Data and the respective interpretation of HT-induced changes in perfusion and oxygenation remain controversial and are briefly described in the following. A comprehensive review of this topic has been published by Vaupel and Kelleher (6). There is evidence that mild HT can increase blood perfusion of the heated tissue, preferentially at the beginning of tumor heating (7, 8). It has been reported that this can lead to increased oxygen delivery via an improvement of microcirculation (9). This is especially true in cases when the oxygen demand of the tissue is reduced. It has been proposed that direct heat-dependent cell killing and loss of mitochondrial membrane potential contribute to this phenomenon (10, 11). On the contrary, other studies showed increased oxygen consumption at elevated tissue temperature (van’t Hoff’s law!) counteracting the oxygenating effect of increased perfusion (12). An increase in oxygen availability may favor oxygenation of hypoxic cells (7). The effect appears to be preferentially in diffusion-limited, chronic hypoxia (13, 14). Whether the radiosensitizing effect outlasts the time frame of increased perfusion remains so far unclear. Some studies have reported increased perfusion extending over 24 h after HT, which would benefit following RT/CT sessions (15, 16). Other studies could not reproduce this result (17). As hypoxia is a central causative factor for radioresistance, a decrease in hypoxia by HT may be responsible for the observed radiosensitization.

Hyperthermia has been shown to confer cell death by apoptosis or mitotic catastrophe (18, 19). It has been reported that HT triggers unfolding of especially heat-labile non-histone nuclear proteins leading to aggregation, due to exposition of hydrophobic groups, with surrounding proteins and subsequent association with the nuclear matrix. As consequence, basic nuclear matrix-dependent functions such as transcription, replication, or DNA repair are impaired (20, 21). Malfunction of DNA replication finally causes chromosome aberrations, genome instability, and cell death by mitotic catastrophe (22). Apoptosis may be mediated by cell death membrane receptor activation and subsequent caspase 3 activation (23). The extent of apoptosis appears to differ among different tumor types (24). In addition, the permeability of the cellular and mitochondrial membranes is altered leading to cellular Ca²⁺-spikes as well as mitochondrial depolarization with resulting bursts of reactive oxygen species. Both mechanisms may further enhance protein instability and apoptosis (25–27).

As mentioned above, there is sufficient evidence showing inhibition of DNA repair mechanisms upon HT. Krawczyk et al. have demonstrated inhibition of homologous recombination at clinically achievable mild HT temperatures (41–42.5°C) associated with BRCA2 degradation and its reduced accumulation at double-strand break sites (28). Further on, HT impairs the function of the Ku heterodimer by reducing its DNA-binding capacity and preventing the initiation of non-homologous end joining at DNA double-strand breaks sites (29). In addition, base excision after cell radiation has been shown to be reduced upon heat administration (30). In summary, HT acts on multiple levels including excision repair, non-homologous end joining, and homologous recombination influencing the repair of DNA lesions as well as single-strand and double-strand breaks (29–31). As a consequence, the effects of DNA damaging treatments such as CT or RT are enhanced. A more detailed review was recently published discussing existing evidence (32).

Besides direct effects on cell metabolism, HT appears to trigger multiple immune responses on local and systemic levels. Toraya-Brown and Fiering published a thorough review covering this aspect (33). In summary, HT increases expression of immunogenic surface receptors such as MICA and MHC-I enhancing effectiveness and function of natural killer (NK) cells and of CD8⁺ cells, respectively (34, 35). The expression of heat shock proteins (HSPs) such as HSP70 is increased. After binding intracellular proteins, HSPs get secreted stimulating the activity of NK cell- and antigen-presenting dendritic cells (36, 37). Presentation of these tumor antigens can cause specific antitumor immune responses effected by CD8⁺ cells (38). Tumor antigens are also provided by increased release of exosomes (39). Direct enhancement of immunogenic activity of leukocytes is mediated by increased lysis acitivy of NK cells, activation of macrophages, maturation of dendritic cells, and increased IFNy production as well as cytotoxicity of CD8⁺ cells (34, 40–42). In addition, immune cell trafficking is enhanced by increased perfusion and permeability (43). Following elevated intratumoral IL-6 signaling, it may further be facilitated by increased cell adhesion molecule expression such as ICAM-I (44).

