Background

Hyperthermia (HT) is used to increase the tumor’s temperature up to 39–43 °C to sensitize cells to the effects of radiation/chemotherapy. Biological effects of HT include changes in perfusion and oxygenation as well as inhibition of DNA repair mechanisms. Moreover, there is evidence for immune stimulation and the induction of systemic immune responses [1].

Evidence-based clinical benefit has been demonstrated in several tumor locations as breast, cervical, rectal and head and neck carcinomas [2, 3]. NCCN guidelines include hyperthermia in the treatment of cancer [4]. In Spain, government accreditation agencies supported hyperthermia in cancer treatment [5]. Capacitive hyperthermia is the most widespread method for loco-regional heating. The carrier frequency of the capacitive coupling is low (8–27 MHz) to be able to penetrate into the depth of a body [6, 7].

The expected SAR (specific absorption rate) to be achieved for HT should be an increase of 0.2 °C/min, that is, 1 °C in 5 min (without perfusion) [8]. Real-life temperature assessment in clinical HT precludes the use of invasive thermometers in most tumor locations [9]. Other non-invasive methods (spectroscopy, ultrasound, and MRI) for thermotherapy planning are not widely available [10]. The use of phantoms is an attracting alternative to estimate the proper power input need to achieve a temperature increase of 0.2 °C/min. There is a strong positive correlation between maximum radiofrequency output power given and maximum temperature reached on tumors [11].

The aim of this study is to analyze the feasibility and tolerability of a hyperthermia treatment programme as a first experience in Spain.

Materials and methods

Study design and participants

From June 1, 2015 to June 1, 2017, patients over 18 years old, suffering from locally advanced/metastatic cancer in different clinical situations under radiotherapy ± systemic treatment were included in this study. Exclusion criteria were pregnant patients and those with metal protheses and pacemakers. Patients were followed prospectively. The study was approved by the Ethic Committee of Hospital Dr. Negrín, Las Palmas and registered by EudraCT number 2018-001089-40. Written inform consent for treatment was obtained from all the patients. Follow-up was closed at December 1, 2018.

Standard of care (SOC) systemic and radiotherapy treatment was used as per protocol. Various radiotherapy dose-fractionation regimens were allowed. Biological equivalent dose (BED) was calculated for every radiotherapy treatment using the appropriate alfa/beta value.

Predefined stratification parameters in the study were:

  1. (a)

    tumor location (cerebral, head and neck, thoracic, abdominal or pelvic).

  2. (b)

    type of tumor (primary, metastases or relapse).

  3. (c)

    type of treatment (reirradiation, curative or palliative).

Hyperthermia procedure

Heat was applied using the 13.56-MHz, HY-DEEP 600WM system, Andromedic SRL, Velletri, Italy. Hyperthermia was applied twice a week (every 72 h) during all radiotherapy treatment schedules. Heating duration was prescribed to 60 min. Power applied varied according to tumor location. Briefly, 150 W were prescribed to cerebral and head and neck tumors, 250 W to the breast ones and 400 W in thorax, abdomen and pelvic tumors. In all the cases, both the upper and lower electrodes were placed on opposite sides of the selected region and treatment posture was the supine/prone position depending on localization. Patients were carefully instructed to mention any unpleasant sensation suggestive of a hot spot. The RF output was increased to reach the prescribed power output or up to the maximum level tolerated by the patient after appropriate adjustments of the treatment setting.

Quality of HT was determined by the relation of energy and time of exposure during treatment. Number of sessions and prescribed energy vary depending on tumor location and intention to treat. Prescribed treatment time of 60 min could not be reached in all sessions. Therefore, we defined W90time and W90treat to get homogeneous parameters to analyze quality of HT treatment. W90time is defined as the percentage of total treatment time at 90% of the prescribed energy. W90treat was defined as the percentage of treatment sessions that reached 90% of prescribed energy.

Clinical assessments were done during treatment to register tolerability and toxicity. Toxicity was scored according to the integrated CTCAE 4.03/QMHT criteria [12] (Table 1). The highest toxicity grade reached for each patient was scored. Clinical and HT parameters and their influence in tolerance were analyzed. Delay in radiotherapy/systemic therapy due to HT was also recorded. All statistical analyses were performed using SPSS, Version 20.0 software (SPSS Inc., Chicago, IL, USA).

Table 1 Tolerability and toxicity of hyperthermia treatment according to the integrated criteria (12) common toxicity criteria adverse effects (CTCAE 4.03) and quality management in hyperthermia (QMHT)
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Results

Patients’ characteristics

Between June 2015 and June 2017, 159 tumor lesions in 106 patients were treated with hyperthermia in our Department. Mean age was 59.40 years (28–86). Lesions characteristics and RT/systemic treatment are detailed in Table 2. Superficially located tumors were locally advanced breast cancer (16 lesions) and head and neck (10 lesions). Skin involvement was present in 8/16 and in 2/10 of them, respectively.

