forum in 2008, is elevation of the tumour temperature between 39 ◦C and 45 ◦C [7]. The biological and physiological mechanisms involved in HT at 38–45 ◦C has been very aptly summarized by van Rhoon [8]. The thermodynamic changes are initiated at around 38 ◦C and results in a gradual increase in tumour blood flow and subsequent oxygenation while the thermoradiobiological mechanisms lead to direct cell kill, thermal sensitization and inhibition of DNA repair between 39 ◦C and 45 ◦C. Thus, at the usual clinically achievable temperature of 40–42 ◦C, HT could lead to appreciable radiosensitization, chemosensitization and immunomodulation along with RT ± CT.

Incorporating HT along with the standard therapeutic modalities, namely RT and/or CT, could thus be expected to augment therapeutic outcomes through the multifaceted actions of HT [3,4]. In LMICs, most patients present in relatively locally advanced stages, thereby limiting the role of primary surgical option. Thus, RT and/or CT forms the mainstay of management of these locally advanced tumours—namely of head and neck, cervix and breast. The treatment needs to be tolerable as patients usually have compromised nutritional status, especially in LMICs. In addition, due to limited health insurance coverage, most patients may have to bear the cost of their treatment through out-of-pocket resources. All these factors, enforces one to consider cost-effective strategies that are also tolerable with low acute and late morbidities. HT, a safe modality, with limited toxicities, and a known potentiator of RT and CT could thus be a possible therapeutic addendum in clinical settings in LMICs. The present report summarizes the available clinical evidence to justify the inclusion of HT in the management of these common cancers in LMICs along with RT ± CT. As evident, HT could indeed emerge as a potential game-changer by improving the therapeutic outcome in the common cancers prevalent in LMICs.

#### **2. Locally Advanced Breast Cancers: Scope for Improvement with Hyperthermia**

Locally advanced breast cancers (LABC) are a fairly common problem in LMICs. Most patients present in an advanced stage where primary surgical intervention is usually not feasible. Thus, patients are usually subjected to neoadjuvant chemotherapy (NACT) to enable tumour downstaging followed by mastectomy. Most CT drugs exhibit thermal synergism by (a) increasing the cellular uptake of drugs, (b) increased oxygen radical production, (c) increasing DNA damage, and (d) inhibiting chemotherapeutic-induced DNA damage [9–11]. HT inflicts oxidative damage and/or strand cross links, as well as single or double strand DNA breaks, along with CT agents, namely adriamycin, cyclophosphamide, 5-flurouracil and taxanes commonly used as NACT agents for LABC. Further, HT also interferes with the various DNA repair process involving excision repair, non-homologous end joining and/or homologous recombination [9,11].

#### *Clinical Outcomes with Hyperthermia in Locally Advanced Breast Cancers*

In a recently reported randomized clinical trial in stages IIB-IIIA breast cancers, patients treated with NACT (adriamycin, cyclophosphamide, 5-flurouracil) with loco-regional HT using 27.1 MHz, experienced a significant reduction in both primary tumour (+15.9%, *p* = 0.034) and axillary lymph nodes (+14.1%, *p* = 0.011) compared to those treated with NACT alone [12]. Further, a higher proportion of patients underwent breast conservative surgery (+13.6%) with NACT + HT following appreciable tumour regression. A significantly improved overall survival at 10-year was also evident in patients treated with NACT + HT (*p* = 0.009).

In a phase I/II study, Vujaskovic et al. [13], evaluated the safety and efficacy of a NACT with paclitaxel, liposomal doxorubicin and HT in LABC. A combined response rate of 72% was reported at the end of NACT with four of the 43 patients achieving a complete response (CR). A 4-year disease-free and overall survival rate of 63% and 75% were attained, respectively.

HT has been reported to increase the systolic blood flow in breast tumours by about 3.5 times compared to pre-HT blood flow [12].

Thus, NACT + HT could be a viable option for LABC and the consequence of its effects on the key outcomes need to be examined systematically in future studies. These should also incorporate a detailed histopathological evaluation to explore HT-induced immunomodulation.

#### **3. Recurrent Breast Cancers and Other Cancers: Scope for Improvement with Hyperthermia**

Locoregional recurrence in breast cancers has been reported in one-third of the patients with 80% of these recurrences evident within the first 5 years of primary treatment [14]. Although surgery is the preferred initial option, its role is restricted mostly to operable lesions. The efficacy of CT is yet to be established as evident from a Cochrane review [15]. In an open label randomized study, the efficacy of chemotherapy was limited only to resected oestrogen receptor negative local recurrences [16]. RT alone has been tried in several studies. However, in patients with previously irradiated chest wall, reirradiation (ReRT) with high ReRT doses could lead to a higher risk of radiation-induced normal tissue morbidity depending on the organs at risk, previous dose of irradiation, total RT dose, dose/fraction and the time interval between the first and proposed ReRT.

#### *Clinical Outcomes with Hyperthermia in Recurrent Breast Cancers*

HT, being a potent radiosensitizer, has been used in various clinical studies along with RT as thermoradiotherapy (HTRT) [14]. These include both phase II single arm and phase III randomized control studies. Variable RT doses (24–60 Gy), dose/fraction (1.8–4 Gy/fr) have been explored. HT has been delivered with either microwaves or radiofrequencies (8–2450 MHz) as one to two weekly sessions (total number of sessions, mean: 6.3 ± 2.7) with variable sequences of HT and RT (both before and after RT), based on the institutional

protocols and availability of HT equipment. An average temperature of 42.5 ◦C was attained with HT of 30–90 min duration. ± 2.7) with variable sequences of HT and RT (both before and after RT), based on the institutional protocols and availability of HT equipment. An average temperature of 42.5 °C

HT, being a potent radiosensitizer, has been used in various clinical studies along with RT as thermoradiotherapy (HTRT) [14]. These include both phase II single arm and phase III randomized control studies. Variable RT doses (24–60 Gy), dose/fraction (1.8–4 Gy/fr) have been explored. HT has been delivered with either microwaves or radiofrequencies (8–2450 MHz) as one to two weekly sessions (total number of sessions, mean: 6.3

*Cancers* **2022**, *14*, x 5 of 13

*Clinical Outcomes with Hyperthermia in Recurrent Breast Cancers* 

5.2%, respectively.

Oldenberg et al. [17] recently reported the efficacy of ReRT with HT in 196 patients of unresectable locoregional recurrent breast cancer en cuirasse who had received a prior RT of 50 Gy. ReRT was delivered as 8 fractions of 4 Gy each or 12 fractions of 3 Gy each along with locoregional HT once or twice a week. An overall clinical response of 72% with a CR of 30% was reported. was attained with HT of 30–90 min duration. Oldenberg et al. [17] recently reported the efficacy of ReRT with HT in 196 patients of unresectable locoregional recurrent breast cancer en cuirasse who had received a prior RT of 50 Gy. ReRT was delivered as 8 fractions of 4 Gy each or 12 fractions of 3 Gy each along with locoregional HT once or twice a week. An overall clinical response of 72% with

A meta-analysis evaluated the efficacy of HTRT over RT alone in recurrent breast cancers [14]. This included 34 studies of which eight were 2-arm comparative trials (*n* = 627 patients) while 26 pertained to single arm studies (*n* = 1483 patients). In the 2-arm studies, a CR of 60.2% vs. 38.1% was evident with HTRT vs. RT alone (odds ratio: 2.64, *p* < 0.001). The risk difference in favour of HTRT was 0.22 (*p* < 0.001) (Figure 2). In the 26 single arm studies, 63.4% attained CR with HTRT. Further, even in 779 patients who had been previously irradiated, a 66.6% CR was documented with a mean ReRT dose of 36.7 Gy (SD: ±7.7 Gy). Mean acute and late grade III/IV toxicities were reported as 14.4% and 5.2%, respectively. a CR of 30% was reported. A meta-analysis evaluated the efficacy of HTRT over RT alone in recurrent breast cancers [14]. This included 34 studies of which eight were 2-arm comparative trials (*n* = 627 patients) while 26 pertained to single arm studies (*n* = 1483 patients). In the 2-arm studies, a CR of 60.2% vs. 38.1% was evident with HTRT vs. RT alone (odds ratio: 2.64, *p*  < 0.001). The risk difference in favour of HTRT was 0.22 (*p* < 0.001) (Figure 2). In the 26 single arm studies, 63.4% attained CR with HTRT. Further, even in 779 patients who had been previously irradiated, a 66.6% CR was documented with a mean ReRT dose of 36.7 Gy (SD: ±7.7 Gy). Mean acute and late grade III/IV toxicities were reported as 14.4% and



**Figure 2.** Forest plots depicting the risk difference for complete response with radiotherapy (RT) with hyperthermia (HT) versus RT alone in recurrent breast cancers, locally advanced cervical cancer (stages IIB-IVA) and locally advanced head and neck cancers (stages III/IV). Data extracted from Datta et al. [14,18,19] and replotted. Addition of hyperthermia to radiotherapy favours the outcome compared to radiotherapy alone in all sites with a risk difference of 23% (*p* < 0.001). (Q test: test for heterogeneity; df: degree of freedom and ns: not significant). For citations of the studies listed, please refer to [14,18,19]. **Figure 2.** Forest plots depicting the risk difference for complete response with radiotherapy (RT) with hyperthermia (HT) versus RT alone in recurrent breast cancers, locally advanced cervical cancer (stages IIB-IVA) and locally advanced head and neck cancers (stages III/IV). Data extracted from Datta et al. [14,18,19] and replotted. Addition of hyperthermia to radiotherapy favours the outcome compared to radiotherapy alone in all sites with a risk difference of 23% (*p* < 0.001). (Q test: test for heterogeneity; df: degree of freedom and ns: not significant). For citations of the studies listed, please refer to [14,18,19].

Thus, based on the randomized studies and meta-analysis, HT along with RT appears to be an effective and safe palliative modality in recurrent breast cancers. One could expect Thus, based on the randomized studies and meta-analysis, HT along with RT appears to be an effective and safe palliative modality in recurrent breast cancers. One could expect a CR with HTRT in nearly two-third of the patients. This is around 22% higher than that with RT alone.

In line with the evidence of role of HT along with RT in recurrent breast cancers, this could be also extended to recurrent tumours of head and neck, cervix and other sites, especially those which have been preirradiated. As seen in recurrent breast tumours, a moderate dose of RT along with a few fractions of HT could be systematically investigated for recurrent tumours in other sites.

#### **4. Locally Advanced Cervical Cancer: Scope for Improvement with Hyperthermia 4. Locally Advanced Cervical Cancer: Scope for Improvement with Hyperthermia**

a CR with HTRT in nearly two-third of the patients. This is around 22% higher than that

In line with the evidence of role of HT along with RT in recurrent breast cancers, this could be also extended to recurrent tumours of head and neck, cervix and other sites, especially those which have been preirradiated. As seen in recurrent breast tumours, a moderate dose of RT along with a few fractions of HT could be systematically investigated for

*Cancers* **2022**, *14*, x 6 of 13

with RT alone.

recurrent tumours in other sites.

Of all the cervical cancer reported globally in 2020, LMICs account for 88.1% of all cases and 91.4% of all mortalities [1] (Figure 1, Table 1). Thus, the %mortality/incidence in LMICs is estimated at 58.7%. This could be attributed to presentation in most patients in LMICs as locally advanced cervical cancer (LACC). Following the National Cancer Institute guidelines in 1992 [20], chemoradiotherapy (CTRT) using cisplatin as single or in combination is the most common therapeutic intervention in LACC. In a meta-analysis from 14 randomized clinical trials which included 2445 patients, CTRT has been shown to improve the CR (+10.2%, *p* = 0.027), locoregional control (+8.4%, *p* < 0.001) and overall survival (+7.5%, *p* < 0.001) over RT alone [21]. Thus, even though CTRT has shown to improve outcomes over RT alone, it appears that there could still be scope to explore for a possible improvement. Of all the cervical cancer reported globally in 2020, LMICs account for 88.1% of all cases and 91.4% of all mortalities [1] (Figure 1, Table 1). Thus, the %mortality/incidence in LMICs is estimated at 58.7%. This could be attributed to presentation in most patients in LMICs as locally advanced cervical cancer (LACC). Following the National Cancer Institute guidelines in 1992 [20], chemoradiotherapy (CTRT) using cisplatin as single or in combination is the most common therapeutic intervention in LACC. In a meta-analysis from 14 randomized clinical trials which included 2445 patients, CTRT has been shown to improve the CR (+10.2%, *p* = 0.027), locoregional control (+8.4%, *p* < 0.001) and overall survival (+7.5%, *p* < 0.001) over RT alone [21]. Thus, even though CTRT has shown to improve outcomes over RT alone, it appears that there could still be scope to explore for a possible improvement.

#### *Clinical Outcomes with Hyperthermia in Locally Advanced Cervical Cancer Clinical Outcomes with Hyperthermia in Locally Advanced Cervical Cancer*

HT has also been used along with RT in several randomized clinical trials in LACC. The outcomes as evident on meta-analysis between HTRT vs. RT, shows a distinct improvement with HTRT in terms of CR at the end of treatment and loco-regional control of 22% (*p* < 0.001) and 23% (*p* < 0.001), respectively (Figure 3) [18]. A non-significant survival advantage of 8.4% with HTRT was also noted without any significant escalation of acute or late morbidities with HT added to RT. Even when HT was used with CTRT, the risk difference from three randomized clinical trials (total patients = 738) for local control and overall survival showed an advantage with HTCTRT over CTRT by 10.1% (*p* = 0.03) and 5.6% (*p*: ns), respectively [22,23] (Figure 3). HT has also been used along with RT in several randomized clinical trials in LACC. The outcomes as evident on meta-analysis between HTRT vs. RT, shows a distinct improvement with HTRT in terms of CR at the end of treatment and loco-regional control of 22% (*p* < 0.001) and 23% (*p* < 0.001), respectively (Figure 3) [18]. A non-significant survival advantage of 8.4% with HTRT was also noted without any significant escalation of acute or late morbidities with HT added to RT. Even when HT was used with CTRT, the risk difference from three randomized clinical trials (total patients = 738) for local control and overall survival showed an advantage with HTCTRT over CTRT by 10.1% (*p* = 0.03) and 5.6% (*p*: ns), respectively [22,23] (Figure 3).



**Figure 3.** Forest plots depicting the risk difference in locally advanced cancer cervix for (**a**) local disease control and (**b**) overall survival with chemoradiotherapy (CTRT) with hyperthermia (HT) versus CTRT alone. Data from Minnaar et al. [23] has been added to the meta-analysis from Yea et al. [22] and replotted. The risk difference for local failure with HT added to CTRT reduces by 10.1% (*p* = 0.03) while the overall survival improves by 5.6% (*p* = 0.07). (ns: not significant). For citations of the studies listed, please refer to [22,23].

Network meta-analysis, which provides the highest level of clinical evidence, was reported in LACC, in which all the 13 different therapeutic approaches were evaluated from 49 clinical trials totalling 9894 patients [24]. The surface under cumulative ranking curve (SUCRA) estimates provide an objective assessment and ranking of the locoregional control, overall survival, acute and late morbidity. The SUCRA values ranked all the 13 different strategies used in randomized clinical trial settings. Incidentally, the top two approaches evident on SUCRA values were HTRT and HTCTRT in LACC (Figure 4). Network meta-analysis, which provides the highest level of clinical evidence, was reported in LACC, in which all the 13 different therapeutic approaches were evaluated from 49 clinical trials totalling 9894 patients [24]. The surface under cumulative ranking curve (SUCRA) estimates provide an objective assessment and ranking of the locoregional control, overall survival, acute and late morbidity. The SUCRA values ranked all the 13 different strategies used in randomized clinical trial settings. Incidentally, the top two approaches evident on SUCRA values were HTRT and HTCTRT in LACC (Figure 4).