Heating techniques can be divided by the size, penetration depth, and region of energy deposition. Local or regional HT is mostly used to enhance local therapy such as RT or CT. Alternatively, hyperthermic isolated limb perfusion to administer CT agents is performed. Whole-body hyperthermia (WBHT) has been applied either alone or in combination with CT for the treatment of metastatic disease. Different approaches including capacitive, radiative, infrared-A, or ultrasound have been used for clinical HT treatments (45). The clinically most relevant methods are described in the following.

Preclinical experiments were initially performed with relatively high temperatures ranging from 43 to 45°C focusing on direct cytotoxic effects. However, in the clinical setting, temperatures above 42.5°C were only achieved in small tumor subvolumes. While trying to reach targeted temperatures, therapy-limiting hotspots occurred causing substantial side effects. In these cases, this led to a reduction of target temperatures or early termination of HT (60, 61). This was regarded as failure of delivering adequate thermal doses, which lead to a rapid decline in HT-usage in the mid-to-late 1990s. It took several more years until the beneficial effects of mild HT (39.5–43°C), as described above, became known. Nowadays, mild HT has become the standard in modern clinical trials and daily clinical usage (5). Modern HT technology has been developed and optimized for minimal hot spot occurrence as a main focus (51, 52). As a consequence, therapy-limitation due to focal hot spots has not been an issue in many recent HT trials (62–64).

As important as heat generation, measurement of the actual tissue temperature distribution is crucial for effective heating of tumors. A homogenous temperature distribution is necessary for optimal treatment effects. Local dose-limiting hotspots have to be avoided. Originally, temperature assessment was restricted to single-point measurements. It can be performed either invasively by insertion of intratumoral catheters or, as applicable in tumors with close proximity to natural cavities such as rectal, cervical, vaginal, urethral or vesical tumors, equally efficient by endoluminal catheters. Insertion of catheters inherits the risk of complications such as pain, inflammation, or abscess formation (65). Thus, the latter option should be used if possible. In superficial tumors, surface skin measurements by contact electrodes constitute a further alternative. In addition, by using infrared thermography cameras, two-dimensional data can be obtained for superficial tumors even though calibration with contact electrodes is necessary for absolute temperature assessment (56). A promising method for deep temperature monitoring is MRI-guided thermometry capable of measuring three-dimensional temperature distributions non-invasively. Temperature can be measured by exploiting either T1w-imaging, diffusion weighted imaging or proton resonance frequency shift-imaging (66). Proton resonance frequency shift-imaging appears to be the most accurate method in the clinical setting. By combining HT with online MRI thermometry, direct changes of temperature delivery can be performed to optimize temperature distribution and suppress hot spots (67). To this end, an adaptive iterative algorithm has been developed (68). First studies have confirmed its applicability in the clinical setting (69).

In general, a dose–effect relationship of HT has been shown (70). The interval of administration of HT relative to RT has great influence on its effectiveness. The actual effect is quantified with the thermal enhancement ratio (TER) defined as the ratio of the respective radiation doses of RT alone divided by the RT + HT dose necessary to receive equal survival curves (4). However, biological aspects of HT react differently to the extent of heating sequence of HT. In the clinical setting, the maximal achievable TER should be combined with the most limited TER for healthy tissue to retain a tumor-specific effect reducing toxicity.

The inhibition of DNA repair has its highest effect when HT is given simultaneously to RT. The effect declines with the end of DNA repair mechanisms approximately 4 h after RT. However, inhibition of DNA repair mechanisms is not tumor specific since it is also present in normal tissues (71, 72). In contrast, direct cell killing is specific to malignant tissue at target temperatures. The respective TER is estimated at 1.5 deriving most likely from direct radiation-independent cell damage to radioresistant hypoxic cells (73). To summarize, optimal effects can be achieved by simultaneous RTHT treatment with no tumor-directed specificity. Treatment selectiveness would completely depend on accuracy of radiation delivery. In the time frame of 1–4 h before or after radiation, a maximal selective TER can be achieved by adding up DNA repair inhibition and direct cell damage. For optimization of the oxygenation-effect, RT should be applied shortly after HT (72). So far, the shortest interval between HT and RT has been described for wIRA followed by RT (56).

When considering time schedules and fractionation schemes, one should also take into account two phenomena termed cellular and vascular thermotolerance. The underlying mechanisms remain incompletely understood (74–77). For this reason, detailed description of these phenomena is not performed in the context of this review. Most probably, thermotolerance in currently used clinical HT schedules (i.e., once or twice/week) seems to play no limiting role.

