Regional hyperthermia combined with chemotherapy in paediatric, adolescent and young adult patients: current and future perspectives

The search strategy identified six reports on prospective clinical trials without control groups (Table 1). The data on RHT or hyperthermic chemotherapy in children and adolescents are currently limited, and only two active German hyperthermia centres treating paediatric patients were identified, the Heinrich Heine University Hospital Düsseldorf and the Charité-Universitätsmedizin Berlin. The study by Romanowski et al. was the first which combined RHT and systemic chemotherapy (ICE: etoposide 4 × 150 mg/m² and ifosfamide 4 × 2000 mg/m² or carboplatin 4 x 150 mg/m²) in 34 intensively pretreated children and adolescents with prognostically unfavourable tumour diseases [10]. Romanowski et al. reported that 20 % of patients experienced a complete remission and 7 patients remained alive up to 64 months after the combined treatment. A second pilot trial treated 9 patients with locoregional recurrences of abdominal germ cell tumors with PEI chemotherapy (PEI: cisplatin 40 mg/m² on days 1 and 4, etoposide 100 mg/m² on days 1 to 4 and ifosfamide 2000 mg/m² on days 1 to 4) in combination with RHT but with or without radiation treatment. Event-free survival (EFS) in these 9 patients (EFS 0.41 ± 0.33) who received RHT was significantly better than in a matched cohort (EFS 0.16 ± 0.25) who did not receive RHT, supporting the idea that RHT can have a relevant impact on local tumor control and patient EFS [11]. A further report on 10 patients from a phase I/II trial in children and adolescents with recurrent or refractory germ cell tumours treated at the University Hospital Düsseldorf with RHT combined with platinum-based PEI chemotherapy demonstrated feasibility and efficacy with objective tumour response rates up to 70 % [12]. Of these 10 patients, 2 responded partially and 5 had a complete response. Schneider et al. reported on a prospective trial without a control group for patients with relapsed malignant sacrococcygeal germ cell tumours who received cisplatin-based first-line polychemotherapy and tumour resection according to the MAKEI trial [7]. In this trial, 22 patients with first relapses, 14 with second relapses and 7 with later relapses were treated by surgery and adjuvant platinum chemotherapy. Pre-operative chemotherapy was administered together with RHT with the aim to improve operability in a subgroup of 8 poor responders or patients with locally advanced tumours. Although the small number of patients limits the informative value, the effect of RHT in this study was better when applied early resulting in 4 complete remissions after first or second relapses.

The group of Wessalowski at the University Hospital Düsseldorf published two further trials. The first trial included 39 patients, 24 with extracranial non-testicular germ cell tumours and 15 with soft tissue sarcomas or chondrosarcomas, of which 29 tumours were locoregional relapses and 10 were unresectable following pre-operative chemotherapy. Of these 39 patients treated with RHT according to the Hyper-PEI protocol, 20 achieved complete remission and 10 achieved partial remission. A consecutive surgical tumour resection was possible in 28 of these patients, while 13 patients required additional radiotherapy. After 5 years of follow-up, EFS was 0.39 ± 0.11 (20/39 patients) and OS was 0.52 ± 0.11 (25/39 patients). This interdisciplinary treatment of RHT with chemotherapy enabled a successful local therapy leading to a sustained remission in most patients with high risk for tumour recurrence [9]. Wessalowski et al. also used RHT in combination with chemotherapy for salvage treatment in 44 children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours [8]. Sufficient data could only be obtained for 35 of the 44 patients, of which 30 (86 %) had an objective response to the combination of RHT and PEI chemotherapy. PEI-regional deep hyperthermia utilised 40 mg/m(2) cisplatin delivered intravenously on days 1 and 4, 100 mg/m(2) etoposide delivered intravenously on days 1–4 and 1800 mg/m(2) ifosfamide delivered intravenously on days 1–4. One hour of RHT (41–43 °C) on days 1 and 4 was applied simultaneously with chemotherapy. Wessalowski et al. showed that 16 of these patients achieved complete remission and 14 achieved partial remission. The 5-year EFS and OS was 62 and 72 %, respectively, and toxicity was tolerable with only reports of WHO grade 3–4 neutropenia and thrombocytopenia occurring after all chemotherapy cycles. This was the first data showing that RHT combined with PEI could improve the long-term outcome of children and adolescents with refractory or recurrent malignant non-testicular germ-cell tumours.