**Figure 3.** Forest plots depicting the risk difference in locally advanced cancer cervix for (**a**) local disease control and (**b**) overall survival with chemoradiotherapy (CTRT) with hyperthermia (HT) versus CTRT alone. Data from Minnaar et al. [23] has been added to the meta-analysis from Yea et al. [22] and replotted. The risk difference for local failure with HT added to CTRT reduces by 10.1% (*p* = 0.03) while the overall survival improves by 5.6% (*p* = 0.07). (ns: not significant). For citations of

*Cancers* **2022**, *14*, x 7 of 13

the studies listed, please refer to [22,23].

**Figure 4.** Surface under the cumulative ranking curve (SUCRA) values for endpoints from all studies (1974–2018) in locally advanced cancer cervix. LRC = loco-regional control; OS = overall survival; AM = acute morbidity (grade ≥ 3); LM = late morbidity (grade ≥ 3) (Reproduced with permission from Datta et al. [24]). **Figure 4.** Surface under the cumulative ranking curve (SUCRA) values for endpoints from all studies (1974–2018) in locally advanced cancer cervix. LRC = loco-regional control; OS = overall survival; AM = acute morbidity (grade ≥ 3); LM = late morbidity (grade ≥ 3) (Reproduced with permission from Datta et al. [24]).

Thus, based on the highest levels of clinical evidence obtained through both conventional pairwise and network meta-analysis, HT with either RT or CTRT appears to provide a superior therapeutic benefit even when compared to the standard practice of CTRT in LACC. Moreover, HT has been shown to be safe with no significant additional acute or late morbidity to RT or CTRT. It would therefore be pertinent to incorporate HT in the routine clinical management of LACC along with RT or CTRT. This may help to mitigate the high %mortality/incidence seen in cervical cancer in LMICs. Thus, based on the highest levels of clinical evidence obtained through both conventional pairwise and network meta-analysis, HT with either RT or CTRT appears to provide a superior therapeutic benefit even when compared to the standard practice of CTRT in LACC. Moreover, HT has been shown to be safe with no significant additional acute or late morbidity to RT or CTRT. It would therefore be pertinent to incorporate HT in the routine clinical management of LACC along with RT or CTRT. This may help to mitigate the high %mortality/incidence seen in cervical cancer in LMICs.

#### **5. Locally Advanced Head and Neck Cancers: Scope of Improvement with Hyperthermia 5. Locally Advanced Head and Neck Cancers: Scope of Improvement with Hyperthermia**

In 2020, 71.8% and 81.5% of all global incidence and mortalities in head and neck cancers were reported in the LMICs [1]. The %mortality/incidence in LMICs for these cancers are estimated at 38.2% (Figure 1, Table 1). As in the cervix, most patients present as locally advanced head and neck cancers (LAHNC), CTRT has been the mainstay of their treatment. CTRT has been shown to improve outcomes in successive reports of the Meta-In 2020, 71.8% and 81.5% of all global incidence and mortalities in head and neck cancers were reported in the LMICs [1]. The %mortality/incidence in LMICs for these cancers are estimated at 38.2% (Figure 1, Table 1). As in the cervix, most patients present as locally advanced head and neck cancers (LAHNC), CTRT has been the mainstay of their treatment. CTRT has been shown to improve outcomes in successive reports of the Meta-analysis of Chemotherapy in Head and Neck (MACH-NC) collaborative group. In their latest update of 107 randomized trials with 19,085 patients published in 2021, a 6.5% absolute benefit at 5 years was demonstrated (hazard ratio: 0.83; 95% CI: 0.79–0.86) [25]. However, this benefit reduced with increasing patient age and poor performance status.

#### *Clinical Outcomes with Hyperthermia in Locally Advanced Head and Neck Cancer*

In LMICs, patients with LAHNC are often in poor performance status due to inadequate nutritional intake. This could have a bearing on the outcomes with CTRT. HT has been used with RT and outcomes compared with RT alone. In a meta-analysis of six clinical trials comprising 451 cases of LAHNC, HTRT improved the overall CR by 25.5% over RT alone (*p* < 0.0001) [19] (Figure 2). Acute and late morbidities appear similar.

The positive outcomes of HTCTRT in LACC, which also share a similar histology with LAHNC, should encourage patients to be recruited for phase III randomized trial with HTCTRT vs. CTRT alone. However, one of limitations could be lack of a proper HT unit for head and neck region that would allow adequate heating and monitoring of HT during individual treatment session. A dedicated HT delivery system working at 433 MHz–the HYPERCollar (Sensius, Rotterdam, The Netherlands) fills in the long-standing gap for a site-specific HT for LAHNC [26–32]. The system initially had 12 antennas, which was later upgraded to 20 antennas. Presently, an MR-compatible version of this applicator is being used within a 1.5 T MR system. This would allow online monitoring of the temperature using non-invasive thermometry with the proton resonance frequency shift method [33,34]. In addition, model-based and other new MR-thermometry temperature reconstruction methods are emerging which are quite promising [35–37]. The unit is currently being validated in clinics for HT delivery in head and neck regions [38].

Thus, LAHNC provides yet another common site in which HT, along with RT or CTRT, could be expected to improve therapeutic outcomes without any significant added toxicities. It is therefore highly desirable that HT should be evaluated systematically in LAHNC. As LMICs harbour more than two-thirds of global head and neck cancers, these patients need to be included in single/multicentric clinical trials for evaluating HTCTRT vs. CTRT alone.

### **6. Setting Up a Hyperthermia Treatment Facility in Low-Middle-Income Countries** *6.1. Choice of Hyperthermia Unit for LMICs*

Local HT treatments could be delivered by a host of methods—external HT (radiative or capacitive), local invasive (intraluminal and interstitial), regional perfusion or waterfiltered infra-red [7,39]. Clinical HT is usually delivered using radiofrequency (radiative or capacitive), microwaves (434–915 MHz), ultrasound or infrared (>300 GHz) devices. A detailed technical description of each of these methods is beyond the scope of this manuscript. Readers may like to refer to the European Society for Hyperthermia Oncology (ESHO) guidelines that also gives a detailed descriptions of these devices for use in clinics [40–43]. However, due to different heating patterns in depth, the choice of equipment, especially in a resource constraint situation, should preferably be based on the type of common tumours prevalent in the geographical area to be catered by the institution. Even the instrument design and the choice of frequencies of the radiative or capitative systems would need to be selected based on the tumour site and its depth that would be commonly treated by a centre [44]. In addition, the availability of trained personnel for HT treatment delivery, thermometry systems for online temperature monitoring, and the resources allocated, need to be considered before planning to set up such a facility. Presently, HT is not available in most LMICs, and therefore, all these factors would have to be carefully weighed before one launches into such a programme.

Radiofrequency capacitive systems operating at 27.1 MHz are cheap and are commonly used in most of the physiotherapy centres in LMICs as a short-wave diathermy. These units are based on plane-wave matching, in which the antenna's plane-parallel plates are tuned as per the standard antenna-tuning method [45]. The target tissue placed between the condenser plates act as a capacitor to store electrical charge, resulting in local heating of the tissue. Heat is induced by the resulting currents and is directed toward the smallest electrode [44,46]. Capacitive heating creates high power densities around the bolus edges, but one needs to be careful due to its preferential heating in the subcutaneous fat layer. This may be of special relevance to obese patients with considerable subcutaneous fat.

Thus, these units need a circulatory water bolus to have adequate skin cooling. The operation of the unit is relatively simple and technical staff can be easily trained on these units compared to the other state-of-the-art commercially available HT units that are based on radiative/microwave technologies, some of which could also be compatible with MRI thermometry. However, fibreoptic single or multi-sensor radiofrequency immune thermometry probes or thermocouples are required for continuous temperature monitoring. Additional components for thermal simulation and treatment planning supported by quality assurance needs to be introduced for a better temperature assessment in the heated volumes. It should be reasonably feasible to treat the common tumour sites in LMICs– LAHNC, LABC and LACC using 27.1 MHz, after incorporating a circulatory water bolus for surface skin cooling and thermometry for temperature monitoring. However, the 27.1 MHz capacitive heating device would not allow non-invasive thermometry as feasible with some of the MR-compatible versions of HT delivery currently available commercially (HYPERCollar from Sensius and BSD-2000 3D/MR from Pyrexar Medical, Salt Lake City, UT, USA).

Capacitive heating using 27.1 MHz radiofrequency has been used clinically for HT in some clinical studies [12,47] with satisfactory outcomes. As discussed earlier, the recently reported randomized phase III trial NACT + HT vs. HT in stages IIA-IIIB was conducted using 27.1 MHz in 200 patients [12]. This had resulted in a significant favourable outcome for patients treated with NACT + HT in terms of the objective response rate, the proportion of women eligible for breast-conserving and reconstructive surgery and the 10-year overall survival rates compared with NACT alone. The objective response at the primary site was reported to be higher by 15.9% with HT + NACT compared to NACT alone (*p* = 0.034). Correspondingly in the lymph nodes, the response was higher by 14.1% (*p* = 0.011). Computer-assisted planning helped to select a personalized distribution of the magnetic, electric and thermal fields generated by the unit.

#### *6.2. Cost Computations and Its Implications for a Hyperthermia Setup in LMICs*

HT units cost a fraction of the RT units and is a one-time investment with minimal recurring costs. These usually have a working life of 10 years. Unlike RT, the daily patient throughput is lower as each treatment may take around 90 min. In an 8 h working day, four to five patients can be treated/day/unit, that is, 20–25 patients/week, as HT is usually delivered once or twice a week. Thus, 170–325 patients/year could be treated with HT, if delivered once a week for 4–6 weeks. This may go down to 85–162 patients, if twice a week HT treatment scheduled is adopted by a department [3].

Thus, a centre may need to compute the break-even point (BEP) and % return on investment (%ROI) following capital investment to set up a HT facility. Assuming, the capital cost to set up a HT unit is "C" USD, number of patients treated with HT per year as "N" and user cost as "U" USD, the BEP would be

$$\text{BEP} = \frac{\text{C}}{\text{NU}} \text{ (in years)}.\tag{1}$$

Assuming that the HT unit has a working life of 10 years, the income generated in the post-BEP period would be estimated as,

$$\text{Income generated in the post} - \text{BERT period } = \left(10 - \frac{\text{C}}{\text{NU}}\right) \times \text{NU}.\tag{2}$$

Thus,

$$\% \text{ROI} = \frac{\text{Income generated in the post} - \text{BEP period} - \text{Cost of investment}}{\text{Cost of investment}} \times 100 = \frac{10 \text{NU} - 2 \text{C}}{\text{C}} \times 100. \tag{3}$$

Using the above expressions, any department in any country can work out the optimal BEP and %ROI based on the planned capital investment, number of patients estimated to be treated per year and the user cost. The investment for HT unit could vary and depend on

the availability of resources–both financial and human. The corresponding returns would hinge on the patient load, treatment charges, working schedule and departmental policy of weekly or biweekly HT treatments. Cost computations and the %returns on investment (%ROI) need to be computed by individual countries, taking into consideration the above factors, as this may vary from country to country. A cost of EUR 6800 was computed for a series of five treatments in the Dutch Deep Hyperthermia Trial, of which half of the amount was for personnel and one-third for equipment [7]. This is likely to be much lower in LMICs and hence higher returns could be expected. HT could contribute to just a minimal fraction of the cost to the primary treatment in comparison to most standard CT regimes and also immunotherapies, which are being increasingly advocated in many tumour sites. This would not only help to bring down the treatment cost, but also make it more affordable, tolerable and by virtue of improving the therapeutic outcomes, could also improve the quality of life with least morbidity.

#### **7. Conclusions**

Apart from being a cost-effective option, HT provides several tangible and nontangible gains and should be explored in LMICs. The tangible gains would comprise cost of treatment, cost efficacy, response rates, survival, etc. while the nontangible would be more subjective and include wellbeing of the patients, reporting back to work early, supporting their families, etc. It is perhaps time to integrate HT in the therapeutic management of cancers, especially the locally advanced and recurrent tumours as seen in LMICs. Though the efficacy of HT has been discussed in three specific sites of LAHNC, LACC, LABC and recurrent breast cancers which are common in LMICs, the benefit of HT with RT ± CT has been documented in various sites, namely superficial tumours, melanoma, choroidal melanoma, brain tumours, malignant germ cell tumours, soft tissue sarcoma, bone metastases, oesophagus, lung, pancreas, urinary bladder, prostate, rectum, anus and others [3,4,48–50]. Clinical evidence indicates a steady benefit of integrating HT with the standard treatments in most sites.

Thus, based on the above thermoradiobiological rationale and clinical evidence, HT could certainly prove to be a "potential game-changer" when integrated in the therapeutic strategies for various malignancies, especially those with locally advanced tumours as prevalent in LMICs. HT is a cost-effective and a unique multifaceted treatment modality and deserves to be incorporated in the present-day clinical oncology practice and management.

**Author Contributions:** Conceptualization—N.R.D.; methodology—N.R.D., B.M.J., Z.M., S.J. and V.S.; data analysis—N.R.D. and S.D.; writing—original draft preparation, N.R.D., B.M.J., A.R.S., P.K. (Pallavi Kalbande), S.D. and V.S.; review and editing, N.R.D., B.M.J., Z.M., S.D., S.J., A.R.S., P.K. (Pallavi Kalbande), P.K. (Pournima Kale), V.S. and S.B.; clinical perspective, N.R.D., B.M.J., Z.M., A.R.S., P.K. (Pallavi Kalbande), P.K. (Pournima Kale), V.S. and S.B.; supervision and funding, N.R.D. and S.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


## *Review* **Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment**

**Adela Ademaj 1,2, Danai P. Veltsista <sup>3</sup> , Pirus Ghadjar <sup>3</sup> , Dietmar Marder <sup>1</sup> , Eva Oberacker <sup>3</sup> , Oliver J. Ott 4,5 , Peter Wust <sup>3</sup> , Emsad Puric <sup>1</sup> , Roger A. Hälg 1,6, Susanne Rogers <sup>1</sup> , Stephan Bodis 1,7, Rainer Fietkau 4,5 , Hans Crezee <sup>8</sup> and Oliver Riesterer 1,\***


**Simple Summary:** Hyperthermia (HT) is a promising therapeutic option for multiple cancer entities as it has the potential to increase the cytotoxicity of radiotherapy (RT) and chemotherapy (CT). Thermometric parameters of HT are considered to have potential as predictive factors of treatment response. So far, only limited data about the prognostic and predictive role of thermometric parameters are available. In this review, we investigate the existing clinical evidence regarding the correlation of thermometric parameters and cancer response in clinical studies in which patients were treated with HT in combination with RT and/or CT. Some studies show that thermometric parameters correlate with treatment response, indicating their potential significance for treatment guidance. Thus, the establishment of specific thermometric parameters might pave the way towards a better standardization of HT treatment protocols.

**Abstract:** Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40–43 ◦C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies.

**Citation:** Ademaj, A.; Veltsista, D.P.; Ghadjar, P.; Marder, D.; Oberacker, E.; Ott, O.J.; Wust, P.; Puric, E.; Hälg, R.A.; Rogers, S.; et al. Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment. *Cancers* **2022**, *14*, 625. https://doi.org/10.3390/ cancers14030625

Academic Editor: David Wong

Received: 30 November 2021 Accepted: 19 January 2022 Published: 26 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Keywords:** hyperthermia; thermometric parameters; preclinical data; clinical evidence

#### **1. Introduction**

Hyperthermia (HT) is a clinical treatment for cancer which extraneously and intrinsically heats malignant cells to a temperature of 40–43 ◦C for a suitable period of time [1,2]. Heat delivered to tumor tissues can act as a cytotoxic or sensitizing agent to enhance their remission or at least regression by utilizing several biological mechanisms and pleiotropic effects when combined with other conventional cancer treatment techniques, such as radiotherapy (RT) and/or chemotherapy (CT).