Table 2 Lesions and treatment characteristics
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Feasibility

A total of 754 HT sessions were given. Most lesions (138 cases, 86.8%) received all HT sessions planned. The treatment was withdrawn only in 21 lesions (20 patients) for different reasons. Eight lesions (eight patients) did not complete HT treatment due to progression of the disease or from different concomitant pathologies. Thirteen lesions (12 patients) withdrew treatment due to intolerance to heat (grade 4: QMHT toxicity; see below).

Among those cases that completed HT treatment, the median W90time was 63.35% (0–100%) and 83.89% of sessions (0–100%) reached the 90% of prescribed energy (W90treat). Highest rates of prescribed energy (W90treat) and treatment time (W90time) were mainly observed in brain and head and neck tumors (p < 0.0001). There were also a positive statistical correlation of metastatic cases and higher W90treat (p = 0.007) and W90time (p = 0.002). Palliative treatment showed also the highest W90time and W90treat rates (p = 0.006 and p < 0.0001, respectively).

Patient receiving systemic treatment had lower W90treat compared with those treated with radiotherapy alone (p < 0.0001). According to radiotherapy treatment, lower BED doses were also related to highest rates of HT treatment parameters (p = 0.002 and p = 0.001, W90time and W90treat, respectively) (Table 3).

Table 3 Associations between patients’ characteristics and HT quality treatment and grade ≥ 3 toxicity
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Toxicity

Hyperthermia treatment was well tolerated in most of the patients. Acute toxicity was generally mild, with grade 0–1 toxicity in 138/151 lesions (91.4%). Grade ≥ 3 was seen at 13 sites (8.6%) in 12 patients.

Grade ≥ 3 toxicity observed was: (a) cutaneous burns (four lesions) including breast (three lesions) and pelvis (one lesion) which disappeared with local conservative treatment and (b) nine lesions in eight patients who did not tolerate heat (thorax one, abdomen two, and pelvis six lesions, respectively) reported as grade 4 QMHT toxicity.

In all these 13 lesions with grade ≥ 3 toxicity, hyperthermia treatment was interrupted definitively. Radiotherapy treatments alone or when associated to systemic therapy were delivered as prescribed without delay in all these patients.

Toxicity was lower in brain and head and neck tumors (p < 0.0001), metastatic cases (p < 0.0001) and palliative treatment (p < 0.0001). No relation was found with superficial tumor location or skin infiltration.

Systemic treatment was associated to higher rates of grade ≥ 3 toxicity (p = 0.017), but no differences were found among different type of treatments (data not shown). According to radiotherapy treatment, lower BED doses were also related to lower toxicity (p = 0.003) (Table 3).

Discussion and conclusions

The clinical efficacy of loco-regional HT as adjuvant to RT/systemic therapy has been well established [2,3,4,5]. Despite these benefits, this technique has not yet included in clinical practice in most oncological departments. Difficulties in temperature assessment have been one of the causes [9].

In our Department, heat was applied at 13.56 MHz regional HT HY-DEEP 600WM system with a power up to 600 W. From June 2015 to June 2017, patients in a wide range of locally advanced/metastatic tumor lesions under radiotherapy ± systemic treatment have been selected for a combination therapy with hyperthermia.

After 2 years of the implementation of the technique in our department, our data show that regional hyperthermia is a feasible technique. As prescribed, power depends on tumoral localization and prescribed treatment time per session is 60 min, we defined parameters based in power and time, to get homogeneous data to analyze quality of HT treatment (W90time and W90treat). We observed a high rate of patient compliance for prescribed HT treatments. In fact, more than 85% of sessions reach the 90% of prescribed energy (W90treat). Moreover, 90% of the prescribed power was reached in 63% of the time of the HT sessions.

Is to be notice that in clinical hyperthermia, not all the treatment time is given to the power/temperature prescribed [6, 11]. Furthermore, direct temperature measurement is not possible in most tumor locations suitable for HT treatment [9,10,11].

Regional hyperthermia was shown to be a safe treatment [13, 14]. Most patients (81.13%) received treatment without relevant toxicity with a very high acceptance. Only 13 cases (8.6%) had grade ≥ 3 toxicity related to HT (9 of them because unpleasant feeling without clinical evidence of toxicity) and all clinically mensurable adverse events (4 cases of cutaneous burns) were easily manageable. Notably, there were no interruptions in any patients during the standard radiotherapy and/or systemic treatment, due to HT toxicity.

Thus, we believe regional hyperthermia is a feasible and safe technique to be used in combination with radiotherapy and systemic treatment.