Notably, more recent data from adult patients with high-risk soft tissue sarcomas treated within the EORTC 62961/ESHO randomised trial showed that peri-operative chemotherapy combined with RHT significantly improved either disease-free survival or OS [13, 14], supporting combined RHT and chemotherapy as a reference therapy for adults with high-risk soft tissue sarcomas. These results indicated that RHT not only improved the local chemotherapy effect, but that it may also have stimulated immunological processes which could permit longer-term tumour control [15, 16]. Whether this approach would also be successful in first-line treatment of paediatric patients with sarcomas has yet to be demonstrated.

There are no data from trials combining RHT and radiation therapy (thermoradiotherapy) in paediatric patients, however, the limited experience reported in case reports on paediatric patients support that application would probably have similar synergistic effects as in adults. Results from the combination of radiation therapy and hyperthermia for locally advanced cervical cancer in adult patients are worth mentioning in this context. The Dutch Deep Hyperthermia Trial not only showed an 83 % local control rate for combined radiation therapy and RHT versus 57 % for radiation therapy alone, but also a 3-year OS of 51 % for radiation therapy combined with RHT, compared to 27 % with radiation therapy alone [17]. The 12-year OS was still almost twice as high after combined radiation therapy and RHT (37 %), versus 20 % with radiation therapy alone [18].

There is currently no data available for whether the post-operative use of RHT together with radiation therapy in on paediatric patients is beneficial compared to radiation therapy alone. It remains unclear whether radiation therapy could be omitted under certain circumstances and the R1 area treated instead with a combination of RHT and chemotherapy. Future prospective trials are necessary to evaluate the outcome and toxicities of these approaches [18].

Less is known regarding whole-body hyperthermia in children, a procedure aiming to establish a steady state with maximal temperatures of 42 °C that is maintained for 1 h. Such a procedure can be achieved only with deep analgesia and sedation or general anaesthesia using radiant systems which have been reviewed before [19]. Therefore, the efforts needed (including intensive medical care) are much greater than for locoregional methods. Apart from a few individual cases [19‐21], there is practically no experience with whole-body hyperthermia in children. There is also no solid data available on the use of whole-body hyperthermia in adults [19].

There were a number of positive reports on RHT and its combination with radiation therapy in patients with desmoid tumours. To date, some limited data for individual cases in paediatric patients support that it could be an appropriate second-line option for complex refractory situations [22‐25].

In paediatrics, body weights range from under 5 kg to adult weight. This means that the technical requirements for the widely differing weights and, thus, widely differing body and organ dimensions are complex. In addition to the special body dimensions in children, their stress tolerance for RHT is considerably lower and decreases with the age of the child. Experience has shown that from the beginning of puberty children are able to tolerate an RHT session without deep sedation or general anaesthesia. Table 2 shows the dimensions of the commercially available applicators that can be used in children together with the respective patient and tumour dimensions treatable. These technical solutions can generate intratumoral temperatures of up to 43 °C, which correspond to the successful treatment protocols in children and adults.

The same body regions accessible in adults are accessible in children, with bones, lungs and the CNS being difficult to reach in all patients regardless of age. Children do have some special needs during RHT, however, and require more analgesics and need them applied earlier in combination with deep sedation or anaesthesia during RHT application [11, 12]. There are no concerns against RHT in combination with deep sedations or narcosis, although the temperature around certain organs at risk, including the skin, must be monitored carefully because of the missing perception of pain. Side effects of RHT are temperature-associated and generally rare events, as children are considerably more tolerant to temperature elevation than adults. Genuine burns are very rare. The greater risk is associated with the additional chemotherapy or radiation therapy and their associated toxicities. RHT offers a possible method to intensify local therapy without significant additional toxicity.