The biological effects of HT, which all favor its use in combination with RT and CT, include direct cytotoxicity, radiosensitization, chemosensitization, and immune modulation. HT-induced cell lethality is predominantly a result of conformational changes and the destabilization of macromolecule structures including the disruptions in cell metabolism, inhibition of DNA repair, and triggering of cellular apoptotic pathways [3–6]. The direct HT-induced cell lethality is known to be intrinsically tumor-selective for hypoxic cells [7]. During heating, enhanced blood perfusion in tumor tissues influences the radiosensitizing and chemosensitizing effects of HT by increasing the tumor oxygenation level and local concentration of CT drugs respectively [4,8,9]. Radiosensitization and chemosensitization effects, as well as the inhibition of DNA synthesis and repair, on the molecular level depend on the aggregation of proteins produced by HT-induced denaturation [10]. Moreover, protein unfolding and the intracellular accumulation of proteins trigger molecular chaperones including the heat shock proteins (HSPs) [11]. The release of HSPs and other "immune activating signals" underly the inflammatory and immunogenic responses to HT in combination with RT and/or CT and can promote anti-tumor immunity [12–14]. Exploiting molecular and physiological mechanisms evoked by HT can improve the efficacy of RT and CT. Therefore, HT in cancer treatment is used mainly within the framework of multimodal treatment strategies [3,8].

Multiple preclinical studies have been designed to unravel the relationship between biological mechanisms induced by HT and thermometric parameters as predictors of tumor response [15–20]. The parameters investigated in these studies include the temperature achieved during HT [6,15], heating duration, thermal dose [21], time interval between HT and the other treatment modality [15,22,23], the number of HT sessions [24], and the sequence of treatment modality [15,25,26]. All of these parameters were shown to influence the extent to which HT enhances the effect of RT or CT using cellular assays and in vivo models. In addition to thermometric parameters, the treatment parameters of RT and CT, such as total radiation dose, number of RT fractions, type of chemotherapeutic drug and the number of CT cycles, prescribed for a specific clinical indication, also play a significant role in attaining a therapeutic window with synergistic effects when combined with HT [25,27,28].

The effectiveness of HT combined with RT and/or CT has been investigated in many clinical studies with different tumor types. Unfortunately, to date, there is no consensus on HT delivery when combined with these cancer treatment modalities, resulting in substantial heterogeneity of the HT treatment protocols applied. Any comparison of these studies in terms of outcome should be made with caution in view of this heterogeneity in HT protocols. A good understanding of thermometric parameters and their interpretation is mandatory in this regard. However, there is inconclusive clinical evidence about the relationship of thermometric parameters with both tumor and normal tissue responses to HT in combination with RT and/or CT. The reason for this is that thermometric parameters are inconsistently reported or analyzed in prospective clinical studies and the retrospective analyses are conflicting. For instance, minimum tumor temperature was identified as a prognostic factor in a few studies [29–31]. However, another study showed that different metrics such as temperature achieved in 90% (T90), 50% (T50), and 10% (T10) in the target volume were more strongly correlated with cancer response than minimum achieved temperature [32]. Furthermore, a short time interval between HT and RT was shown to significantly predict treatment outcome in retrospective analyses of cervical cancer patients [22]. However, conflicting results have been also reported [33] which may be attributed to differences in time interval and tumor temperature achieved, and in patient population [34]. Thermal dose has been successfully tested in several clinical trials as a predictor of tumor response to combined RT and HT treatment [35–42]. These did not result in established thresholds for thermal dose for treating different cancer sites, even though European Society for Hyperthermic Oncology (ESHO) guidelines recommend superficial HT maintains T<sup>50</sup> ≥ 41 ◦C and T<sup>90</sup> ≥ 40 ◦C [43]. The concept of a relationship between thermometric parameters with treatment outcome is highly attractive because it could improve the understanding of tumor-specific mechanisms of interaction between HT and RT and/or CT. Defining thermometric parameters is therefore important for a meaningful clinical evaluation of HT treatment outcomes when combined with RT and/or CT.

A limited amount of clinical information is available about the effect of thermometric parameters on treatment response. Increasing awareness of the importance of such parameters on the efficacy of HT combined with other cancer treatments is important, and thus these parameters should be evaluated and reported routinely. Achieving the defined thermometric parameters during HT treatment would further increase the effectiveness of biological mechanisms when combined with RT and/or CT. Future prospective clinical studies should include description of all relevant thermometric parameters to pave the way towards the proper analysis and standardization of thermometric parameters for each clinical indication treated with HT in combination with RT and/or CT.

This work summarizes the evidence underlying thermometric parameters as predictors of treatment outcomes as reported in clinical studies using HT in combination with RT and/or CT for treating different cancer types and emphasizes the need for reference thermometric parameters to improve HT efficacy. For completeness, the findings pertaining to thermometric parameters from preclinical studies are also discussed, to provide comprehensive information about their significance and underlying mechanisms.

#### **2. Materials and Methods**

#### *2.1. Data Sources and Search Strategies*

The literature search included databases of clinicaltrials.gov and pubmed.ncbi.nlm. nih.gov from March to September 2021 and randomized prospective and retrospective clinical studies with specific criteria were identified. The search terms were hyperthermia, cancer treatment, randomized clinical studies, prospective clinical studies, and retrospective clinical studies. Those terms were used mainly to search for the title and abstract. We also found articles which were recommended, suggested, or sent to us on the internet. Additionally, we handsearched the reference lists of the most relevant clinical studies and review articles.

#### *2.2. Inclusion and Exclusion Criteria of Clinical Studies*

This non-systematic review included randomized, prospective, and retrospective clinical studies that recruited patients with cancer who were treated with HT and RT and/or CT. The data from randomized trials are only from the patient group which received HT in combination with either RT and/or CT. Data from the non-HT arm were not extracted.

The main inclusion criteria was the use of either electromagnetic, radiative, or capacitive HT systems, independent of cancer type. Another criterion was more than 10 patients recruited in prospective and retrospective studies. Retrospective studies were only included if analysis of thermometric parameters for HT in combination with RT had been performed.

Clinical studies which used the thermal ablation technique, interstitial-based/modulated electro HT techniques, interstitial RT techniques, high intensity focused ultrasound (HIFU) HT, whole body HT, and studies in pediatric patients were not included in this review. Pilot and feasibility studies were also excluded.

#### *2.3. Data Extraction and List of Variables Included*

The data extracted from the clinical studies contained the following information:


#### *2.4. A Summary of HT Techniques*

The clinical studies included in this review administered HT using externally applied power with electromagnetic–based techniques, such as radiofrequency, microwave, or infrared. These techniques differ with regard to their application to treat superficial or deep-seated tumors, as summarized elsewhere [44].

For superficial tumors, the electromagnetic radiative and capacitive systems are the those used in the clinical trials included in this review. The superficial HT techniques and their application are explained in detail elsewhere [43]. The radiative and capacitive systems differ in the way they are applied in the clinic. A study showed that for superficial cancers, the radiative HT system performs better than capacitive systems in terms of temperature distribution [45]. The commercially available radiative superficial systems are the BSD-500 device (Pyrexar Medical, Salt Lake, UT, USA), the ALBA ON4000 (Alba Hyperthermia, Rome, Italy) and contact flexible microwave applicators (SRPC Istok, Fryazino, Moscow region, Russia). Thermotron RF8 (Yamamoto Vinita Co, Osaka, Japan), Oncotherm (Oncotherm Kft., Budapest, Hungary) and Celsius TCS (Celsius42 GmbH, Cologne, Germany) are examples of commercial capacitive systems used for superficial tumors.

Different HT techniques with unique specifications, characteristics, and limitations are used to treat deep-seated tumors [46]. The ESHO guidelines provide information as to how and when a specific particular HT device should be used to treat deep-seated tumors [46,47]. The radiative HT systems for deep-seated tumors used in clinical trials are the BSD-2000 device (Pyrexar Medical, Salt Lake, UT, USA), the ALBA 4D (Alba Hyperthermia, Rome, Italy), and the Synergo RITE (Medical Enterprises Europe B.V., Amstelveen, The Netherlands), and capacitive systems are Oncotherm (Oncotherm Kft., Budapest, Hungary), Celsius TCS (Celsius 42 GmbH, Cologne, Germany), and Thermotron RF8 (Yamamoto Vinita Co, Osaka, Japan). Another simulation study showed a difference in heating patterns between radiative and capacitive HT for deep-seated tumors [48]. The radiative technique yields more favorable simulated temperature distributions for deep-seated tumors than the capacitive technique.

#### *2.5. Definition of Thermometric Parameters*

In this work, the thermometric parameters were extracted from the selected perspective and retrospective clinical studies. The definitions of these parameters are listed in Table 1.


**Table 1.** Definition of thermometric parameters.

Temperature measurements in the target volume or surrounding tissue are crucial for assessing treatment quality and are represented by temperature metrics. During a HT session, the temperature is usually monitored and recorded using high resistance thermistor probes, fiber optic temperature probes or thermocouples by invasively placing the probes in the target volume or in the vicinity of the target volume [43,46,50]. The ESHO guidelines recommend that after the definition of the tumor volume as a planning target volume, a target point should be defined where the probe is positioned intraluminally or intratumorally [46]. In addition, the guidelines strongly suggest keeping a record of thermometry measurement points within or close to the tumor sites [43]. After completion of the HT session, recorded temperature data during ttreat are evaluated by computing temperature metrics. For instance, Tmax is calculated as the maximum temperature value recorded in the target volume (Table 1). T10, another maximum temperature metric, is computed as the temperature value received by 10% of the target volume [32]. Similarly, the other temperature metrics listed in Table 1 are computed. In current practice, the thermometric parameters and thermal dose are computed by software integrated in the HT systems or using thermal analysis tools such as RHyThM [51].

To illustrate how temperature, tpre and ttreat terms are measured in clinical practice, Figure 1 shows the temperature and heating duration parameters of a patient treated with HT in the radiation oncology center at Cantonal Hospital Aarau (KSA) using BSD-500 system (BSD Medical Corporation, Salt Lake City, UT, USA).

**Figure 1.** Recorded treatment data of a single HT session for a breast cancer patient. Temperature in ◦C and heating duration in minutes are measured non-invasively using four sensors located in close proximity to the tumor tissue. tpre and ttreat of 33 and 60 min respectively according to the KSA clinical protocol are indicated.

The temperature metrics and thermal doses can be also computed by using the data from Figure 1. A decade ago, a new thermal dose entitled "TRISE" was proposed by Franckena et al. [36]. However, this parameter has not yet been evaluated in experimental studies. Another newly proposed thermal dose parameter is the area under the curve (AUC) [49]. In contrast to CEM43◦C and TRISE, AUC is computed without any prior assumptions by summating AUC for the entire treatment session, including tpre and ttreat. Similarly to TRISE, AUC has not yet been investigated in preclinical studies. Another parameter related to HT used in this review is thermal enhancement ratio (TER), defined as 'the ratio between RT dose required to achieve a specific endpoint and RT dose to achieve the same endpoint in combination with HT' [52].

### **3. Evidence for Predictive Values of Thermometric Parameters in Preclinical Studies** *3.1. Heating Temperature*

The responsiveness of a tumor to HT is determined by different heat-induced mechanisms at the cellular level. The oxygenation rate is affected by temperature, as a higher rate was reported at 41–41.5 ◦C in comparison to higher temperature (at 43 ◦C) in rodent tumors, human tumor xenografts, canine, and human tumors [53]. Heating at 40 ◦C potentiated the cytotoxicity of CT drugs in human maxillary carcinoma cells [28], and the cytotoxicity was further increased on heating to 43.5–44 ◦C [54]. In contrast, another preclinical study showed no such dependency at 41–43.5 ◦C [55]. An in vitro study showed that apoptosis in human keratinocytes occurred at temperatures of 39 ◦C and above [56]. However, the majority of studies show synergistic actions of HT with RT and CT at temperatures above 41 ◦C [5,57], leading to the inhibition of DNA repair and chromosomal aberrations, induction of DNA breaks by RT and CT, and protein damage as an underlying molecular event of heat treatment [5,58,59]. To benefit from additive and synergistic effects of HT when combined with RT and/or CT, uniform temperature in the target volume should be delivered during the whole treatment course.

The temperature metrics are used to present the heating temperature achieved during treatment, not only in the target volume, which encompasses the tumor, but also for adjacent healthy tissue. T90, T80, T50, T20, and T<sup>10</sup> are considered to be less sensitive than Tmin, Tavg and Tmax, due to the number and arbitrary positioning of sensors in the tissue. Such temperature metrics can be used to understand the response to heat of various cancer types for a specific duration and, at the same time, the heat-induced effects on surrounding normal tissues. However, except for Tmin and Tmax, most descriptive metrics of temperature have no specific reference values yet (Table 2).



\* According to ESHO guidelines for superficial HT [43].

T<sup>50</sup> and T<sup>90</sup> reference values are defined according to ESHO guidelines for treatment with superficial HT, but not for the deep HT technique. No reference values for temperature metrics are based on experimental data (Table 2), even though temperature distributions can be better controlled in preclinical than in clinical studies. In an in vivo study, no temperature variations were observed in tumors as they were recorded intratumorally [15]. Temperature at a reference value with minor variations (±0.05 ◦C) was reported in a vitro study [60]. In contrast, the temperature data recorded in patients are limited for various reasons. For example, thermistor probes inserted in deep-seated tumors in patients have the potential to cause complications or sometimes are impractical to insert intraluminally or intratumorally [61]. The value of the lowest temperature achieved during HT treatment is shown to have a prognostic role in describing the biological effects of HT. According to an in vivo study, T<sup>90</sup> was a predictive parameter of reoxygenation and radiosensitization effects [62]. An in vitro experiment which investigated the difference in thermal sensitivity between hypoxic and oxic cells demonstrated that direct cytotoxicity induced by HT is more selective to the hypoxic cells [7]. Thus, temperatures required to achieve comparable thermal enhancement effect of HT vary depending on tissue type and characteristics.

#### *3.2. Heating Duration*

Temperature fluctuations, such as a decrease by 0.5 ◦C, have been shown to have a strong effect on the extent of cell kill, which was compensated by doubling the heating duration [6,63]. Therapeutic ratio, defined as the ratio of thermosensitive liposomal doxorubicin delivered to the heated tumor increased from 1.9-fold with 10 min heating to 4.4-fold with 40 min heating [64]. In an in vivo study, TER for mouse mammary adenocarcinoma (C3H) increased with respect to heating exposure longer than 30 min at 41.5 ◦C [15]. A study used mouse leukemia, human cervical carcinoma (HeLa), and Chinese hamster ovary (CHO) cells to demonstrate that the time required to kill 90% of the cells at 43 ◦C varied according to type [65]. The survival data from different tissues were analyzed using the Arrhenius equation to understand the effect of ttreat for different cell types [66]. These analyses showed that the reference ttreat value is set at 60 min when heating constantly at reference temperature (Table 3).

**Table 3.** Reference heating duration parameters for HT.


<sup>1</sup> According to the Arrhenius plot [66].

Heating for longer than 60 min is restricted by thermotolerance, which was observed after 20 min while heating at 43.5 ◦C [67]. In addition, the surviving fraction of asynchronous CHO cells heated to 41.5 ◦C was decreased with increasing ttreat, until the thermotolerance effect appeared [21]. Thermotolerance is activated by different forms of stress including heat exposure for a specific time [68], which depends on the temperature and the amount of HT damage induced [69]. In an experimental study, the effect of thermotolerance was observed using the human tumor cell line (HTB-66) and CHO cells after 4 h of heating at 42.5 ◦C and 3 h of heating at either 42.5 or 43 ◦C [70]. The degree of thermotolerance is determined by cell type, heating temperature, and time of heating including the interval between successive heat treatments [71].