Breast cancer constitutes the most widely investigated malignant entity. Vernon et al. published the results of five randomized trials conducted between 1981 and 1991 that were combined due to insufficient patient accrual. The pooled analysis of 306 patients with inoperable primary or recurrent disease yielded a significantly better complete response (CR) (RTHT: 59%, RT alone: 41%, odds ratio (OR): 2.3, p < 0.001) but no survival benefit. However, 50% of patients had metastases at the time of randomization. The effect was most prominent in preirradiated recurrent lesions. Skin toxicities such as blisters, ulceration, and necrosis were higher in the HT group, however with low impact on the patients well-being and generally treatable with conservative measures (60).

In cases of locoregional recurrence, breast surgery is recommended if possible. However, radical resection only appears to be feasible in 65% of patients and may cause significant treatment-related morbidity (78). Thus, RT constitutes a significant alternative, and depending on the time interval between first and second RT and other pretreatment characteristics offers substantial clinical benefit. Since nowadays most patients receive RT in the primary situation, HT may help to enhance the effects of reirradiation in the recurrence scenario, especially since in some clinical situations only reduced radiation doses may be prescribed. A recent meta-analysis by Datta et al. included 8 two-arm studies and 24 single-arm studies involving 2,110 patients with locoregional recurrent disease (79). CR was similar between one-arm studies (CR: 63.4%) and two-arm studies as well as significantly higher compared to RT alone (RTHT: 60.2%, RT: 38.1%, OR 2.6, p < 0.001). In preirradiated patients (779 patients), a CR of 66.4% was achieved (mean re-RT dose: 36.7 Gy). Treatment-related toxicity was overall not increased with mean acute grade 3/4 toxicities of 14.4%. Among the analyzed studies, there was great heterogeneity in RT dose, HT fraction schedules, total number of HT fractions, HT duration, or average achieved temperatures. However, no prognostic treatment variables could be identified in a subgroup analysis and meta-regression. Similar results were recently published by Linthorst et al. In a retrospective study encompassing 248 patients with unresectable recurrences, reirradiation + HT yielded a CR of 70% (80). In resectable cases, a regimen including surgery, RT, HT, and partly CT or hormone therapy, a local control (LC) rate of 78% after 5 years was achieved (81). Notter et al. have treated patients with locally recurrent breast cancer with RTHT using a hypofractionation scheme of 5 × 4 Gy with one fraction per week. A wIRA system was used for superficial HT. A CR rate of 61% was achieved without any treatment-related toxicities (56). In summary, there is sustained evidence demonstrating a value of adjunct HT in locoregional, recurrent breast cancer as definitive or adjuvant treatment.

Several randomized trials have been conducted to test HT in combination with RT. A Cochrane database meta-analysis was performed analyzing six trials involving a total of 487 patients (82). The studies included mostly patients with locally advanced disease (74% FIGO stage IIIB). Except in one study, RT was delivered as a combination of external beam therapy (EBRT) and brachytherapy (BT). The pooled data analysis showed a significantly higher CR [CR relative risk (RR): 0.56, p < 0.001] and OS [hazard ratio (HR): 0.67, p = 0.05] in favor of RTHT as well as a reduced local recurrence rate (HR: 0.48, p < 0.001). No difference was found regarding acute and late toxicity rates. The authors criticized a lack of uniformity among the trials concerning HT delivery, HT schedules, as well as RT treatment protocols, RT dose, and RT techniques. Therefore, the authors conclude that the results do not suffice for a definitive recommendation to apply HT along standard treatment regimen. The included Dutch deep HT trial was updated for long-term results after 12 years of follow-up showing sustained improved LC (RT: 37%, RTHT: 57%, p = 0.01) and survival (RT: 20%, RTHT: 37%, p = 0.03) (83). All studies have in common that concurrent CT was not included in the treatment regimen.