#### *3.3. Thermal Dose*

The relationship between temperature and ttreat was demonstrated experimentally in two preclinical studies, which showed that the same thermal enhancement of ionizing radiation in cells lines was achieved by heating for 7–11 min at 45 ◦C or for 120 min at 42 ◦C [26,72]. It was also shown that different survival rates were obtained when heating asynchronous CHO cells to different temperatures for varying ttreat [66]. These preclinical data showed that heating temperature and ttreat influence thermal damage. The relationship of temperature and ttreat to the biological effects induced by HT is described using the Arrhenius equation, which models the relationship of the inactivation rate in a biological system [21]. This led to the discovery that the relationship between temperature and ttreat depends on the activation energy required to induce a particular HT-induced biological event, such as protein denaturation [59,66]. The thermal dose concept, CEM43◦C, was established to account for the biological effects induced by HT in terms of both temperature and ttreat [21]. More specifically, CEM43◦C calculates the equivalent time of a HT treatment session by correlating temperature, ttreat and inactivation rate of a biological effect induced by heat based on the Arrhenius equation. The reference temperature of 43 ◦C was shown as a breakpoint in the Arrhenius plot with a steeper slope between 41.5 and 43 ◦C in comparison to 43–57 ◦C [66]. The threshold values of CEM43◦C for tissue damage differ for specific tissues as identified in in vivo studies and are reviewed elsewhere [70,73,74]. In addition, these data underline that CEM43◦C is an important parameter that has biological validity to assess the thermal damage in tissues. CEM43◦CT<sup>90</sup> is one of the most frequently used thermal dose descriptors at T90, not only in clinical, but also in experimental settings. In an in vivo study, Thrall et al. [75] showed a relationship between CEM43◦CT<sup>90</sup> and local control in canine sarcomas, but not with CEM43◦CT<sup>50</sup> and CEM43◦CT10. Another in vivo study using breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts showed that at relatively low values of CEM43◦CT90, tumor volumes could be reduced by exposure to heat alone [76]. However, none of the preclinical studies proposed reference values for clinical validation, as shown in Table 4.


**Table 4.** Reference thermal dose parameters for HT.

Although there is no reference threshold value for the CEM43◦C, its efficacy to predict tumor response and local control has been experimentally proven [75,77]. CEM43◦C is considered as a thermal dose parameter with few weaknesses which have been discussed elsewhere [78].

#### *3.4. Number of HT Sessions*

Thermotolerance is an undesirable side effect of HT which renders tumor cells insensitive to heat treatment for 48 to 72 h [79]. Thermotolerance consists of an induction phase, a development phase, and a decay phase. Each of these components may have its own temperature dependence as well as dependence on other factors, such as pH and presence of nutrients [80]. Thermotolerance plays an important role on how HT sessions are scheduled during the treatment course. An in vivo study using C3H mouse mammary carcinoma confirmed that preheating for 30 min at 43.5 ◦C induced thermotolerance for the next heating session [81]. Twice weekly heating to 43 ◦C for 60 min in combination with RT at 3 Gray (Gy) per fraction for 4 weeks was shown to result in a steady state decline in oxygenation level suggesting vascular thermotolerance [82]. In comparison, Nah et al. reported that heating at 42.5 ◦C for 60 min could render the tumor blood vessels resistant to the next heating session after an interval of 72 h [83]. It has also been shown that when HT was delivered daily with RT 5 days a week, no significant thermal enhancement could be detected in comparison to one single HT session, even when heat was delivered simultaneously or sequentially [84]. With the agreement of these findings, Nweek is defined as 1 or 2 sessions separated by at least 72 h (Table 5).

**Table 5.** Reference HT treatment session parameters. *N*: positive constant value.


<sup>1</sup> Depending on RT and CT schedules; <sup>2</sup> Depending on cancer site.

In summary, HT should be delivered once or twice weekly, taking into account the type of cancer, RT fractionation and CT drug scheduling. Due to logistical reasons, the Ntotal usually depends on, the treatment plan for different cancer sites, number of RT fractions or number of CT cycles (Table 5).

#### *3.5. Time Interval Parameter between HT and RT and/or CT*

The tint between HT and RT and/or CT treatment is another parameter that affects sensitization due to time-dependent biological effects and its contribution to thermotolerance.

Recently, an in vitro study of human papillomavirus (HPV)-positive (HPV16<sup>+</sup> , HPV18+) and HPV-negative cell lines that were treated with HT either 0, 2 and 4 h before and after RT showed that the shortest tint resulted in lower cell survival fractions and decreased DNA damage repair [85]. The influence of tint has been investigated in an in vivo study, which reported that TER is greatest when heat and radiation are delivered simultaneously [15]. Unfortunately, simultaneous delivery is currently technically impossible in clinical routine and therefore heat and radiation are usually delivered sequentially. A very short tint of approximately five min is considered as an almost simultaneous application [86]. Dewey et al. concluded that HT should be applied simultaneously or within 5–10 min either side of radiation to benefit maximally from the radiosensitizating effect of heat [6]. TER is decreased faster for the normal cells than for cancerous cells when tint ≤ 4 h between HT and RT [15]. Thus, it can be argued that a slightly longer tint could ensure the sparing of normal tissue from radiosensitization before or after RT. A tint longer than 4 h, no sensitization effects induced by HT were observed [15,85]. The wide range of acceptable tint values reported in experimental studies is from 0 (when CT is delivered during HT) to 4 h (Table 6).

**Table 6.** Reference tint parameter for HT in combination with RT or CT.


In contrast to RT, CT can be given simultaneously or immediately after or before HT [87]. A preclinical study, in which cisplatin and heat were used to treat C3H xenografts, showed that a higher additive effect can be obtained when cisplatin was given 15 min before HT in comparison with an interval longer than 4 h [55].

Furthermore, HT has been shown to sensitize the effects of gemcitabine at 43 ◦C when the drug was given 24 h after heating [88], whereas another study showed an optimal effect when the drug was given 24–48 h before heating [89]. The type of CT agent and its interaction with heat are factors which determine the tint between HT and CT (Table 6).

#### *3.6. Sequencing of HT in Combination with and RT and/or CT*

An additional predictive parameter for the effectiveness of radiosensitization and chemosensitization is the sequencing of heat prior to or after the application of RT or CT. Usually, HT and RT are delivered sequentially but there is no consensus as to the optimal sequence. An in vivo study by Overgaard investigated the impact of sequence and interval between the two modalities on local tumor control and normal tissue damage in a murine breast cancer model and found that the sequence did not have any significant effect on the thermal enhancement in tumor tissues [15]. However, an experimental study using Chinese hamster ovary (HA-1) and mouse mammary sarcoma (EMT-6) cell lines showed that sequencing of radiation and heat altered radiosensitivity for these two cancer cell types [90]. HT before RT showed more thermal enhancement in synchronous HA-1 cell lines and the opposite sequence increased the thermal enhancement in EMT-6 cell lines. Other experimental studies reported no impact of the sequence of RT and HT in V79 cells on thermal enhancement [26,72]. In line with these results, an experimental study with HPV cell lines showed no difference in radiosensitization or cell death when heat was delivered prior or after radiation [85]. Due to conflicting results with regard to the treatment sequencing of HT and RT, additional preclinical mechanistic studies on different cell types are required.

An in vivo study where heat was combined with cisplatin CT showed that simultaneous application of both treatments resulted in prolonged tumor growth delay in comparison with administration of cisplatin after HT [55]. Another study found that simultaneous exposure of human colorectal cancer (HCT116) cells to HT and doxorubicin was more effective than sequential administration because of higher intercellular drug concentrations at 42 ◦C [91]. In conclusion, better insight into the interaction of various CT drugs with HT and RT is required to define the optimal sequencing of specific drugs and RT dose.

#### **4. Evidence for the Predictive Values of Thermometric Parameters in Clinical Studies Combining HT with RT**

Numerous prospective and retrospective clinical studies have been conducted to assess the efficacy of HT in combination with RT for treating superficial and deep-seated tumors. The design of most clinical studies was based on the translation of experimental findings aiming to reproduce benefit of HT when combined with RT.

Tables 7 and 8 show the results of the most important clinical studies. The prospective clinical studies in Table 7 reported improved clinical results, apart from the study by Mitsumori et al. which did not show a significant difference in the primary clinical endpoint of local tumor control between two treatment arms [92]. The underlying reason could have been differences in RT dose prescriptions and missing patient treatment data. Although the study showed a significant difference in progression free survival, this was judged to be not a substantial benefit. The authors stressed the need for internationally standardized treatment protocols for the combination of HT and RT.

In reality, temperature and thermal dose are usually reported as post-treatment data recordings (Tables 2 and 4) to account for temperature homogeneity or sensitivity. Even though temperature cannot always be measured invasively, depending on the location of the tumor, a strong correlation was reported between intratumoral and intraluminal temperatures, suggesting that intraluminal temperature measurements are a good surrogate for

pelvic tumor measurements [50,93]. In addition, retrospective studies showed that a higher intra-esophageal temperature (>41 ◦C) predicts longer overall survival, improved local control and metastasis-free rate [94,95]. The difficulty of performing invasive measurements was illustrated by a randomized phase III study by Chi et al. [96] in which only 3 out of 29 patients with bone metastases had directly measured intratumoral temperature. In the study by Nishimura et al. [97], the HT session was defined as effective if an intratumoral temperature exceeded 42 ◦C for more than 20 min. However, according to the Arrhenius relationship, this is not considered long enough to induce a significant biological effect [21].

Another obstacle during HT is the non-standardized methodology for describing the temporal and spatial variance of temperature fields. Several groups have investigated the correlation between various temperature metrics. The study by Oleson et al. showed that Tmin, tumor volume, radiation dose, and heating technique play significant roles in predicting treatment response for patients treated with RT in combination with HT [29]. In contrast, Leopold et al. reported that the more robust parameters T90, T50, and T<sup>10</sup> are better temperature descriptors and predictors of histopathologic outcome than Tmin and Tmax [32]. The median Tmin, Tmin during the first heat treatment and tumor volume were reported to be factors predictive for the duration of cancer response (Table 7) [98], even though it is considered that skin surface temperature is not representative for superficial tumors and cannot be associated with clinical outcomes [42]. For deep-seated tumors, Tilly et al. reported that Tmax was a predictive treatment parameter for prostate-specific antigen (PSA) control [99]. The relationship of high (Tavg ≥ 41.5 ◦C) and low (Tavg < 41.5 ◦C) tumor temperature with clinical response has been analyzed in a study by Masunaga et al. [100]. They showed that heating the tumor to temperatures of Tavg ≥ 41.5 ◦C for a duration of 15–40 min achieved better tumor down-staging and better tumor degeneration rates [100]. This finding supports the concept that direct cytotoxic effects of HT are enhanced at temperatures higher than 41 ◦C, as suggested in preclinical studies [5,57]. A higher response rate was also reported when tumors were heated with Tavg > 42 ◦C for 3–5 HT sessions [97]. In contrast, a study showed no difference in clinical outcome when patients were treated with mean Tmin = 40.2 ◦C, Tmax = 44.8 ◦C or Tavg = 42.5 ◦C for Ntotal of 2 or 6 [24]. Other studies also reported no impact of Ntotal and Nweek on clinical outcome [40,101]. The contradictory results derived from clinical studies with regard to the predictive power of temperature descriptors and Ntotal are why we did not list reference values for these descriptors in Table 5.

The predictive role of thermal dose has been investigated in both prospective and retrospective clinical studies (Tables 7 and 8). However, there is still no conclusion about the values for thermal dose that should be obtained during HT treatment for maximal enhancement effect. In prospective studies (Table 7), the correlation between thermal dose and treatment outcome is rarely reported. Retrospective studies reported that thermal dose, CEM43◦C, is an adequate predictor of treatment response and its best prognostic descriptor is CEM43◦CT<sup>90</sup> [32,33,36–38,102].



parameters and response

or toxicity.









188



CR rate.





complete response; 2 PR: partial response; 3 PD: progressive disease; 4 LC: local control; 5 CEM42.5 ◦C: cumulative equivalent minutes at reference temperature 42.5 ◦C; 6 OS:overall survival, 7 NC: no change; 8 LRFS: local relapse-free survival; 9 DFS: disease free survival; 10 RR: responserate; 11 LR: local response; 12 pCR: pathological CR; 13 LF: local failure; 14 DM: distant metastasis; 15 RrR: recurrence rate; 16 PSA: prostate specific antigen; 17 DHG: Daniel den Hoed Cancer Center in Rotterdam; 18 MRC: Medical Research Council at the Hammersmith Hospital; 19 ESHO: European Society of Hyperthermic Oncology; 20 PMH: Princess Margaret Hospital/Ontario Cancer Institute; 21 NR: no response; 22 DSS: disease specific survival; 23 HDR-IRT: high dose rate interventional radiotherapy; 24 LDR-IRT: low dose rate interventional radiotherapy.

In a phase III study of the International Collaborative Hyperthermia Group, led by Vernon et al. [113], thermal dose was associated with complete response (CR) in patients treated for superficial recurrences of breast cancer [39]. Another randomized study showed that the best tumor control probability was dependent on thermal dose [106]. Further, retrospective analyses indicate that thermal dose is a significant predictor of different clinical endpoints (Table 8) [33,36]. A few studies did not find such significant relationships between clinical endpoints and thermal dose [103,109,110]. For example, in the prospective study of Maguire et al., a total CEM43◦CT<sup>90</sup> with a threshold above 10 min did not show a significant effect on CR [110]. However, the association of CEM43◦CT<sup>90</sup> with CR was later reported for patients treated with superficial malignant cancers [35]. Similar to the study by Maguire et al., the minimum effective thermal dose was set as 10 CEM43◦CT90. In addition, a test HT session was performed to verify if the tumor was heatable, and a thermal dose of higher than 0.5 CEM43◦CT<sup>90</sup> could be achieved [35,110]. The objective of the study by Hurwitz et al. was to achieve a CEM 43 ◦CT<sup>90</sup> of 10 min, yet the resulting mean of thermal dose for all 37 patients was only 8.4 min [112]. The cumulative minutes T<sup>90</sup> > 40.5 ◦C, defined as 'the time in minutes with T<sup>90</sup> > 40.5 ◦C for the whole Ntotal', with a mean of 179 ± 92 min, together with T<sup>90</sup> and Tmax were reported to correlate with toxicity and prostate specific antigen clinical endpoints [99]. Similarly, Leopold et al. showed that cumulative minutes of T<sup>90</sup> > 40 ◦C is a predictor of treatment endpoints [40]. In retrospective studies, TRISE thermal dose concepts [36] were shown to have a predictive role in treatment response. These retrospective analyses showed that TRISE had a significant effect on local control for a cohort of patients with cervical cancer [33].

The effect of the tint parameter has been only analyzed with respect to treatment endpoints in retrospective studies. The study by van Leeuwen et al. reported that a tint less than 79.2 min between RT and reaching 41 ◦C during HT was associated with a lower risk of in-field recurrences (IFR) and a better overall survival (OS) in comparison to a longer tint [22]. In contrast, another retrospective study showed that neither a shorter tint of 30–74 min nor a longer tint of 75–220 min between RT and the start of HT were significant predictors of local control (LC), disease free survival (DFS), disease specific survival (DSS) or OS [33]. Thus, the optimal tint between HT and RT to achieve a maximal effect on the tumor remains unknown.

Apart from heat-related parameters, the total dose of ionizing radiation and its fractionation in combination with HT has an impact on clinical treatment response [118,119]. Valdagni et al. [103] reported that increasing the total dose of RT appeared to improve clinical response as 71% (5/7) and 90% (9/10) CR rates were observed for patients with nodal metastases of head and neck cancers who received total doses of 64–66 Gy or 66.1–70 Gy, respectively. In addition, it was reported that previously irradiated tumors, which are typically more resistant to ionizing radiation, achieved higher CR rates when treated with combined RT and HT in comparison with RT alone [35].