In recent years, many trials have discussed the value of the combined treatment regimes such as RTHT, RTCT, or trimodal RTHTCT. A recently published meta-analysis has revised all relevant publications including 23 articles with a total patient number of 1,160 (84). In a network meta-analysis (NMA), all four possible treatment modalities (RT, RTHT, RTCT, RTHTCT) were compared. All studies, but one, included patients with locally advanced disease. RT always comprised EBRT + BT. The comparison of RTHT and RT yielded similar results as the previously described Cochrane analysis. The same six trials with minor updates were included. For the direct comparison of RTHTCT and RTCT, only one study including 68 patients was available (85). It showed a significant better CR for the trimodal treatment arm (RTCT: 46.7%, RTHTCT: 83.3%, risk difference 36.7%, p = 0.0001). No significantly increased grade 3/4 toxicities were found. The NMA showed a significant advantage of RTHTCT over all other treatment combinations in direct and indirect comparisons as well as in the SUCRA value-based ranking for CR and patients alive. RTCT and RTHT had similar performance even though RTHT had a small advantage over RTCT regarding CR. In coherence, a recent randomized phase III trial, which was closed early due to poor accrual with only 87 of 376 planned patients, did not show any significant difference in event-free survival and pelvic recurrence-free survival between RTHT and RTCT (86). In summary, by adding radiosensitizing treatments such as CT or HT to RT, better treatment outcomes are achievable. In locally advanced cervical cancers, RTHT appears to be a valuable substitute for RTCT if CT is not applicable. By combining all three modalities, the best treatment effect may be possible. Additional phase III trials are necessary directly comparing RTHT, RTCT, and RTHTCT for optimal treatment stratification.

To evaluate the effect of HT in head and neck carcinomas, a meta-analysis was recently performed including six 2-armed studies encompassing 451 patients. Five of the six studies were randomized trials. The CR rate appeared to be significantly better in patients treated with combined RTHT compared to RT alone (RT alone: 39.6%, RTHT: 62.5%, OR 2.92, p < 0.0001). Acute and late grade 3/4 toxicities were not significantly different (87). One study included exclusively nasopharyngeal carcinomas, whereas all other studies considered all cancer sites of the head and neck. However, all studies involving surgery or concurrent CT were excluded.

Three other randomized trials with a total of 417 patients recently analyzed the effects of trimodal treatment combing RT, CT, and HT in patients with nasopharyngeal carcinomas (88–90). Two studies reporting CR showed a significant advantgae for RTHTCT treatment. The same patients had an increased OS in two of the studies. Progression-free survival (PFS) or disease-free survival (DFS) was significantly better in the RTHTCT group in all three studies. Patients with higher tumor temperatures and higher HT fraction numbers showed a better outcome (88). In all three studies, no difference in treatment-related toxicity has been described. Patients receiving HT showed even better quality of life scores after completion of therapy (90). These studies demonstrate that trimodal therapy including RT, CT with different agents, and HT constitute an effective and safe treatment alternative. To our knowledge, no other randomized studies have been published in other head and neck sites investigating trimodal therapy. As shown in other malignancies, re-treatment may constitute a further clinical situation in which HT may be a valuable treatment option. In a small cohort receiving reirradiations combined with HT, a CR of 46% was achieved showing feasibility of such an approach (91). To conclude, HT constitutes a valuable treatment option in cancers of the head and neck. However, due to relatively high perfusion rates and fast adaptation to local temperature changes, HT delivery appears to be especially challenging. By using a site-tailored radiative heating device, treatment outcomes may be better in the future (92). HT could be used in multimodal treatment schemes further improving treatment outcome. Alternatively, it may constitute a toxicity-sparing alternative for concurrent CT in elderly or multimorbid patients. Further clinical studies are necessary to evaluate the true clinical value.

In 2009, a Cochrane analysis of six phase II and III randomized-controlled trials including 520 patients with locally advanced rectal carcinomas was performed. Patients received neoadjuvant RT with or without HT. Increased CR (RR 2.81, p = 0.01) as well as increased OS at 2y follow-up (HR 2.06, p = 0.001) could be observed. The survival benefit, however, could not be measured for any later time point. No difference in acute toxicity was found in the two studies reporting on this side effect (93). A positive impact on pathologic complete response (pCR) could as well be shown in a retrospective study of 106 patients. Sphincter-sparing surgery was higher for tumors in close proximity to the anal verge (94). In a further retrospective study encompassing 235 patients, HT appeared to confer better downstaging of the primary tumor and involved lymph nodes (95). Two small studies evaluated hypofractionated RTHTCT schemes showing principal efficacy and safety (96, 97). Additional HT appears to be well tolerated without increased impairment of quality of life (98). To conclude, the Cochrane analysis demonstrated a fundamental possibility of increased response by applying adjunct HT. However, further randomized prospective trials are necessary to evaluate the true value of neoadjuvant RTHTCT as well as of treatment of recurrent disease.