Furthermore, RT technique has been reported to have a beneficial effect on combined RT and HT treatment outcomes [29]. For example, technological advance such as MRIguided brachytherapy were shown to improve the treatment outcome when RT is combined with HT [36].

The weak, and in part contradictory, evidence from clinical studies clearly shows that further analyses of thermometric parameters are required to define reference values for clinical use. The reported values for thermometric parameters from prospective and retrospective clinical studies (Tables 7 and 8) can be translated into standard references after being tested and validated in prospective clinical trials.








*n*: number of patients assigned to be treated with HT in combination with RT; † : mean value (±standard deviation) or mean value (range); ‡ : median (range); n.r.: not reported; 1 CR: complete response; 2 PR: partial response; 3 SD: stable disease; 4 PD: progressive disease; 5 PTC: pelvic tumor control; 6 DSS: disease specific survival; 7 DFS: disease free survival; OS:overall survival; 9 IFR: in-field recurrence; 10 NC: no change; 11 HDR-IRT: high dose rate interventional radiotherapy; 12 LDR-IRT: low dose rate interventional radiotherapy.

8

with median

radiofrequency-output power.

### **5. Evidence for Predictive Values of Thermometric Parameters in Clinical Studies Combining HT and CT**

The added value of combining CT with HT has been established, not only in in vitro and in vivo studies, but also in clinical studies. Randomized clinical studies, which demonstrate that the combination of CT and HT results in improved clinical outcome in comparison with single modality treatment [122–125], confirm the preclinical findings [126]. The positive prospective and retrospective clinical studies are summarized in Tables 9 and 10 respectively, with a focus on thermometric parameters.

The effectiveness of CT drugs has been enhanced by HT in a variety of clinical situations, such as localized, irradiated, recurrent, and advanced cancers, but only few indications are really promising. Long term outcome data, e.g., regarding the combination of CT with HT for bladder cancer, underline the clinical efficacy of this treatment strategy [125]. Chemosensitization by HT is induced by specifics biological interactions between CT drugs and heat. The increased blood flow and the increased fluidity of the cytoplasmic membrane of the cells induced by HT increase the concentration of CT drugs within malignant tissues. Interestingly, Zagar et al. performed a joint analysis of two different clinical trials and reported no significant correlation between drug concentration and combined treatment effect of CT and HT [127]. However, only a few CT drugs with specific properties (Tables 9 and 10) are good candidates to use with HT. Alkylating agents, nitrosureas, platinum drugs, and some antibiotic classes show synergism with HT, whereas only additive effects are reported with pyrimidine antagonists and vinca alkaloids [59]. For example, heat increases the cytotoxicity of cisplatin, as shown by in vitro and in vivo studies [28,55]. Cisplatin concentration increases linearly with temperatures above 38 ◦C when applied simultaneously [28,128]. Synergy between HT and CT could be obtained at temperatures below 43.5 ◦C in a preclinical study [55]. Similarly, enhanced toxicity has been demonstrated for bleomycin [126,129], liposomal doxorubicin [130], and mitomycin-C [131]. Based on the summary of preclinical data, van Rhoon et al. suggested a CEM43◦C of 1–15 min from heating to 40–42 ◦C for 30–60 min for any free CT drug, including thermos-sensitive liposomal drugs [132].

Lower temperatures might increase the therapeutic window by differential chemosensitization of cancer and normal tissues. In the prospective study of Rietbroek et al. [133] in patients with recurrent cervical cancer treated with weekly cisplatin and HT, three temperature descriptors, T20, T50, and T90, including the time in minutes in which 50% of the measured tumor sites were above 41 ◦C, indicated a significant difference in these parameters between patients who did and who did not exhibit a CR after treatment. However, there was neither a difference in Tmax between responders and non-responders in a cohort of patients with recurrent soft tissue sarcomas treated with CT and HT [134], nor in a cohort of patients with recurrent cervical cancer [135].

In a prospective study of patients treated with CT and HT for recurrent ovarian cancer, no significant relationship of T<sup>90</sup> and T<sup>50</sup> and CEM43◦CT<sup>90</sup> and CEM43◦CT<sup>50</sup> with clinical outcome was found [136]. Similarly, the independency of T<sup>90</sup> and CEM43◦CT<sup>90</sup> was also demonstrated in a retrospective study in soft tissue sarcoma [137]. Although a relationship of thermal dose with treatment response has been reported by Vujaskovic et al. [138], the parameters CEM43◦CT<sup>50</sup> and CEM43◦CT<sup>90</sup> were not statistically different between patients who did or did not respond to the treatment. The low mean value of T<sup>90</sup> =39.7 (33.5–39.8) ◦C reported in this study might be the reason for the non-significant relationship of thermal dose with the clinical endpoint in addition to other factors such as hypoxia and vascularization level of the tumor. The first randomized phase III study that assessed the safety and efficacy of CT in combination with HT also recorded a low (≤40 ◦C) mean value of T<sup>90</sup> = 39.2 ◦C (38.5–39.8 ◦C). However, the thermometric data were not analyzed or reported in correlation with treatment response [123]. Further investigations are required to understand which temperature is needed to achieve a maximum therapeutic effect, according to the type of CT drug and its concentration.


199

not presented)




*n*trial 1 = 18 *n*trial 2 = 11

Trial B: 40–50 LTDL every 21–35 days ×6

min T90: 36.0

patients (10.3%) and grade III:

six patients (20.7%).

•

 No drug dose response relationship was observed between trial A and B. (correlation of thermometric parameters with clinical outcome

not presented)




free survival; 8 PFR: progression free rate; 9 RR: response rate; 10 DFS: disease free survival; 11 QoL: quality of life; 12 NC: no change; 13 LTDL: low temperature liposomal doxorubicin.



*n*: number of patients assigned to be treated with HT in combination withCT; † : mean value (±standard deviation) or mean value (range); ‡ : median (range); 1 CR: complete response; PR: partial response; 3 SD: stable disease; 4 PD: progression disease; 5 ORR: objective response rate; 6 DCR: disease control rate; 7 OS: overall survival; 8 RECIST: Response Evaluation Criteria in Solid Tumors; 9 WHO: world health organization.

2

Based on preclinical studies, the delivery of simultaneous CT and HT is recommended to achieve the greatest chemosensitization effect by HT [55,142]. However, in contrast to experimental results [20,55], most of the prospective studies listed in Table 9 were designed to deliver heat sequentially, and in most studies the CT drugs were administered prior to HT. Despite the fact that a considerable supra-additive or synergistic effect can be achieved by the simultaneous delivery of CT and RT, the sequential application of CT and HT may protect normal tissues from chemosensitization. The cell killing of hypoxic and oxygenated tumor cells can still be obtained with sequential delivery of CT drugs and HT [54]. In clinical studies, the tint between modalities is usually kept under an hour [122,127,133,136,138]. Of note, the study of Ishikawa et al. showed a different scheduling of gemcitabine and HT for the treatment of locally advanced or metastatic pancreatic cancer [139]. Patients enrolled in this clinical study were treated with HT prior to CT with a tint of 0–24 h. This unique flexible relationship of gemcitabine cytotoxicity with the tint and sequence was revealed in an in vitro study [143]. The specific properties of CT drugs are main factors in determining the most efficient treatment sequence between CT and HT for each class of drugs.

That treatment protocols might require individualized standards for HT thermometric parameters as has recently been illustrated by an interim analysis of cisplatin and etoposide given concurrently with HT for treatment of patients with esophageal carcinoma. This analysis showed a relationship between tumor location and temperature reporting, i.e., higher temperatures were achieved in distal tumors [144]. Similar treatment site-dependent analysis of thermometric parameters should be performed in future trials. Although the biology underlying the interaction between CT drugs and heat in cancer and normal tissues is largely unknown, thermometric parameters have been shown to predict outcome when HT is combined with CT. Therefore, as discussed above, no definitive conclusions can be drawn regarding the optimal thermometric parameters for an enhanced effect of HT with CT.

### **6. Evidence for Predictive Values of Thermometric Parameters in Clinical Studies Using RT and CT in Combination with HT**

Clinical malignancies, in particular advanced and inoperable tumors, can be treated using triplet therapy consisting of CT, RT and HT as a maximal treatment approach. The number of prospective and retrospective clinical studies investigating this approach is limited, the most important of which are listed in Tables 11 and 12, respectively. These studies have already reported the feasibility of this trimodal approach for cervical cancer, rectal cancer, and pancreatic cancer.

The optimal combination of CT, RT, and HT in a single framework is complex, be-cause so many biological processes underly the interactions between the three modalities. In addition, clinical factors often influence the optimal combination of RT and CT. A template with fundamental specifications for designing a clinical study with the trimodal treatment is proposed by Herman et al. [145].

Even though there is no consensus as to the optimal scheduling of trimodal treatment, clinical studies to date integrate HT in combination with daily RT and CT drugs based on the concept that CT should interact with both RT and HT. Scheduling CT weekly is most feasible in terms of maintaining an optimal tint between HT sessions, drug administration, and RT fraction [145].

The reason why cisplatin is most frequently used in trimodality regimens is less based on a specific interaction with heat, but rather on extensive evidence from phase III randomized trials showing that cisplatin potently improves the antitumor efficacy of radiotherapy, albeit at the cost of increased toxicity. Drug concentration has been shown to affect treatment response [146], as proven experimentally [147]. A phase I-II study reported that a higher cisplatin dose (50 mg/m<sup>2</sup> ) in comparison with a lower dose (20–40 mg/m<sup>2</sup> ) combined with RT and HT was positively correlated with CR [146]. Interestingly, overall survival between patients treated with two different CT regimes in combination with RT and HT did not differ [148]. However, the study was limited by the small size of the patient

cohort. With reference to Table 11, clinical studies using trimodality treatment usually used conventional fractionation schemes with 1.8–2.0 Gy per fractions, leaving it largely unknown whether other schedules such as hypofractionation (>10 Gy per week or large single fractions) might be biologically more favorable. The total dose varied according to cancer type. In the case of cervical cancer, brachytherapy at high dose rate (HDR) or low dose rate (LDR) was applied to deliver the boost dose [149,150]. Furthermore, high or low total RT dose was reported to have an influence on CR rate when combined with 5-FU, leucovorin and HT [151]. In contrast to CT and RT treatment parameters, HT treatment parameters were frequently not reported. Thermometric parameters, such as temperature and thermal dose including tint, are reported but not set as fixed treatment requirements as there are no accepted reference values.

Disregarding the Arrhenius relationship of heating temperature and ttreat, Amichetti et al. [152] reported a short ttreat of 30 min with mean temperature range values of Tmax = 43.2 ◦C (41.5–44.5 ◦C) and Tmin = 40.1 ◦C (37–42 ◦C). This might explain why this study did not result in a higher CR rate in comparison to the previous study by Valdagni et al. [103]. A correlation of achieved temperature with treatment response such as disease-free interval to local relapse (DFILR) was reported in the study by Kouloulias et al. [153]. This study showed that the DFILR rate was greater in patients who achieved heating temperature T<sup>90</sup> > 44 ◦C for longer than 16 min during HT treatment. No significant correlation of DFILR with mean values of temperature descriptor Tmin was confirmed. Referring to the last row in Tables 7–12, the clinical endpoints among studies differ, which adds another level of complexity to generalizing the thermometric parameter correlations reported in studies.

Thermal dose was reported less frequently than temperature measurements, hence there is a lack of information about its predictive role for treatment response. In one study, thermal dose was directly and proportionally associated with CR, as patients who exhibited CR after treatment with a measured CEM43◦CT<sup>90</sup> of 4.6 min in comparison with patients with a PR and a CEM43◦CT<sup>90</sup> of only 2.0 min [146]. Recently, a prospective phase II study investigating neoadjuvant triplet therapy in patients with rectal cancer showed that patients achieving good local tumor regression had received a high thermal dose [154]. However, no threshold, only the mean of CEM 43 ◦C, was reported. The retrospective analysis of thermometric parameters of the prospective study by Harima et al. [149] showed that >1 min CEM43◦CT<sup>90</sup> is the threshold value which significantly correlates with treatment response (CR and disease-free survival rates). It also confirmed that CEM43◦CT<sup>90</sup> below 1 min are insufficient to achieve enhancement of RT and CT [155]. Unfortunately, no further analyses of the relationship between HT treatment parameters with clinical outcomes in studies using triplet therapy were reported.

Furthermore, the optimal interval between heat, radiation and anticancer drugs is still unclear. With reference to preclinical and clinical outcomes, tint affects the thermal enhancement effect of HT on both ionizing radiation and CT drugs. A particular interaction between HT and CT in terms of tint was reported according to properties of the CT drugs. A short tint between sequential HT and doxorubicin resulted in more rapid treatment response [153]. However, it is not clear whether the CT drug interacts primarily with RT only when administered on the same day or also during an extended time period. In the first scenario, CT and HT could typically be administered within a range of 1–6 h prior to RT to optimally exploit the biological interaction.


208

outcome not presented)





not with Tmax

†

.



CR: 50% (12/24), PR: 50%

 With thermal dose of CEM43◦CT90

50% of patients achieved

50% patients achieved PR.

 Cisplatin concentration amount correlated  12 (18.7%) and 1 (1.6%) patients had grade III and IV toxicity, respectively.

(correlation of thermometric parameters with clinical outcome not presented)

 R0 resection was achieved in 59 (92.2%). only five (7.8%) untreated patients remained inoperable.

 2-year OS: 91%, DFS: 83% and local RR: 13.6%

= 2.0 min,

= 4.6 min,

 Late toxicity, grade IV: only 1 patient.

idazole on days 8 and 15





: median (range); 1 CR: complete response; 2 PR: partial response; 3 NC: no change; 4 OS: overall survival, 5 DFS: disease free survival; 6 LPFS: local progression free survival; 7 DFILR: disease-free interval to local relapse; 8 DLT: dose limiting toxicities; 9 FR: feasibility rate; 10 CTR: complete tumor regression; 11 LC: local control; 12 EORTC-QLQ: European Organization for research and treatment of cancer-quality of life questionnaire; 13 ORR: objective response rate; 14 RR: response rate; 15 DFSR: disease-free survival rate; 16 MFS: metastasis-free survival; 17 DMFS: distant metastases-free survival; 18 LPFR: local progression-free survival; 19 LARC: locally advanced rectal cancer; 20 LCC: recurrent rectal cancer.


outcome not presented)

215



216


Moreover, the Ntotal was shown to be a prognostic factor for OS for bladder cancer patients treated with combined CT, RT, and HT followed by surgery [161]. In contrast, Gani et al. [164] reported that the number of HT sessions was not predictive for OS, DFS, LC, or distant metastasis-free survival. Neither did the sequencing of CT, HT, and RT in clinical reports follow a specific pattern. Preclinical studies are required to better understand the interaction of CT, RT, and heat and how they should be combined in future clinical trials.

#### **7. Future Prospects**

The main limitations of HT as a cancer treatment in current clinical practice are the need for better standardization of treatment protocols, up-to-date quality assurance guidelines that are widely applicable and dedicated planning systems to generate patient treatment plans. The wide variation of thermometric parameters derived from clinical studies indicate that HT treatment is currently delivered according to individual clinical center guidelines. Consequently, the comparison of clinical study outcomes is substantially hampered by the large degree of variation in treatment parameters. Regarding the data summarized in Tables 6–11, apart from thermal dose and temperature measured during treatment, other thermometric parameters reported often include only ttreat, tint, or Nweek.

Monitoring and measuring temperature is one of the main challenges in routine clinical practice and has hindered the clinical expansion of HT. The future of HT in combination with RT and CT requires novel technical developments for the delivery and measurement of homogenous heating of the malignant tissues. Not all studies (Tables 7–12) recorded temperatures in the region of the tumor. The process of inserting temperature probes to monitor and record the HT is considered invasive and uncomfortable, and sometimes the tumor site is inaccessible for the temperature probe. For example, Milani et al. [162] reported that even though the tumors were not deep-seated, intratumoral temperature measurements were only feasible in one of 24 patients, so no representative thermal doses could be reported. One of the non-invasive approaches currently under clinical evaluation is magnetic resonance thermometry (MRT) that provides 3-D temperature measurements. Hybrid MR/HT devices are currently installed in five European clinical centers.

Temperature measurements in anthropomorphic phantoms with MRT are accurate in comparison with thermistor probes [167], but clinical measurements are currently inaccurate in most pelvic and abdominal tumors [168]. The physiological changes in tissue microenvironment, patient movements, magnetic field drift over time, limited sensitivity in fatty tissues, and respiratory motion, including cardiac activity in regions of the pelvis and abdomen, hamper the accurate temperature measurement by MRT [168]. The temperature images from MRT systems contain image distortion, artifacts, and noise, leading to inaccurate temperature measurement, low temporal resolution, and low imaging to signal-to-noise ratio (SNR) [169]. The sources and solutions of image artifacts as a result of additional frequencies were described by Gellermann et al. [170]. Proton-resonance frequency shift (PRFS), apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), transversal relaxation time (T2), and equilibrium magnetization (M0) are the imaging techniques used to exploit temperature-dependent parameters [170–173]. The PRFS technique is the most frequently used MRT method, even though it was shown that when there is a poor magnetic field homogeneity, ADC or T<sup>1</sup> techniques are preferable [174]. However, the accuracy of temperature measurements was in the range of ±0.4 to ±0.5 ◦C between PRFS method and thermistor probe using a heterogeneous phantom [175]. A stronger correlation between MRT and thermistor probes was found in patients with soft tissue sarcomas of lower extremities and pelvis [176] in comparison with recurrent rectal carcinoma [177]. The successful implementation of MRT in clinical centers, as automated temperature feedback during the HT session, might have a considerable impact on clinical outcomes to deliver the desired heating and conform the heat distribution to spare healthy surrounding tissues. This could substantially help to standardize data collection and the analysis of thermometric parameters. Another experimental approach to monitoring treatment temperature during HT sessions is electrical impedance tomography (EIT) as

recently reported in a simulation study by Poni et al. [178]. EIT captures the electrical conductivity of tissues depends on temperature elevation. For example, the multifrequency EIT technique detects the changes in conductivity due to perfusion increase induced by the change in temperature [179]. The accuracy of EIT for temperature measurements was reported to range from 1.5 ◦C to 5 ◦C [180]. The potential of EIT to monitor temperature in the cardiac thermal ablation field is being investigated [181]. This technique also holds promise for HT treatment. Both MRT and EIT may allow for improvement of the spatial homogeneity of heat to the cancer tissues.

The technological advances and standardization of international treatment protocols for different cancer types will improve the effectiveness and synergy of HT in combination with RT and/or CT. In line with this, there is a need for clinically accepted processes for the recording and reporting of thermometric data. This will allow for the inclusion of specific thermometric parameters in future clinical studies combining HT with RT and/or CT. For any future prospective study, it should be mandatory that thermometric parameters are recorded and some recommendations are available in the current guidelines [43,46]. The integration of thermometric parameters is one of the objectives of the HYPERBOOST ("Hyperthermia boosting the effect of Radiotherapy") international consortium within the European Horizon 2020 Program MSCA-ITN. The HYPERBOOST network aims to create a novel treatment planning system, including the standardization of thermometric parameters derived from retrospective and prospective clinical trials.

#### **8. Conclusions**

In this review, we provide an extensive overview of thermometric parameters reported in prospective and retrospective clinical studies which applied HT in combination with RT and/or CT and their correlation with clinical outcome. It is recognized that there is a wide variety in the practice of HT between clinical centers, and we aimed to elucidate the use and reporting of thermometric parameters in different clinical settings. It emerged that the sequencing of HT and RT varies more than the sequencing of HT and CT. Only a few standards seem to exist with regard to the sequence of HT with RT and CT in a triplet for specific CT drug, RT fractionation and thermal dose. According to the evaluated studies, tint is a critical parameter in clinical routine, but no clinical reference values have been established. Of note, a constant ttreat of 60 min throughout the HT treatment course was described in most clinical studies. The most important parameter seems to be temperature itself, which correlates with thermal dose. Revealing the relationship between thermal dose and treatment response for different cancer entities in future clinical studies will lead to the improved application of heat to promote the synergistic actions of HT with RT and CT. We suggest that it become mandatory for new clinical study protocols to include the extensive recording and analysis of thermometric parameters for their validation and overall standardization of HT. This would allow for the definition of thermometric parameters, in particular of thresholds for temperature descriptors and thermal dose.

**Author Contributions:** Conceptualization, O.R. and P.G.; writing, A.A. and O.R.; writing— review and editing, A.A., O.R., D.P.V., P.G., D.M., H.C., E.O., O.J.O., S.R., P.W., R.A.H., E.P., S.B. and R.F.; visualization, A.A. and O.R.; supervision, H.C., R.F., O.R. and P.G. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research has received support from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (MSCA-ITN) grant "Hyperboost" project, no. 955625.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


## *Article* **Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland**

**Emanuel Stutz 1,2, Emsad Puric <sup>2</sup> , Adela Ademaj 2,3 , Arnaud Künzi <sup>4</sup> , Reinhardt Krcek <sup>1</sup> , Olaf Timm <sup>2</sup> , Dietmar Marder <sup>2</sup> , Markus Notter <sup>5</sup> , Susanne Rogers <sup>2</sup> , Stephan Bodis 2,6,7 and Oliver Riesterer 2,\***


**Simple Summary:** Moderate hyperthermia is a potent radiosensitizer and its efficacy has been proven in randomized clinical trials for specific tumor entities. In spite of this, hyperthermia still lacks general acceptance in the oncological community and implementation of hyperthermia in clinical practice is still low. Reimbursement is one key factor regarding the availability of hyperthermia for deep-seated tumors, with high variability in reimbursement between countries. We report the current reimbursement status and related pattern of care for the use of deep hyperthermia in Switzerland over a time period of 4.5 years. This analysis will provide the basis for the national standardization of deep hyperthermia treatment schedules and quality assurance guidelines, as well as for the expansion of deep hyperthermia indications in the future. This comprehensive insight into deep hyperthermia reimbursement and practice in Switzerland might also be of interest for other national hyperthermia societies.

**Abstract:** Background: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. Methods: All indications presented to the national hyperthermia tumor board for dHT between January 2017 and June 2021 were evaluated and treatment schedules were analyzed using descriptive statistics. Results: Of 183 patients presented at the hyperthermia tumor board, 71.6% were accepted and 54.1% (99/183) finally received dHT. The most commonly reimbursed dHT indications were "local recurrence and compression" (20%), rectal (14.7%) and bladder (13.7%) cancer, respectively. For 25.3% of patients, an individual request for insurance cover was necessary. 47.4% of patients were treated with curative intent; 36.8% were in-house patients and 63.2% were referred from other hospitals. Conclusions: Approximately two thirds of patients were referred for dHT+RT from external hospitals, indicating a general demand for dHT in Switzerland. The patterns of care were diverse with respect to treatment indication. To the best of our knowledge, this study shows for the first time the pattern of care in a national cohort treated with dHT+RT. This insight will serve as the basis for a national strategy to evaluate and expand the evidence for dHT.

**Keywords:** moderate hyperthermia; deep hyperthermia; radiative hyperthermia; radiotherapy; patterns of care; reimbursement

**Citation:** Stutz, E.; Puric, E.; Ademaj, A.; Künzi, A.; Krcek, R.; Timm, O.; Marder, D.; Notter, M.; Rogers, S.; Bodis, S.; et al. Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland. *Cancers* **2022**, *14*, 1175. https://doi.org/10.3390/ cancers14051175

Academic Editor: Girolamo Ranieri

Received: 28 January 2022 Accepted: 18 February 2022 Published: 24 February 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Moderate-temperature (39–45 degree Celsius) regional hyperthermia (HT) is concurrently applied with radiotherapy (RT) or chemotherapy [1]. Adding HT to RT improves treatment outcomes such as local tumor control or overall survival in specific tumor entities with a negligible toxicity profile [2,3]. HT can be applied with superficial HT devices for superficial tumors (less than 4 cm depth below the skin) or with deep HT (dHT) devices for tumors located at depth (more than 4 cm from the skin). Several techniques and devices for the clinical application of dHT exist [1,4,5]. Although its effect has been proven in several tumor entities with positive phase III randomized trials and meta-analyses [3], there is no widespread use in Europe. Reasons are multifactorial and have been previously summarized by Van der Zee et al. [1] and Overgaard et al. [6], but are still "hot". Briefly, not only proving that the tumor region was adequately heated but also to heat and sustain a uniform temperature in the tumor region are challenging as the body attempts to maintain temperature homeostasis. Some earlier trials with dHT reported questionable results with worse outcomes with dHT, most probably caused by insufficient heating, missing quality assurance and an imbalance in the patient groups ([7] and discussion in [8]). This confusion resulted in a persistent loss of credibility in the oncological community [6,8,9].

Another reason for the lack of widespread availability is that HT, and especially dHT, is relatively labor-intensive and needs trained staff [1,10]. Furthermore, the use of dHT as a radiosensitizer competes with concurrent chemotherapy. The advantages of chemotherapy include easy administration, a lesser requirement of technical experience and comprehensive availability. The prime example of this is cervical cancer ([11], discussion in [12]). A financial obstacle is the uncertain cost reimbursement of HT treatment in most countries, limiting HT practice to university centers [8,9] and withholding it from the broader target population. Therefore, despite good but aged evidence, only a few dHT indications were incorporated into international oncology treatment guidelines.

HT has a long tradition in Switzerland, starting in 1980 with the first clinical application of superficial HT with RT at the Center for Radiation-Oncology Kantonsspital Aarau. In 1988, the first dHT treatment in combination with RT (dHT+RT) was performed there. Superficial HT was later rolled out to a second hospital in Switzerland and clinical applications, mainly for recurrent breast cancer, were maintained at this site. Thus, prior to 2017, there were only two centers applying HT based on ESHO guidelines [13–16] in Switzerland (Kantonsspital Aarau and Lindenhofspital Bern), with only the Kantonsspital Aarau applying dHT. During this time, for every HT treatment, an individual request to the patients' health insurance for reimbursement was required. The national Swiss Hyperthermia Network (SHN) was founded to synchronize and coordinate HT research activities at the national level, guarantee treatment quality and improve the evidence base for HT. In 2016, the SHN submitted a proposal for the reimbursement of HT+RT for selected evidence-based indications to the Swiss Federal Office of Public Health for superficial HT and dHT. Subsequently, four indications for superficial HT and five indications for dHT were temporarily approved for reimbursement for a period of two years as from 2017 (Table 1). It was stipulated that every patient receiving HT had to be presented to and have the indication confirmed by the national SHN tumor board, which was constituted by HT experts to guarantee the high quality of treatment decisions [17–20]. For patients who were likely to benefit from dHT+RT without a listed reimbursed indication, a specific request for insurance cover was necessary.


**Table 1.** Indications for deep hyperthermia (dHT) with granted reimbursement in Switzerland [18–20] are stated with specifications and underlying evidence.

Prerequisites are (i) combination with radiotherapy (RT), (ii) the indication has to be presented and confirmed at the Swiss Hyperthermia Network (SHN) tumor board, (iii) the combined dHT + RT has to be performed at an institution affiliated with the SHN. The reimbursement status is indicated per time period and coded with underlying colors. Green = time-unrestricted reimbursement; yellow = reimbursed indications limited for two further years; red = indications no longer reimbursed; grey = initially not reimbursed indications (request for insurance cover was required). Abbreviations: ChT: chemotherapy, HT: hyperthermia.

At the end of the 2 years, the SHN submitted an update of the current evidence for dHT to the Swiss Federal Office of Public Health. After reevaluation, dHT indications were expanded in 2019 with the indications of "local tumor recurrence and compression" and "painful bone metastasis", making a total of seven reimbursed dHT indications. As of July 2021, the Swiss Federal Office of Public Health granted unrestricted coverage for the dHT indications of "cervical cancer" and "painful bone metastasis". Reimbursement for the dHT indications "local tumor recurrence and compression" and "soft tissue sarcoma" has been temporarily prolonged, again for another 2-year time period. The indications for bladder, pancreatic and rectal cancer lost their reimbursement status (Table 1) [20].

Regarding superficial HT, four indications (specific situations in breast and head and neck cancer, malignant melanoma and palliative indications with local tumor compression), were granted for two years and then without time restrictions [17,19]. However, superficial HT is not within the scope of the present analysis.

To the best of our knowledge, this is the first analysis of an unselected, dHT patient cohort regarding treatment indications, patient and tumor characteristics and treatment schedules. We aimed to perform a pattern of care analysis to shed more light on dHT practice in Switzerland and build a basis for a national strategy to evaluate, consolidate and expand the evidence for dHT.

#### **2. Materials and Methods**

All patients presented at the SHN tumor board between January 2017 and June 2021 for the evaluation of radiative dHT+RT based on ESHO guidelines [13,14] were collected in a database. In July 2021, the reimbursed dHT indications changed and, since the end of 2021, a second center in Switzerland has started to apply dHT. This time period included a patient cohort treated by a single dHT center with only one modification of reimbursed dHT indications.

Data from tumor board protocols were independently extracted and crosschecked by two authors regarding reimbursed dHT indications, patient and tumor characteristics and information regarding referring hospitals. These data then were crosschecked and completed with dHT and RT treatment details by three other authors. In case of any discrepancy, a consensus was reached. This project was approved by the local ethics committee (EKNZ2021-01022, 1 July 2021).

Possible candidates for dHT were presented at the weekly national SHN tumor board by their referring physicians. The individual indication for dHT was discussed with at least two radiation oncologists with clinical experience in moderate dHT, including also senior medical oncologists. Indications were approved if the patient exhibited no contraindications for dHT (e.g., metal implant, cardio-pulmonary insufficiency, etc.), if dHT was technically feasible (only treatable lesions in accessible tumor locations) and if there was no other more appropriate treatment option (i.e., RT alone, hormone therapy, chemotherapy or immunotherapy).

#### *2.1. Principles of Application of Deep Hyperthermia*

From 2017 to 2021, Kantonsspital Aarau was the only institution providing radiative dHT+RT in accordance with ESHO guidelines [13,14] and therefore received referrals from centers throughout Switzerland. Not only the optimal treatment sequence of HT and RT but also the optimal time interval between RT and HT or vice versa is still a matter of debate. Multiple working mechanisms requiring different optimal temperature ranges contribute to the effectiveness of HT, as comprehensively presented in Oei et al. [40]. In the absence of robust clinical data, the decision on the therapeutic sequence of HT and RT is made individually by the respective center. Preclinical studies indicated that the time interval between RT and HT should be kept as short as possible [41] but clinical studies addressing the time interval are sparse [42–45]. In two retrospective clinical studies investigating the effect of the time interval on treatment outcomes in cervical cancer patients, one revealed a strong correlation of a short time interval between RT and dHT for a better clinical outcome [44], where the other study showed that a time interval up to 4 h has no effect [45]. These contradicting results initiated a comprehensive discussion that depicted the complexity of this topic [46–48]. However, with regard to the dHT standard operating procedure at the Kantonsspital Aarau, dHT is given before RT with a minimal time interval.

dHT was performed with the BSD 2000 3D Hyperthermia Systems© (BSD Medical Corporation/Pyrexar, Salt Lake City, UT, USA) using either the SigmaEye© or Sigma 60© applicator, depending on the diameter of the abdomen or limb. The interval between two dHT treatments was at least 72 h. For pelvic dHT, thermometry probes were inserted in the bladder, the rectum, the vagina, the anal margin and superficially on both groins for continuous thermometry and thermal mapping where possible/necessary. Interstitial thermometry was not performed except for patients receiving interstitial brachytherapy. For all other patients, the hyperthermia treatment planning software Sigma Hyperplan© (M/s Dr. Sennewald Medizintechnik GmbH, Munich, Germany) was used to estimate suitable power and steering parameters to achieve the targeted tumor temperature of 41 ◦C. A dHT session starts with a warm-up heating phase. The following plateau phase had a duration of 60 min and started when (a) the targeted temperature in the tumor was

reached (this option was only possible if the heated tumor was adjacent to an intraluminal thermometry probe), (b) the targeted power and steering parameters were reached or (c) latest after a 30 min warm-up heating phase, respectively. During treatment, vital functions were continuously monitored.