For the treatment of bladder carcinomas, HT has been predominantly applied in combination with intravesical CT. However, a few trials have evaluated RTHT. In an early study, 56 patients with bladder carcinomas were treated with intravesical CT (bleomycin) simultaneously to RTHT with reduced total dose (40 Gy) or RT alone with higher dose prescription (50–70 Gy). HT was delivered by intravesical infusion of warmed saline solution containing bleomycin. The RTHT group had a higher response rates (RTHT: 84%, RT: 56%, p < 0.001) with decreased toxicity rates (less bladder capacity reduction) (99). In a different approach, 49 patients with nodal-negative disease of all T stages were treated with a hypofractionated RT scheme (24 Gy, 4 Gy/fraction) with or without HT. The HT group was split into a high (Tmean > 41.5°C) and a low temperature cohort (Tmean < 41.5°C). The high temperature cohort showed significantly better downstaging compared to both other groups indicating the importance of adequate temperature delivery (100). In a more recent German trial, high-risk T1 and T2 cancers were treated with transurethral resection followed by RTHTCT (50.4 Gy + 5.4–9 Gy; cisplatin and 5FU). At six weeks follow-up, a pCR of 96% was achieved. After a median follow-up of 34 months, OS was 89% with 80% of the patients being satisfied with their bladder function (63). The Dutch deep HT trial also included bladder carcinomas besides cervical and rectal carcinomas. In a randomized protocol, 101 patients with T2–T4 N0 M0 bladder carcinoma were treated with either RT or RTHT. RTHT yielded a significantly better CR (RTHT: 73%, RT: 51%, p = 0.01). However at 3y, LC and OS were not significantly different. There was no difference in toxicity (61). Taken together, some studies exist demonstrating a clinical benefit for adjunct HT with no additional toxicity. However, the patient cohorts in the different studies appeared to be quite heterogeneous by mixing locally restricted and advanced tumors. The treatment regimens used differed among studies impairing adequate comparisons. Randomized studies are necessary with clearly defined risk profiles and adequate direct comparisons with guideline-based treatment regiments.

One multicentric randomized trial analyzed the benefit of adjunct HT in melanomas treated with RT. Patients either received RT (24 Gy or 27 Gy in three fractions) alone or with HT (43°C for 60 min). There was no significant difference in toxicity. CR (RT alone: 35%, RTHT: 62%, p < 0.05) and LC after 2y were significantly increased (RT alone: 28%, RTHT: 46%, p = 0.008) (101). As these results are very promising, more randomized trials would help to establish a distinct role for RTHT in the treatment of melanomas, for example in combination with less hypofractionated treatment schemes.

Only few studies have investigated the role of HT for the treatment of NSCLC. A multi-institutional prospective randomized trial investigated the role of HT in addition to primary RT for locally advanced NSCLCs. No significant difference of OS, local response, or treatment-related toxicity could be observed. However, with a significantly higher 1y-PFS, a certain benefit was apparent (67.5%, 29%, p = 0.036) (102). In a small case–control study encompassing 13 patients with direct bone invasion treated with RTHT (60–70 Gy) showed a possibly high efficacy in LC and survival under this unfavorable condition (103). The benefit of HT in addition to reirradiation for recurrent NSCLC after primary RT was investigated in a small retrospective study involving 33 patients. Median doses used initially and for reirradiation were 70 and 50 Gy, respectively. Toxicity was moderate and limited to a maximum toxicity of grade 3 in 9% of patients. In patients with smaller tumors (<4 cm) and no distant metastases, long time survival was partly achieved (104). All three studies employed radiofrequency capacitive heating systems. So far, only limited evidence exists showing a true benefit of HT in NSCLC treatment. More studies are necessary to explore potential areas of application.