The frequency of dHT was determined individually. Usually, dHT once per week was used for curative indications and dHT twice per week for palliative indications.

As not every patient started RT on a Monday, a reliable subdivision of dHT once versus twice per week was not possible. For the purpose of this study, dHT frequency was therefore categorized as once or once to twice a week. For patients referred from other hospitals, the optimal RT schedule in combination with dHT was discussed at the SHN tumor board; however, the final responsibility for the RT schedule lay with the referring center. Whenever possible, patients were treated within or analogous to an existing treatment protocol.

Some patients treated for bladder, rectal, anal and pancreatic cancer received a trimodal treatment with dHT+RT and concurrent chemotherapy. These patients were treated within [49–51] or analogous to a clinical trial [50–54]. Patients were divided into "in-house" and "referred" patients. Every patient originating from the Kantonsspital Aarau was considered "in-house". Additionally, patients from other hospitals without RT facilities, which referred patients for RT to the Kantonsspital Aarau, were also considered "in-house". Patients from other hospitals with RT facilities who were referred for dHT were classified as "referred patients", independent of where they finally received the RT treatment. To depict the spatial policy of referrals, referring hospitals were further divided into intracantonal and extra-cantonal and the distance by road from the referring hospitals to the Kantonsspital Aarau was calculated. There were three options for the organization of the dHT+RT treatment: (1) the patient received both dHT+RT at the Kantonsspital Aarau, (2) the patient received RT at the day of the dHT session at the Kantonsspital Aarau and the remainder of the RT at the referring hospital or (3) the patient received dHT sessions only at Kantonsspital Aarau and all RT sessions at the referring hospital. The latter option was deemed suboptimal based on the standard operating procedure at the Kantonsspital Aarau, wherein dHT should be given before RT with a minimal time interval. If not possible, a latency of 90 min between HT and RT was deemed acceptable. For patients treated with protons at the Paul Scherrer Institute, only option 3 was possible; however, the distance by road was less than 30 km. For referred patients, option 2 was preferred due to the short latency between RT and dHT. During the COVID-19 pandemic, this option was omitted to avoid mixing in-house and external patients to decrease the risk of infection. The time interval between dHT and start of the following RT was measured in patients receiving both dHT and RT at the Kantonsspital Aarau and was defined as the time between switching power off on the dHT device and first beam-on of the RT. Time points were extracted from automatical treatment recordings and stated in minutes.

#### *2.2. Statistics*

Descriptive statistics were used to describe patient and tumor characteristics and treatment details, which were presented as mean with standard error, median with (interquartile) range or frequencies with percentages, depending on their distribution.

Data were represented using Statistical Package R (released 2021, 10 August, Version 4.1.1) and the ggplot2 package, version 3.3.5. Due to the combination of the small sample size, many stratification levels and wide heterogeneity of treatment and patient characteristics, statistical inference was not performed beyond the summary tables presented here as it was judged that a qualitative assessment of the data would be more suited to the aims of this study. Continuous values were summarized with mean, standard deviation, median and max/min values. Categorical variables were summarized as frequencies and proportions.

The river plot was generated using the free, internet-based software SankeyMATIC [55].

#### **3. Results**

#### *3.1. Patient Flow through the Swiss Hyperthermia Network Tumor Board*

Between January 2017 and June 2021, 567 patients were presented for the evaluation of superficial or deep hyperthermia, with 32.3% (183/567) qualifying for dHT. Of these 183 patients, 28.4% (52/183) were deemed unsuitable. The remaining 131 patients were further assessed at a medical consultation and by their ability to tolerate the patient positioning required for dHT. This resulted in the further exclusion of 24.4% of patients (32/131). The reasons are stated in Figure 1a. In total, 54.1% (99/183) of patients initially presented at the SHN tumor board actually received dHT. Four patients had to be excluded due to withdrawal of consent, resulting in a total of 95 patients for analysis. Patients for superficial HT were beyond the scope of this analysis. *Cancers* **2022**, *14*, x FOR PEER REVIEW 6 of 18

**Figure 1.** Patient flow through the SHN tumor board. (**a**) Patients presented for dHT were excluded if dHT was not indicated (green) or a physical examination and treatment tolerability check revealed an exclusion criterion (yellow). Only patients with informed consent were eligible for analysis (vio‐ **Figure 1.** Patient flow through the SHN tumor board. (**a**) Patients presented for dHT were excluded if dHT was not indicated (green) or a physical examination and treatment tolerability check revealed

let). Background colors match the corresponding bar chart plot. (**b**) Patients presented at the SHN tumor board from January 2017 to June 2021 were depicted per semester. Events that may have affected the number of patients and indications treated were the two new "reimbursed dHT indica‐

especially the COVID‐19 lockdown in Switzerland (11 March to 26 April 2020; 1st semester 2020). Abbreviations: CI: contraindication, CIED: cardiac implantable electronic device, Claustroph: claus‐ trophobia, dHT: deep hyperthermia, Sem: semester, SHN: Swiss Hyperthermia Network, Pts: pa‐

tients, S1: 1st semester, S2: 2nd semester.

an exclusion criterion (yellow). Only patients with informed consent were eligible for analysis (violet). Background colors match the corresponding bar chart plot. (**b**) Patients presented at the SHN tumor board from January 2017 to June 2021 were depicted per semester. Events that may have affected the number of patients and indications treated were the two new "reimbursed dHT indications" as of 2019 and the changes in oncological treatment patterns during the COVID-19 pandemic, especially the COVID-19 lockdown in Switzerland (11 March to 26 April 2020; 1st semester 2020). Abbreviations: CI: contraindication, CIED: cardiac implantable electronic device, Claustroph: claustrophobia, dHT: deep hyperthermia, Sem: semester, SHN: Swiss Hyperthermia Network, Pts: patients, S1: 1st semester, S2: 2nd semester.

#### *3.2. Patient Characteristics*

The median age of patients receiving dHT was 65 years (range, 18–88). Moreover, 57.9% (55/95) of patients were male and 49.5% (47/95); 41.1% (39/95) and 9.5% (9/95) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2, respectively. A total of 47.4% (45/95) of patients received dHT with curative intent. Meanwhile, 42.1% (40/95) of patients had been previously irradiated and received dHT combined with reirradiation (re-RT). In addition, 7.4% (7/95), 23.2% (22/95) and 69.5% (66/95) of patients were treated within a study protocol [49–51], analogous to a protocol [50–54] or as part of routine clinical practice, respectively (Table 2).

Patients were divided into groups based on treatment indication regarding reimbursement status (reimbursed dHT indications vs. indication requiring an individual "request for insurance cover") and based on primary tumor entities, respectively (Table 2, Figure 2, Supplementary Data, Figure S1). This revealed that "local tumor recurrence with compression" was the most common reimbursed dHT indication treated, representing 20.0% (19/95) of patients, followed by "rectal cancer" with 14.7% (14/95) and "bladder cancer" with 13.7% (13/95) of patients. Over the 4.5-year time period, 24.2% of patients (24/95) were treated with an indication not directly covered or not yet covered and therefore required an individual "request for insurance cover" to obtain reimbursement. Details of this patient group are provided in the Supplementary Data in Table S1. 15 of 24 patients who were treated from 2017 to 2018 and therefore before the two new dHT indications ("tumor local recurrence and compression" and "painful bone metastasis") were added, as well as 9/24 patients in the time period from 2019 to the first semester of 2021. Ten of these 15 patients would have fallen within the two new indications, showing that the two new indications covered an existing demand.

Regarding primary cancer entities, the most common was rectal cancer, with 22.1% (21/95), followed by bladder cancer with 15.8% (15/95) and soft tissue sarcoma with 13.7% (13/95) of patients (Table 2). Tumor entities with less than three treated patients are not individually represented but summarized in the group "others", which contributed with 18.9% (18/95). Primary cancer entities, i.e., anal, colon and prostate cancer, presented in a clinical situation belonging to the reimbursed indications "local tumor recurrence and compression", "painful bone metastasis" or to the group "request for insurance cover". The time trend is shown in the Supplementary Data, in Figure S1.

The patient population treated with dHT consisted of 36.8% (35/95) in-house and 63.2% (60/95) of patients referred from external radiation oncology institutions. To depict the spatial policy of referrals, the distance from the referring hospital to the Kantonsspital Aarau was calculated, resulting in a mean of 61.5 km (SD 54.3 km) and a median of 42 km (range 23–238 km) (Table 2).

the two new indications covered an existing demand.

*3.2. Patient Characteristics*

routine clinical practice, respectively (Table 2).

The median age of patients receiving dHT was 65 years (range, 18–88). Moreover, 57.9% (55/95) of patients were male and 49.5% (47/95); 41.1% (39/95) and 9.5% (9/95) had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2, respec‐ tively. A total of 47.4% (45/95) of patients received dHT with curative intent. Meanwhile, 42.1% (40/95) of patients had been previously irradiated and received dHT combined with re‐irradiation (re‐RT). In addition, 7.4% (7/95), 23.2% (22/95) and 69.5% (66/95) of patients were treated within a study protocol [49–51], analogous to a protocol [50–54] or as part of

Patients were divided into groups based on treatment indication regarding reim‐ bursement status (reimbursed dHT indications vs. indication requiring an individual "re‐ quest for insurance cover") and based on primary tumor entities, respectively (Table 2, Figure 2, Supplementary Data, Figure S1). This revealed that "local tumor recurrence with compression" was the most common reimbursed dHT indication treated, representing 20.0% (19/95) of patients, followed by "rectal cancer" with 14.7% (14/95) and "bladder cancer" with 13.7% (13/95) of patients. Over the 4.5‐year time period, 24.2% of patients (24/95) were treated with an indication not directly covered or not yet covered and there‐ fore required an individual "request for insurance cover" to obtain reimbursement. De‐ tails of this patient group are provided in the Supplementary Data in Table S1. 15 of 24 patients who were treated from 2017 to 2018 and therefore before the two new dHT indi‐ cations ("tumor local recurrence and compression" and "painful bone metastasis") were added, as well as 9/24 patients in the time period from 2019 to the first semester of 2021. Ten of these 15 patients would have fallen within the two new indications, showing that

**Figure 2.** Trend of patients treated with combined deep hyperthermia (dHT) and radiotherapy over time. Bar chart where numbers of patients receiving dHT between January 2017 and June 2021 are depicted per semester (S1 and S2) and divided into "reimbursed dHT indications" with specific subgroups and "request for insurance cover". From 2017 to 2018, a linear increase in patient numbers with approx. 1 patient per semester was showed. Two new reimbursed indications, "local tumorrecurrence with compression" and "painful bone metastasis", were granted as from 2019 (blue shaded background). COVID‐19 lockdown in Switzerland was during 1st semester 2020 (11 March to 26 April 2020). **Figure 2.** Trend of patients treated with combined deep hyperthermia (dHT) and radiotherapy over time. Bar chart where numbers of patients receiving dHT between January 2017 and June 2021 are depicted per semester (S1 and S2) and divided into "reimbursed dHT indications" with specific subgroups and "request for insurance cover". From 2017 to 2018, a linear increase in patient numbers with approx. 1 patient per semester was showed. Two new reimbursed indications, "local tumor recurrence with compression" and "painful bone metastasis", were granted as from 2019 (blue shaded background). COVID-19 lockdown in Switzerland was during 1st semester 2020 (11 March to 26 April 2020).

> All in-house patients received their RT at the Kantonsspital Aarau. Regarding the patients referred from other hospitals, 23.3% (14/60) of them received both, dHT with all irradiations, at the Kantonsspital Aarau. Moreover, 10.0% (6/60) of patients received all irradiations at their referring hospital except at the day of dHT, where RT was applied at the Kantonsspital Aarau to minimize the time delay between HT and RT. In addition, 66.7% (40/60) of patients received only dHT treatment at the Kantonsspital Aarau and were irradiated at their referring hospital (Figure 3).

> Patient characteristics are described more in detail in Supplementary Table S2, comparing (1) in-house vs. referred patients, (2) patients receiving dHT in the setting of a re-RT vs. primary RT, (3) patients treated with palliative vs. curative intention or (4) patients treated within a clinical trial, analogous to a trial or in clinical routine practice, respectively (Supplementary Table S3A). Interestingly, (5) a gender difference was noted (Supplementary Table S4).

**Table 2.** Patient and tumor characteristics with treatment indications, referral status and deep hyperthermia treatment adherence. Specifications of "reimbursed dHT indications" are given in Table 1.


Abbreviations: dHT: deep hyperthermia, dHT+RT: combined dHT and RT, ECOG: Eastern Cooperative Oncology Group, intra and extra-cantonal: cantons in Switzerland are equivalent to states, provinces or regions in other countries, KSA: Kantonsspital Aarau (=dHT center), Others: the definition is given in the text, RT: radiotherapy, SD: standard deviation.

Regarding primary cancer entities, the most common was rectal cancer, with 22.1% (21/95), followed by bladder cancer with 15.8% (15/95) and soft tissue sarcoma with 13.7% (13/95) of patients (Table 2). Tumor entities with less than three treated patients are not individually represented but summarized in the group "others", which contributed with 18.9% (18/95). Primary cancer entities, i.e., anal, colon and prostate cancer, presented in a clinical situation belonging to the reimbursed indications "local tumor recurrence and compression", "painful bone metastasis" or to the group "request for insurance cover".

The patient population treated with dHT consisted of 36.8% (35/95) in‐house and 63.2% (60/95) of patients referred from external radiation oncology institutions. To depict the spatial policy of referrals, the distance from the referring hospital to the Kantonsspital Aarau was calculated, resulting in a mean of 61.5 km (SD 54.3 km) and a median of 42 km

All in‐house patients received their RT at the Kantonsspital Aarau. Regarding the patients referred from other hospitals, 23.3% (14/60) of them received both, dHT with all irradiations, at the Kantonsspital Aarau. Moreover, 10.0% (6/60) of patients received all irradiations at their referring hospital except at the day of dHT, where RT was applied at

The time trend is shown in the Supplementary Data, in Figure S1.

were irradiated at their referring hospital (Figure 3).

(range 23–238 km) (Table 2).

**Figure 3.** River plot showing the proportions of in‐house and referred patients and where the RT and dHT were applied. On the left, patients are grouped according to source of referral. On the right, the three options regarding where and how dHT+RT treatment was applied are stated. The thickness of the connecting flowlines represents the proportion of patients. Abbreviations: dHT: deep hyperthermia, dHT+RT: combined dHT and RT, KSA: Kantonsspital Aarau (dHT center), RT: **Figure 3.** River plot showing the proportions of in-house and referred patients and where the RT and dHT were applied. On the left, patients are grouped according to source of referral. On the right, the three options regarding where and how dHT+RT treatment was applied are stated. The thickness of the connecting flowlines represents the proportion of patients. Abbreviations: dHT: deep hyperthermia, dHT+RT: combined dHT and RT, KSA: Kantonsspital Aarau (dHT center), RT: radiation.