Feasibility of adjuvant HT treatment for prostate carcinomas has first been shown in two phase I/II studies involving locally advanced disease or recurrences after radical prostatectomy. Toxicity was limited to grades 2 and 3, respectively. Quality of life was not significantly changed by addition of HT to RT treatment (105). A HT-dependent burn occurred in one patient indicating critical temperature delivery (106, 107). Similar results were obtained in a larger phase II study involving 144 patients with high-risk disease (T2 + serum-PSA > 10 ng/ml or Gleason score ≥ 7) or locally advanced disease (T3/4) treated with RTHT and antihormonal therapy (108). A 5y-OS of 87% and 5y-biochemical PFS of 49% was observed with limited toxicity (maximum grade 2). Hurwitz et al. combined radiation with or without hormone deprivation therapy and transrectal ultrasound HT in locally advanced disease showing promising results with a 2y-DFS of 84% compared to historical 2y-DFS of 64% observed in patients in the 4-month androgen suppression cohort of the RTOG 92-02 trial (62). Currently, a phase II study examines the safety of combining HT and dose-escalated external salvage RT for recurrent prostate cancer (109). Another study is examining salvage BT combined with interstitial HT (110). In a retrospective analysis of 146 patients, no significant difference was found between patients receiving HT or not. The authors discussed that this might be due to insufficient heat delivery, since a significant difference was apparent for patients receiving a high thermal dose (111). To summarize, a set of phase II studies show promising results. However, randomized phase III trials are necessary to evaluate the actual value of adjuvant HT in the treatment of prostate carcinomas.

In 1998, Sneed et al. investigated the impact of adjuvant interstitial HT after a BT boost for patients with newly diagnosed, supratentorial GBM smaller than 5 cm treated with postoperative RT and concomitant hydroxyurea. After patient exclusions, 68 patients were randomized to BT with or without HT (112). HT was administered 30 min before and after a BT boost via placement of helical-coil microwave antennas. The HT group showed significantly increased survival (2y-survival 31% vs. 15%, p = 0.02) and time to progression (TTP) (median TTP 49 vs. 33 months, p = 0.045); however, this treatment was accompanied by increased grade 3 toxicity rates. In recent years, efforts were made to optimize HT delivery by improving interstitial catheters or applying focused ultrasound (113, 114). No data exist so far validating these new techniques or the combination with temozolomide.

Randomized trials have shown a significant benefit of HT in addition to CT (115). However, evidence of combined RTHT in sarcoma treatment remains scarce. An early phase II study involving 17 soft tissue sarcomas (STS) patients neoadjuvant RTHT with twice weekly HT showed significantly more extensive changes in histopathological examinations than the once weekly HT group (116). In another study, 16 patients received irradiation with concurrent HT for the treatment of radiation-associated sarcomas (predominantly angiosarcoma) showing a total response rate of 75%. Toxicity was mild except one grade 4 adverse event (117). First clinical results show general feasibility of applying RTHT to sarcoma treatment. However, randomized trials are necessary to assess whether a similar benefit exists as it has been shown for neoadjuvant HTCT.

Several phase II studies have investigated the feasibility of trimodal neoadjuvant RTHTCT treatment. Nakajima et al. treated 24 patients with neoadjuvant RTHTCT using docetaxel. A general response rate of 41.7% with a pCR rate of 17.6% was observed (118). Described toxicities were limited to grade 2 and grade 3. In a further study, 28 patients received RTHTCT with carboplatin and paclitaxel. R0 resection was possible in all patients with mild toxicity. Pathologic evaluation yielded a pCR rate of 19%. Treatment was tolerated well with mild toxicity rates (maximum grade 2) (119). A third study treated 35 patients with advanced disease with RTHTCT (bleomycin/cisplatin and 5FU) yielding a good CR rate of 33.3% (120). In addition, multiple retrospective analyses have shown a significantly increased survival benefit in favor of RTHTCT over RTCT (121–123). In summary, there is existing evidence promising a substantial clinical value of RTHTCT. However, randomized trials are necessary directly comparing RTHTCT to standardized treatment protocols involving RTCT.

Apart from the described entities, in multiple trials, RTHT has been applied to rather rare RT indications with only low levels of evidence (see Table 4 for a detailed summary of the cited trials).

A Dutch retrospective trial analyzed the efficacy of hypofractionated (28/32 Gy with a single dose of 4 Gy) reirradiation with concurrent HT for the palliation of painful unresectable recurrent rectal cancer with good to complete response in 72% of 47 patients (124). Similar results (70% pain relief) were reproduced in a prospective phase II trial by Milani et al. with normofractionated RTCTHT (125). Klaver et al. proposed a novel treatment strategy in a case series for locally advanced rectal cancer with concurrent peritoneal carcinomatosis by combing hyperthermic intraperitoneal chemotherapy with intraoperative RT showing general feasibility (126).

Thermoradiotherapy was evaluated for the palliation of symptomatic locally advanced or recurrent hormone-refractory prostate cancer in a small phase I/II study. All patients demonstrated partial response or complete response as well as complete symptom relief (127). However, two of eight preirradiated patients developed grade IV toxicities.

Primary or recurrent locally advanced pancreatic cancer was subject to an open-label study comparing RTCT with RTHTCT (gemcitabine ± 5FU/cisplatin/oxaliplatin) showing a significantly increased survival benefit without increased toxicity (mean OS: RTHTCT: 15 months, RTCT: 11 months, p = 0.025) (128). Moreover, the influence of adjunct HT for the treatment of liver lesions has been assessed. In a randomized Chinese trial of hepatocellular carcinoma patients, 1y-recurrence (RTHT: 10%, RT: 15%, p < 0.001) and mortality rates (RTHT: 12.5, RT: 20%, p < 0.001) were significantly lower for combined RTHT compared to RT alone (129). Chemorefractory colorectal cancer metastases were treated with whole-liver RT and concimittant HT showing partial response and pain relief in 30% of treated patients, respectively (130). Vaginal cancers have been chosen as target for HT in small prospective Dutch trial. Patients with vaginal carcinomas with a tumor size larger than 4 cm were treated with RTHT, whereas smaller tumors were primarily treated with RT showing no significant difference in 5y-survival (131).

In a more general approach, Jones et al. performed a randomized prospective trial pooling superficial tumors of various entities (breast carcinoma, melanoma, head and neck cancer, and others). Only tumors that appeared to be heatable on a pretest were randomized. Addition of HT to RT lead to significantly increased CR (RTHT: 66.1%, RT 42.3%, OR 1.7, p = 0.02). In coherence with many other studies, the highest difference was achieved in preirradiated patients (CR: RTHT: 68.2%, CR 23.5%) (64).

Despite the limited amount of evidence, substantial benefits of RTHT, especially for preirradiated, locally advanced and recurrent tumors, became apparent. Since there is a lack of randomized trials, definite recommendations for treatment cannot be made. In situations of recurrent or metastatic disease, RTHT may be justifiable as “individual treatment approach” on the basis of the existing evidence. In order to reach necessary patient number in potential future randomized trials, multiple entities with a similar condition (such as “recurrent,” “preirradiated,” or “locally advanced”) could be combined, following the approach of Jones et al. (64). In addition, HT centers should work more closely together for the establishment of multicenter trials capable of gathering critical patient numbers.

Thermochemotherapy has been evaluated in multiple clinical trials. In contrast to RTHT, CTHT is also being combined with WBHT. A limited number of phase II studies have shown feasibility of applying WBHT to CTHT treatment of various entities such as recurrent ovarian cancer, malignant pleural mesothelioma, metastatic STS, melanoma, and pretreated metastatic colorectal cancer (132–136). Up to date, no phase III trials exist. In contrast, regional HT has been evaluated in a large phase III trial (341 patients) of STS performed as joint effort by the European Organization for the Research and Treatment of Cancer and European Society for Hyperthermic Oncology. It showed a substantially and significantly improved local PFS, DFS, and OS after adding HT to EIA (etoposide, ifosfamide, doxorubicin) CT (HR for local progression/death: 0.58, p = 0.003, local 2y-PFS: HTCT: 76%, CT: 61%; 2y-DFS: CTHT: 58%, CT: 44%, p = 0.011; per-protocol OS: HR 0.66, p = 0.038) changing daily clinical practice in HT treatment centers (115). Further randomized trials have evaluated neoadjuvant CTHT in esophageal carcinoma (40 patients; histologic effectiveness: CTHT 58.3, CT: 14.3, p < 0.05) and adjuvant CTHT after transurethral resection of bladder carcinomas (83 patients; 10y-DFS: CTHT: 53%, CT: 15%, p < 0.001) demonstrating increased treatment efficacy (137, 138). A randomized trial with NSCLC showed a small benefit regarding “clinical benefit response” (80 patients, CTHT: 82.5%, CT: 47.5%, p < 0.05) (139). General feasibility of local CTHT has also been shown in other entities such as refractory or recurrent non-testicular germ cell carcinomas, recurrent or persistent ovarian cancer, breast carcinoma, or peritoneal carcinomatosis in several phase II studies (140–143). As alternative to regional HT, hyperthermic isolated limb perfusion has been established for the treatment of STS and unresectable melanomas showing favorable results (144, 145). In summary, the few existing randomized trials suggest substantial benefit by adding HT to CT. More randomized trials are necessary to broaden the spectrum of CTHT.