#### Patient characteristics are described more in detail in Supplementary Table S2, com‐ paring (1) in‐house vs. referred patients, (2) patients receiving dHT in the setting of a re‐ *3.3. Treatment Characteristics*

radiation.

RT vs. primary RT, (3) patients treated with palliative vs. curative intention or (4) patients treated within a clinical trial, analogous to a trial orin clinicalroutine practice,respectively One of the 95 treated patients stopped dHT+RT after three RT fractions due to reasons unrelated to treatment. This patient was excluded from treatment schedule analysis. In the whole cohort, a mean of 5.24 (SD ± 1.94) and a median of 5 (range 1–10) dHT sessions were applied, with 52.1% (49/94) of patients receiving it once a week and 47.9% (45/94) once to twice a week. Concurrent dHT was applied with external body RT (EBRT), stereotactic body RT (SBRT), protons and interstitial HDR-brachytherapy in 84% (79/94), 2.1% (2/94), 9.6% (9/94) and 4.3% (4/94) of patients, respectively. The mean total number of fractions was 21.7 (SD ± 8.89), with a median of 25 (range 4–38), a mean dose per fraction of 2.49 Gy (SD ± 1.35) and a median of 2 Gy (range 1.8–9 Gy). The mean total dose was 46.2 Gy (SD ± 12.8), with a median of 50 Gy (range 12.5–76 Gy). Moreover, 20.2% (19/94) of patients received an RT boost. RT was delivered daily in 83% (78/94) of patients (Table 3, Supplementary Table S3B). In total, 55 of 95 patients (57.9%) received dHT followed by RT at the Kantonsspital Aarau. The remaining 40 patients travelled to their referring hospital after the dHT session for the same-day RT (Figure 3). In the first group, the time interval between dHT and RT was available in 98.1% of patients (54/55). The mean and median time between the end of the dHT session and start of the RT was 19 min (SD ± 5.5) and 18 min (range 11–32 min), respectively. Evaluation of the time interval of the 40 patients receiving all RT at their referring institution was not possible due to the retrospective nature of this study and because these patients were irradiated at several RT facilities located all over the country. Treatment characteristics were compared between specific patient subgroups, including in-house vs. referred patients, primary RT vs. re-RT and curative vs. palliative intention (Table 3). The treatment schedules employed are stated per dHT indication and per individual patient in detail in Supplementary Table S5.


**Table 3.** Treatment characteristics for specific patient subgroups comparing in-house vs. referred patients, primary RT vs. re-RT and curative vs. palliative intention.

One patient stopped treatment very early and was excluded from the treatment characteristics table. Abbreviations: dHT: deep hyperthermia, EBRT: external body radiotherapy, Gy: Gray, HDR: high dose rate, RT: radiotherapy, SBRT: stereotactic body radiotherapy, SD: standard deviation.

The specific treatment schedules were dependent on the treatment indication, aim of treatment, pre-irradiation status, primary tumor entity and tumor stage. Patients treated with curative intent generally received a higher total dose, more RT fractions, usually 2 Gy per fraction and one dHT session per week. Palliative or re-RT treatment schedules mostly consisted of lower total doses, less RT fractions using moderate hypofractionation with 1–2 dHT sessions per week, but nearly the same total number of dHT sessions as in the curative setting. This coincides with the expected current practice in radiation oncology.

#### *3.4. Hyperthermia Treatment Adherence*

The adherence to dHT was high, with 94% (89/95) of patients finishing all dHT sessions as initially prescribed. Six patients did not complete the prescribed sessions.

Three of these six patients were treated for bladder cancer, two of them with tetramodal treatment (transurethral resection of bladder tumor (TUR-BT), chemotherapy, dHT+RT) and one with dHT+RT only. The reason for early discontinuation in these three patients was bladder irritation and/or bacterial cystitis, which prevented further catheterization for thermometry. Furthermore, 2/6 patients were treated for rectal cancer with local tumor recurrence with compression with palliative intent and were of ECOG 2. The reason for early discontinuation of dHT was deterioration of health status. The sixth patient was scheduled to receive neoadjuvant dHT+RT for soft tissue sarcoma of the limb. dHT was discontinued after the first HT session due to heat-induced pain in the tumor.

#### **4. Discussion**

During the investigated time period, only one RT center in Switzerland provided radiative dHT and seven dHT indications were approved for reimbursement in Switzerland. For other tumor situations that were likely to benefit from combined dHT+RT, an individual request to the patient's insurance company was necessary. A prerequisite for coverage of the costs stipulated by the Swiss Federal Office of Public Health was the presentation and confirmation of the dHT indication at the SHN tumor board.

Our analysis of the patient flow through this tumor board revealed a high number (approximately 50%) of patients who were not approved for dHT. This might be explained not only by the critical evaluation of the dHT indication by an expert panel, thus reflecting the quality of the tumor board decisions, but also by the fact that some referring physicians were not yet familiar with dHT as they presented patients with obvious contraindications, such as metal implants in the tumor region. We noted that only for two patients dHT could not be applied due to lack of cost recovery (Figure 1a), showing that health insurance companies in Switzerland will cover dHT when no other local treatment options than dHT+RT exist and the indication can be justified. The strict supervision of meaningful indications by the SHN tumor board probably contributed to the high acceptance rate of the health insurers. Therefore, we conclude that the SHN tumor board serves not only for the preselection of patients, besides contributing to the transparency and harmonization of treatment schedules, but also plays a role in teaching newcomers to the field.

This analysis presents compelling evidence of an existing clinical demand for dHT for both palliative and curative indications. The majority (74.7%, 71/95) of patients in this analysis were treated based on the seven "reimbursed dHT indications" and only 25.3% (24/95) of patients required an individual "request to the insurance company" to cover the costs of therapy (Table 2). A closer look at the latter group revealed that, in the two years (2017 to 2018) before the introduction of the two new reimbursed dHT indications (local tumor compression and painful bone metastasis), more requests for dHT were submitted to insurance companies (15 vs. 9 patients). From 2017 to 2018, dHT was mainly prescribed for the two indications mentioned above (10 of 15) (Supplementary Table S1). With the approval of these two indications, the number of requests to insurance companies decreased, reflecting that an existing clinical demand had been covered. The linear time trend observed over the first two years, with an increase of one patient per semester, could be interpreted as epidemiological growth or may be due to the fact that hyperthermia achieved more visibility within the Swiss (radiation) oncology society. However, the COVID-19 pandemic has clearly influenced case numbers and indications treated from the first semester of 2020 onwards (Figure 2). Due to this confounding bias, a reliable time trend analysis of patient numbers was not possible; however, it is important to note that an uncontrolled increase in case numbers did not happen despite reimbursement of new treatment indications. Taken together, the dHT indications negotiated jointly by the Swiss Federal Office of Public Health and the SHN appear not to have induced a commercially driven increase in patients treated.

With regard to the referral pattern, our analysis revealed that only 36.8% (35/95) of patients originated in-house and that 63.2% (60/95) patients were referred from external radiation oncology institutions (Figure 3). This shows that a dHT unit in Switzerland, even when integrated into a radiation oncology center, not only treats in-house patients. Patients have been referred for dHT from university hospitals and as well from the proton therapy center at the Paul Scherer Institute explicitly for the treatment of challenging oncological situations (Supplementary Table S2). This indicates that a dHT unit covers an existing demand for specific oncological situations, such as re-irradiation, organ-preserving treatment combinations (bladder and rectal cancer, soft tissue sarcoma) and other complex situations such as inoperable pancreatic cancer, soft tissue sarcoma or bulky, radioresistant tumors. In Switzerland, HT is frequently and incorrectly regarded as a mainly palliative treatment option. In the present analysis, we refute this by showing that 47.4% (45/95) of patients were treated with a curative treatment approach.

The characteristics of the in-house patients revealed that they generally had a lower performance status and were more likely to be treated with palliative intent. Accordingly, dHT was more often used for the indication "local recurrence and compression". Patients of low performance status are not fit to travel long distances for dHT, even if they would benefit from a radiosensitizer such as dHT, with its good toxicity profile. For palliative indications, the use of dHT could allow for a reduction in RT dose and thereby improve the tolerability and effect of RT, i.e., regarding pain relief, as has been shown by Chi et al. [39] for painful bone metastases. The referred patients in the present cohort travelled a relatively long mean distance of 62.2 km (SD ± 54.6 km), with a maximum of 238 km, to receive dHT (Supplementary Table S2). This effort is unreasonable for palliative and frail patients, which supports the future higher spatial availability of dHT units in Switzerland.

The three most commonly reimbursed dHT indications were "local tumor recurrence with compression" (20%), "rectal cancer" (14.7%) and "bladder cancer" (13.7%) (Table 2). Unfortunately, the approval for reimbursement for the most common curative and organpreserving indications, "rectal cancer" and "bladder cancer", was withdrawn by July 2021 [20]. Patients treated for the dHT indication "rectal cancer" were mostly referred from external radiotherapy centers (Supplementary Table S2) and predominantly for reirradiation (71.4%; 10/14 patients, data not shown). More than half (8/14 patients) were treated analogously to the HyRec trial [31] (Supplementary Table S5). The indication "bladder cancer" closes a gap in treatment options for either elderly and frail patients or patients seeking a bladder-sparing treatment approach. Patients were referred from external hospitals for these indications, underlining the demand for this treatment option as well. The SHN board is convinced that there is good evidence for dHT for these two indications [26–29,32], especially in rectal cancer, since two recent studies showed a promising effect of dHT [30,31].

Regarding the other dHT indications, the present analysis revealed that only a few patients are treated for the dHT indication "cervical cancer", although it is associated with the strongest clinical evidence [21–23]. This could be explained by the low incidence of cervical cancer in Switzerland and the fact that this indication only receives direct reimbursement in the case of re-RT and for patients with contraindication to concurrent chemotherapy, which is rarely the case in Switzerland. This is in contrast to, for example, the Netherlands, where dHT is reimbursed in the primary treatment setting in combination with RT and brachytherapy based on evidence from randomized trials [11]. Another observation is the low patient numbers treated for "painful bone metastases", although its superior effect regarding pain control was shown in a phase III randomized trial [39]. At Kantonsspital Aarau, the combination of dHT+RT for the indication of painful bone metastases was intended to be increasingly used in the future, because, with the longer survival of metastatic patients, long-lasting pain control is also becoming more important. However, because, during the COVID-19 pandemic, non-mandatory treatments were minimized and painful bone metastases could be often sufficiently treated with hypofractionated RT schedules alone, dHT was not offered. After returning to normality in the first semester of 2021, dHT patient numbers almost doubled (Figure 2), reaching the limited capacity of treatment slots for dHT. Therefore, patients with curative treatment indications were prioritized and dHT+RT again was not actively offered to patients qualifying for painful bone metastases. With the increasing dHT treatment capacity and controlled establishment of more dHT

units in Switzerland, more patients with painful bone metastases could benefit from the increased analgetic effect of dHT+RT.

The present patterns-of-care analysis was conducted as an inventory/survey of current practice and as the basis for a national objective to define standardized treatment schedules in Switzerland. All reimbursed indications, except for the indications "tumor recurrence and compression" and "painful bone metastasis", showed relatively standardized treatment schedules in analogy to clinical trials (Supplementary Table S5). In contrast, the indication group "local tumor recurrence with compression" represents a patient collective with enormous heterogeneity regarding primary cancer entities, re-RT status, RT modalities and treatment schedules. The only common denominator is that they were treated mostly with palliative intent (Supplementary Tables S2 and S5). Importantly, these patients often have no other treatment option apart from dHT+RT and local treatment effect has a high impact on their quality of life. Withholding dHT+RT as a last treatment option from these patients would, in our view, be unethical. Because these patients frequently required individually tailored treatment schedules based on their previous treatment, the standardization of the treatment schedules, especially for clinical trials, would also be difficult. It is therefore clear that an analysis of dHT efficacy in this patient group is a challenge. A good example for the standardization of dHT+RT treatment schedules in patients with tumor recurrences is the subgroup of the HyRec trial from Ott et al. [31,52] and the schedule with 5 × 4 Gy once weekly combined with weekly wIRA superficial HT in recurrent breast cancer from Notter et al. [56] for superficial HT. Such innovative study designs and further treatment schedules are required to evaluate and consolidate the effect of dHT in these heterogeneous patient groups.

#### **5. Conclusions**

To the best of our knowledge, we report the first retrospective analysis of an unselected national patient cohort treated with dHT, evaluating patient numbers over 4.5 years, specific treatment indications, patient characteristics, tumor entities, the referral practice and corresponding treatment schedules in Switzerland.

Nearly 50% of patients were treated with curative intent. Around two thirds of patients were referred from external institutions from all over Switzerland, including from university hospitals and the proton therapy center, for challenging oncologic situations such as re-RT, complex palliative situations, organ-preserving treatment combinations (bladder and rectal cancer, soft tissue sarcoma) and inoperable, bulky or radioresistant tumors. This observation refutes the common prejudice, at least in Switzerland, that HT is only used for palliative situations and clearly underlines the medical need for the combination of dHT+RT.

Patients treated within the reimbursed dHT indications with predominantly curative intent were homogenous subgroups with relatively standardized treatment schedules according to published clinical trials. On the other hand, the present patterns-of-care analysis revealed that patients treated within the two palliative reimbursed indications "tumor local recurrence and compression" and "painful bone metastasis" exhibit immense heterogeneity regarding patient characteristics and treatment schedules, demonstrating the need for standardization as a basis for future clinical studies.

This analysis will provide the basis for standardized national dHT treatment schedules and quality assurance guidelines to consolidate and expand dHT evidence. We think that this insight into dHT practice in Switzerland could be of interest for centers interested in the implementation of a dHT unit and for other HT societies, especially regarding reimbursement policy, and could also foster international study collaborations.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/cancers14051175/s1, Figure S1: Number of cases presented at the Swiss Hyperthermia Network tumor board by primary cancer entity. Table S1: Patients and tumor characteristics of patients treated with deep hyperthermia who required an individual request for insurance cover. Table S2: Patient characteristics regarding referral status, re-irradiation status and by treatment

indication. Table S3: Patient, tumor and treatment characteristics according to treatment protocol. Table S4: Patient characteristics by gender. Table S5: Deep hyperthermia and combined radiotherapy treatment schedules by specific reimbursed dHT indications.

**Author Contributions:** Conceptualization, E.S., E.P., S.B. and O.R.; methodology, E.S., A.K., S.B. and O.R.; software, A.K. and E.S.; validation, E.S., E.P., A.A., A.K., R.K., O.T., D.M., M.N., S.B. and O.R.; formal analysis, E.S., A.K. and O.R.; data curation, E.S., A.A., E.P. and R.K.; writing—original draft preparation, E.S.; writing—review and editing, E.S., E.P., A.A., A.K., R.K., O.T., D.M., M.N., S.R., S.B. and O.R.; visualization, E.S. and A.K.; supervision, S.B. and O.R.; funding acquisition, E.S. and O.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by a Scientific Association of Swiss Radiation Oncology (SASRO) research grant (to E.S.) and by the Swiss Hyperthermia Network (SHN). In addition, this research has received support from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (MSCA-ITN) grant "Hyperboost" project, no. 955625 (to O.R. and S.B.).

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee Nordwest—und Zentralschweiz of Switzerland (protocol code 2021-01022, 1 July 2021).

**Informed Consent Statement:** Informed consent was obtained from subjects involved in the study. Patients declining use of their data were excluded from analysis, as stated in Figure 1a.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical reasons.

**Acknowledgments:** We thank Sonja Schwenne, for the administrative support.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

